Burn-out

I have been doing this for so long, I can barely remember the person I was before I started writing about CLL, back in 2002.  It has been a pretty wild ride!  My heart-felt thanks to all the friends I have made on this journey.  You made it possible for me to get out of bed each morning, especially in the aftermath of my husband’s death in the summer of 2008. I do not think I would have made it but for the generosity and affection of this patient community.  Thank you, from the bottom of my heart.

But I must confess I have been experiencing burn-out for the past few months and I realize it is time for me to step back for a while.  You need a patient advocate who is quick on her toes, brings a high level of energy & empathy to the “job” but takes no prisoners in the process of representing you.  I hope I have been all that, and I hope I will fit that job description again sometime in the future. Wish me luck.  I would like  to think this is  just a “so long” and not a “good-bye”.

Before you freak out, I want to make sure you understand we are not (repeat, not) shutting down the websites.  CLL Topics, Updates and Harvey’s Journal websites will continue to be hosted and available to all who are interested in visiting them (many thanks to our devoted webmaster, Radha.  Way to go, kid).  Between the three websites we have a tremendous amount of information.  I hope you will continue to use these resources to learn more about your disease, your therapy options etc.  Please develop the habit of using the search box at the top right hand corner of the home page.  It is a pretty good search engine and it will help you find specific articles that are of interest to you.

Many of you have honored me with your friendship and support.  You know who you are!  You are not just “members” or “patients” to me, I can no more walk away from you than I can walk away from my own family.  I will continue to respond to emails from you, and if you need my help, I will do my best to help in any way I can –  including my infamous “2 cents” worth of layperson reading of the tea-leaves.

Monthly meetings at my home will be on hold until I get back from my “sabbatical”.  We just finished our October 6 meeting.  Very intense, full house.  It has been a pleasure meeting so many of you face-to-face.  November and December meetings we had announced earlier are hereby cancelled as well.

I will still honor requests fortelephone consultations when we have complex issues that cannot be discussed in emails.

There is no question that I will be writing far less frequently.

Seeing how things are going to be different around here, I think it is only fair that we will stop accepting donations, starting January 1, 2013.  If you had been planning on hitting that donate button but have been putting it off – hint, hint – this is your chance to stop procrastinating.  As of the beginning of the New Year, the “Donate” button will be removed from the website.

The last four years have been a very hard slog for me.  You have CLL of the  body.  As for me, I have CLL in my soul.  It is just as incurable, just as deadly as the physical variety, there is just as much mind-numbing fatigue of the body and spirit that  ”normal” people do not understand, just as much grief when I lose friends.  There have been too many of them over the years, scars on my psyche that won’t heal because I keep picking at them.  When there is a cure for you, I too will be cured. In the meantime, I need a bit of time to sort things out in my own head and recharge my emotional reserves.  Spend more time playing with my new puppy dog. Perhaps re-visit Dharamsala when I go off to India in a couple of weeks.  If he had been still around, PC would have done his typical snarky thing, rolling his eyes at my need to contemplate my own navel for a while.

Remember, no one is indispensable – not  even little ol’ me! There will be other patient advocates stepping up to the plate.  The only one who gets to sit in the driver’s seat is you, so please stay engaged in your own healthcare.

Be well,

Chaya

When there are few good options left..

In my last article I wrote about the withdrawal of Campath as  a marketed drug for CLL.  This was such a blatantly cynical decision, based on nothing more than profit.  I am not a huge fan of Campath.  It has a high degree of immune suppression associated with it, especially in terms of drastically reduced T-cell counts for many months after completion of therapy – which in turn leaves patients vulnerable to opportunistic infections, secondary cancers etc.  So, why am I upset about Campath getting pulled from the market for CLL folks?  Because Campath is one of very few drugs that is thought to work to some degree for patients with the dreaded 17p (TP53) deletion.  Are there any others?  Yes, but it is a frighteningly small list.  Flavopiridol is one of them.  This drug has been in clinical trials for more years than I can remember – and it is still stuck there.  The only place you can get it is at Ohio State University, under the watchful eye of Dr. John Byrd.  Over the years, it has been shown this drug is not easy to administer – serious risk of tumor lysis syndrome –  and hence no one outside of OSU currently uses this drug.  Another option with possible benefit is Revlimid (lenalidomide).  However, initial hopes that the drug will work with 17p deleted folks have been somewhat dampened when a large scale study showed less than expected response in this subset of patients.

Hope on the horizon

Kinase inhibitors are all the rage these days.  In particular, ibrutinib (PCI-32875) has demonstrated some remarkable activity in CLL, with no major adverse effects demonstrated thus far.  I have written about this drug several times thus far, you can find the earlier articles by searching for the key words in the search box at the top right hand corner of our home page.

What is most exciting about ibrutinib is that it seems to have remarkable efficacy even in high risk patients, especially those with 17p deletions.  This is tremendously hopeful news.  However, phase-3 trials have just gotten underway and it will be some time before it even comes up for FDA review for approval.  Phase-2 clinical trials presently going on are pretty much sold out, and in any case each of these trials has a long list of inclusion criteria that limits who can get in.  Double arm phase-3 trials have the added complication of randomization into either of the two arms.

I have had to face this heartbreaking question several times in the past few months:  what do I tell patients with aggressive CLL with the 17p chromosomal deletion, who cannot get into one of the ibrutinib trials underway, and who cannot afford to wait for future trials and definitely cannot wait for the drug to become commercially available?  This drug may give them a much needed lifeline, perhaps set them up with a good enough remission that allows them to get into a transplant program.  Or it may give them a couple more years of high quality of life with their families.  Who can put a dollar value on that?

Compassionate use access programs

Initiating a compassionate use access program is not a simple process.  But it can be done, if the company in question actually wants to do it. It takes money, people resources and the desire to reach out to the patient community.  Ibrutinib is owned by Pharmacyclics.  Janssen pharmaceuticals, a subsidiary of Johnson & Johnson has purchased the rights to the drug in the USA.  Pharmacyclics is not a large company.  But J&J is  very large, more money than god as they say, and with massive financial resources,  people, and of course, lawyers to protect its crown jewels.

I figured that while it may be difficult for Pharmacyclics to initiate a compassionate use access program because of their size, it should be well within the reach of  an industry leader such as J&J.  Fortunately for me, one of the folks at J&J wrote to me, to see if they can work with our patient community – they were interested in working with me on some sort of a survey, along the lines of the very large patient feedback survey we did with Mayo Clinic.  I took the opportunity to raise with J&J the question of compassionate use access program so that some of our patients who desperately need ibrutinib but cannot get into the clinical trials have a path forward.  Here is the relevant  part of my letter to the company:

There is one important topic that I would really appreciate your bringing it up with your senior management. It has to do with compassionate use access to ibrutinib. I fully understand the need to conduct clinical trials with well defined inclusion criteria. Scientific experiments and the results from them are only as credible as the rigor with which the experiments are conducted – I am enough of a scientist myself to accept that wholeheartedly. We need well conducted clinical trials in order to get this valuable drug through the FDA approval process and last thing we need is hiccups along the way because of poorly defined clinical trial protocols and “squishy” methodology in data collection.

 But at the same time, there are always individual patient stories that need to be addressed, if at all possible; people who fall between the cracks as it were, who do not fit the exact profile demanded by the inclusion criteria of clinical trials. Well publicized compassionate use access programs are a hugely important way of reaching out the patient community, a way of establishing good faith on behalf of the pharmaceutical company. J&J is a large company, with the human and financial resources needed to manage such a program, a corporate culture that does not look only at profits or stock price. If anyone can take the lead in establishing a badly needed new paradigm for working with the patient community, it is going to be companies such as J&J. There is common ground and much to be gained here, but we need vision and leadership to make it happen. If there is anything I can do to help initiate / progress such a program, I would be honored to do so.

On a very personal note, my husband was granted compassionate use access to ofatumumab back in 2006, well before its commercial availability. He had developed severe allergic response to the murine components of Rituxan and I am convinced ofatumumab gave him a precious couple more years of high quality life. He was a very high visibility patient in the CLL community and I think it made a difference to how Genmab was viewed by patients. I was delighted to testify on behalf of the patient community before the FDA scientific panel as they deliberated approval of ofatumumab – perhaps my testimony made a difference.

How did J&J respond to my heartfelt plea?  I heard back from my initial contact at J&J.  No dice.  He could not even get anyone at J&J to talk to me on the phone.  The best he could do, he said, was give me the general phone number at J&J that I can call, where I can get the public domain boilerplate that some lawyer at the company has drafted on the subject of compassion.  That, is if I succeeded getting through the telephone tree in the first place, I suppose.  To say that I am disappointed is putting it mildly.  I am steamed!

Editorial

It seems the last time I wrote about ibrutinib and in my editorial comments I discussed the potential bleeding risk, someone at the Yahoo finance group message board on Pharmacyclics picked up my article and it created a minor brouhaha - heck, it may have even caused a very temporary downward blip on the stock price.  But I will be the first to admit I am no expert on that front.  I do not own a single share of Pharmacyclics or J&J, nor do I plan to in the future.  And I doubt anything I can say or write will ever have much of an impact on a company of the size of J&J.  I got a bit of an ego sugar high when a few financial analysts called me to ask if I would consult with them – for a fee of course.  The deal would be that I give them a heads up before publishing the next article.  How many different ways would I be compromising my promises to this patient community if I did that? No thank you.  I don’t need money that badly.

Does J&J have a history of reaching out directly to the patient community when it comes to their oncology drugs?  As it turns out, it is one of the more proactive companies on that front.  Does anyone remember the direct-to-consumer television  ads the company took out on their drug Procrit?  This is an epo drug, a red blood cells growth factor.  If I remember correctly, the advertisement would show an elderly gentleman, moping around because his red blood cell count was too low to let him go out and play with his grandson.  Or dance at his daughter’s wedding.  Whatever.  Then he gets Procirt, and lo and behold, there he is out playing ball and the soul of the party at the wedding.  I may not have remembered the exact story-line, but you get the gist.  Heck, they may even have had violin music as background,  these TV ads were clearly expensive, well produced and slick affairs.

The only problem was that epo growth factors had tell-tale adverse effects when used heavily in cancer patients.  I was one of the very first people to raise the alarm on this front (as far back as 2003!!).   My article was titled “The dark side of epo“.  It is now well established that Procrit and similar epoetin  red blood cell growth factors can act as growth factors for cancer as well, increasing risk of cancer progression and relapse.  We now have pretty strict guidelines on how these drugs can be used.

I don’t blame pharmaceutical companies for trying to make money, even lots of it.  Cancer patients with poor red blood cell counts would have been a huge market for expensive red blood cell growth factor drugs.  I just wish J&J is as proactive in reaching out to the patient community when it comes to establishing compassionate use access programs – or even bothering to talk to the patient community about it.  Outreach should be the norm, not the exception only when the company is trying to sell us something.

The perfunctory brush-off I got is nothing personal, I am well aware of that.  But it is one more sour note in the long story of pharmaceutical industry’s inability to establish good-faith and two way communications with the very patients that they will be marketing to down the road.  How about a little bit more respect, folks?  

As for me, my apologies.  I am truly sorry I was not able to do better for you guys.  If some of you have ideas on how to breakthrough this typical logjam, I am only too willing to listen.

How come we get no respect?

Some of you may be familiar with the comedian Rodney Dangerfield – his signature  line was “I don’t get no respect!”  Sometimes CLL patients are like this guy.  Sometimes we get no respect.

A few years ago, Campath (alemtuzumab) won across the board FDA approval for treating CLL – as a frontline drug, single agent therapy, in combination with other drugs, the whole enchilada.  They were the first to discover the fine art of doing straw-man comparisons with low dose chlorambucil, thereby “demonstrating” the impressive efficacy of their drug.  Any number of CLL experts were touting the use of Campath as a consolidation regimen, something to do after completion of regimens like FCR, R+HDMP etc, as a way of getting more people into the coveted MRD (minimum residual disease) negative status.  I got a lot of push-back because I was not sold on this concept. I thought the toxicity of Campath as a consolidation drug after prior chemoimmunotherapy was too high, a case of the reward not being worth the risk.  Campath kills T-cells, and keeps T-cell counts very low for months after completion of therapy.  This means higher risk of opportunistic infections, even secondary cancers.

Talk about irony.  Campath is no longer available as a commercial drug to treat CLL patients.  What caused this massive change of heart on the part of the drug company that owns this monoclonal?  Simple.  Money.  Lots of it.  You see, the very thing that made Campath so immune suppressive in CLL patients – its well documented ability to kill off T-cells and keep T-cell counts low for a long time thereafter – proved to be useful in treating multiple sclerosis.  MS is an autoimmune disease, caused by T-cells gone berserk and attacking the myelin sheath of nerves.  For these patients, reduced T-cell counts is a blessing, since it gets them much desired remission.

Why not market Campath both for CLL and MS?  Aha.  That is the billion dollar question.  You see, MS patients  need very small amounts of  Campath.  If it is marketed at the present price Campath commands to treat CLL, the company would be selling the drug to MS patients at a significantly cheaper price than other MS therapies.  Oy vey!  If the drug was available in the marketplace at the present price it gets for CLL, doctors and patients would be buying it at that price, even if they were actually going to use it for treating MS.  What to do?  Stop selling Campath to CLL patients!  Genius!  Now the company can jack up the price several times over, sell it only to the MS patient community.  I wonder how much they pay the guy who came up with this idea.  And how he sleeps at night.

Oh yes, in an attempt to avoid scathing public opinion, the company says they will give away Campath free of charge to CLL patients in this country.  However, doctors cannot prescribe it in the usual manner, hospital pharmacies cannot supply it, physicians have to call a special phone number and the physician has to go through a lot of hoops and hassles to justify why a given patient needs Campath..  The Campath website hosted by Genzyme for this purpose  is suddenly very stark in the list of potential dangers of this drug for CLL patients.  How long will the company continue the compassionate use program?  No one knows.  Is this only for USA patients?  How about CLL patients elsewhere?  I do not know.

Meanwhile, all the CLL experts who were ecstatic about using Campath in prior years are doing a fast back step.  Suddenly no one likes Campath anymore.  Sour grapes, anyone?

Pity of it is that while Campath was hardly the wonder drug its supporters claimed it was a few years ago, it was nevertheless an important drug for CLL patients.  It was one of few options for patients with the dreaded 17p deletion.  If you were not cynical about drug company agendas before, this story might be enough to push you over the edge.

Secondary cancers in CLL

We have discussed this issue in many previous articles.  A  detailed ASCO2012 abstract from the prestigious Moffitt Cancer Center brought this subject up again – coupled with deeply troubling news that a couple of friends have been identified with solid cancers secondary to their CLL diagnosis (one non-small cell lung cancer and one colorectal cancer) just this last week – made it necessary for me to bring up this subject once again.  There are a couple of lessons that all of us can learn from this latest information.  First, the abstract.  Then the discussion.

Incidence of second and secondary malignancies in patients with CLL: A single institution experience.

J Clin Oncol 30, 2012 (suppl; abstr 6568)

Author(s):  Samir Dalia, Julio C. Chavez, Gelenis Domingo, Estrella M. Carballido, Paibel I. Aguayo-Hiraldo, Kendra Lynn Sweet, Robert M. Crescentini, Lubosh Sokol, Celeste M. Bello, Jennifer L. Cultrera, Bijal D. Shah, Jeffrey E. Lancet, Rami S. Komrokji, Eduardo M. Sotomayor, Javier Pinilla-Ibarz; H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL

Background: Patients with chronic lymphocytic leukemia (CLL) have a higher incidence of second malignancies than the general population with one study showing the risk at 2.2 times the general popualtion. The increased incidence is thought to be due to immunosupression which results in decreased cell surveillance and proliferation of malignant cells. Our study aims to present the rate of second malignancies by cancer type in patients with CLL at our institution.

Methods: The Moffitt Cancer Center Total Cancer Care (TCC) database was used to identify patients who had a diagnosis of CLL between January 1993-December 2009. Individual charts were reviewed to confirm the diagnosis of CLL, collect demographic data, and to assess for the presence of a second malignancy under an IRB approved protocol. A second malignancy was defined as another malignancy or transformation of CLL reported in the medical record. Second malignancy data was placed in three categories; skin cancers, solid tumor malignancy, and hematologic malignancy. Results: 546 CLL patients were included in the study. Median age was 62.5 years. 84 (43%) were Stage 0 and 62 (32%) were Stage 1 RAI at diagnosis indicating earlier disease. 266 (49%) patients had a second or secondary malignancy. A total of 304 cancers were identified. 14% of patients had more than one malignancy. Melanoma was identified in 44 (16.5%) patients and non-melanoma skin cancer was identified in 54 (20%). Lung cancer was identified as the most frequent solid tumor malignancy with 36 (13.5%) cases, followed by prostate (35), breast (21), colorectal (15), and bladder (14). 10 patients had a Richter’s transformation of their CLL. 26 patients developed either myelodysplastic syndrome or acute myelogenous leukemia. Conclusions: Second malignancies are frequent in CLL patients. Immunosupression, increased UV light exposure, longer life expectancy in low risk CLL, and tertiary cancer center referral bias are likely reasons for these increased rates. Further research is needed to identify the precise mechanism which cause patients with CLL to have higher rates of second malignancies and to identify if there is an increased risk of a specific type of malignancy in patients with CLL.

Editorial

No responsible CLL expert questions the increased likelihood of secondary cancers in CLL patients.  Here is the short version of why that is the case.  One of the jobs of our immune system is to keep on the look out for cancer.  T-cells are particularly good at it.  They troll the blood circulation highways and the nooks and crannies of the tissues of the body, looking for trouble.  And even in perfectly healthy individuals, there are always microscopic clusters of cancer cells, in the lungs, gut, skin, breast, prostate etc.  Fortunately for us, most of the time  T-cells are able to identify these cancerous cells and kill them on the spot, before they have a chance to make a lot more cancerous babies and become a full fledged problem.  How about CLL patients?  By now you should know CLL is a cancer of the very immune system that is supposed to protect you from these random cancers.  True, CLL is cancer of the B-cells.  But B-cells and T-cells are buddies, each group influences the other a great deal.  CLL patients have less than effective T-cell surveillance on the look out for cancer clusters.  This is particularly true if the patient has been treated by T-cell killing drugs such as Campath, fludarabine etc.  You get the picture.

That said, this article from the reputable Moffitt Center was stunning in the statistics reported.  A whopping 49% of the 546 CLL patients Moffitt saw between 1993- 2009 developed secondary cancers.  14% were doubly blessed, with more than one secondary cancer on top of the CLL.  As you would expect skin cancer topped the list, with 36.5% developing melanoma or non-melanoma skin cancer.  Lung cancer came in second, with 13.5% of the patients.  You can read the rest of the statistics in the abstract, I tried to highlight the scary bits.

I confess I was blown away by these statistics, these risks were far higher than I expected.  What gives?  One small ray of hope for the general run of CLL patients is identified by the researchers themselves:  ”tertiary cancer center referral bias”.  That is a fancy way of saying higher risk folks than the run of the mill CLL patient are more likely to be referred to an expert center such as Moffitt.  A “smoldering” CLL patient with no other health issues or secondary cancers is likely to stick with his locally convenient oncologist.  I can see why places like Moffitt, M. D. Anderson, Mayo etc see more of the tough cases, and these guys are also likely to be more at risk of secondary cancers of all sorts.  Let us hope that is the reason for these  frighteningly high secondary cancer statistics.  But all the same, it is sobering news and I hope it provides a much needed kick in the butt for those of our members who (1) indulge in excessive UV exposure (2) smoke (3) skip regular prostate, breast and colorectal screenings.

Chew your way to fewer ear and upper respiratory infections

OK, here is a more upbeat and fun little factoid.

Vaccine. 2000 Dec 8;19 Suppl 1:S144-7.

Xylitol in preventing acute otitis media.

Uhari M, Tapiainen T, Kontiokari T.

Department of Paediatrics, University of Oulu, FIN-90220 Oulu, Finland. matti.uhari@oulu.fi

Xylitol is a polyol sugar alcohol and is referred to as birch sugar, because it can be produced from birch. Natural sources of xylitol include plums, strawberries, raspberries and rowan berries. Xylitol inhibits the growth of Streptococcus pneumoniae and it inhibits the attachment of both pneumococci and Haemophilus influenzae on the nasopharyngeal cells. In two clinical trials xylitol was found efficient to prevent the development of acute otitis media with a daily dose of 8.4-10 g of xylitol given in five divided doses. The efficacy in these 2-3 months follow-up trials was approximately 40% when chewing gum was used and approximately 30% with xylitol syrup. The need to use antimicrobials reduced markedly when using xylitol. In a high-risk group of children with tympanostomy tubes xylitol was ineffective in preventing otitis. Xylitol appears to be an attractive alternative to prevent acute otitis media. A more practical frequency of doses should be found before its use can be widely recommended.

PMID: 11163479

Xylitol is a sugar substitute.  You can find it in the forms of lozenges, chewing gum, syrup, nasal spray, mouthwash etc.  The abstract above reports on a clinical trial done in Finland, using a large group of high risk pediatric patients.  Lo and behold, it reduced the incidence of severe ear infections, to the tune of 40%, when children chewed gum containing xylitol.

Wikipedia has a very nice write-up on this interesting molecule, easily readable, so I won’t belabor the points made there.  Basically, xylitol has half the calories of plain table sugar, no after taste and no known toxicity.  Here are a few quotes, for those of you lazy enough not to click on the link:

• Xylitol is a “tooth-friendly”, nonfermentable sugar alcohol; dental health benefits in caries prevention; recent research confirms a plaque-reducing effect.
• Bacteria prefer fermentable six-carbon sugars (i.e., normal table sugar), or disaccharides such as sucrose, as opposed to the nonfermentable xylitol, whose antimicrobial properties then “starve” the bacteria, reducing their growth and reproduction.
• Xylitol also inhibits the growth of Streptococcus pneumoniae, as well as the attachment of Haemophilus influenzae on the nasopharyngeal cells. (since strep and flu cells find it harder to attach to the cells of of your nose and throat in the presence of xylitol, there is hope for reduced bronchitis, pneumonia etc.  As I have told you on many previous occasions, the single biggest cause of death in CLL patients is lung infections in general, pneumonia in particular).
• Studies have shown xylitol chewing gum can help prevent ear infections.
• Xylitol has been found to increase the activity of neutrophils, the white blood cells involved in fighting many bacteria. This effect seems to be quite broad, acting even in cases such as general sepsis. (but please be aware this is from an animal study. I have not been able to find a similar study in humans).

So, how reliable is all this good news?  Some of you may be aware of a group called the Cochrane Collaboration.  This group does an excellent job of looking at clinical trial results and sorting out credible stuff from poorly done studies or results biased by ugly agendas.  Well, we are fortunate that they have looked at the Finnish study and in their considered opinion, the results are valid.  You can read the full chapter and verse of their findings here.  While these studies were done with pediatric patients, I am reasonably convinced that the results are equally valid in the case of adults.  Xylitol is quite safe (except to dogs, so please be careful), so the risk is minimal.  Like chewing gum?  Choose to chew xylitol containing gum.  Use a mouthwash?  Find a brand that contains xylitol.  Frequent bronchial infections during the flu season?  There are all kinds of nasal sprays available that contain xylitol.

Valley Fever

Do you know what this is?  It is also called coccidioidomycosis.  Valley fever is a fungal infection most commonly seen in the desert regions of the southwestern United States. One can get it by breathing in fungal particles from soil. The infection starts in the lungs.  While normal people can fight off the fungus, immune compromized people – yup, that is us guys – are at significant risk.  Here is a PubMed write-up that gives all the necessary details.  The map below shows the regions of the country where it is endemic.

Why am I suddenly talking about valley fever – surely it has been around for a long time?  Well, the recent drought meant a lot more dry land and dust storms – prime conditions for spread of the fungal spores.  Here is quote from the Arizona Department of Health:

The reported number of cases of Valley Fever in Arizona has been increasing since it became laboratory-reportable in 1997. In 2005 there were 3515 cases reported; only 958 cases were reported in 1997. Between January and April 2006, ADHS received over 2,000 case reports of Valley Fever. This is more than three times the five-year average for these months.

Not convinced CLL patients are at risk?  Here is a link to an article that describes valley fever in a Swiss CLL patient.

What can you do, if  you live in one of the high risk areas?  Obviously, it is not always easy to move someplace else, on account of valley fever.  But you can be more careful not to go out when there is a lot dust blowing around, wear a proper mask (N95 or better) if you do have to go out, break the habit of touching your nose, eyes and mouth with your hands (that might have picked up the viral particles by touching surfaces contaminated with dust), keep a careful eye out for potential symptoms and ask around to find who is the local expert on valley fever so that you have someone to contact if you get infected.  There is a blood test to check people for exposure to valley fever fungus – something to discuss with your physician if you think you have been exposed.  Please remember the fungal spores can lie dormant in your body for many years, making their presence felt during a period of vulnerability – say after you have been through immune suppressive therapy to control CLL.  A valley fever advocacy organization does a terrific of debunking many of the myths surrounding valley fever.  Suggest you read it, if you live or visit high risk areas.

Gold standards come and go

Uneasy is the head that wears the crown, they say.  Same goes for “gold standard” CLL regimens, there is always a new kid on the block that would like to replace the present day top gun and take its place.  FCR (fludarabine, cyclophosphamide and Rituxan) has been the gold standard for several years now.  Bendamustine (brand name “Treanda”) has been getting a lot of press and marketing hype recently.  Combination of bendamustine plus Rituxan is a new chemoimmunotherapy combination that is getting attention as a possible rival to better understood combinations such as FCR and FR.

As a potential salvage therapy for people who have relapsed soon after FCR, bendamustine combinations are a very welcome development.  But how about B+R as a frontline therapy?  I can think of at least a couple of CLL experts here in the USA who are pushing this angle, many more are doing so in Germany (bendamustine was discovered in East Germany, around the time of the second world war.  Nothing like home town pride, it seems).  Is B+R a  better choice than FCR, for frontline therapy?  Unfortunately, we do not (yet) have a head-to-head double arm trial results  to make truly credible comparison.  However, this latest article in Journal of Clinical Oncology detailing B+R as frontline therapy gives us a pretty good idea of what to expect.  Abstract is given below, do send me a private email if you would like help locating the full text article.

J Clin Oncol. 2012 Aug 6. [Epub ahead of print]

Bendamustine in Combination With Rituximab for Previously Untreated Patients With Chronic Lymphocytic Leukemia: A Multicenter Phase II Trial of the German Chronic Lymphocytic Leukemia Study Group.

Fischer K, Cramer P, Busch R, Böttcher S, Bahlo J, Schubert J, Pflüger KH, Schott S, Goede V, Isfort S, von Tresckow J, Fink AM, Bühler A, Winkler D, Kreuzer KA, Staib P, Ritgen M, Kneba M, Döhner H, Eichhorst BF, Hallek M, Stilgenbauer S, Wendtner CM.

PURPOSE: We investigated the safety and efficacy of bendamustine and rituximab (BR) in previously untreated patients with chronic lymphocytic leukemia (CLL). PATIENTS AND METHODSIn all, 117 patients, age 34 to 78 years, 46.2% of patients at Binet stage C, and 25.6% of patients age 70 years or older received BR chemoimmunotherapy for first-line treatment of CLL. Bendamustine was administered at a dose of 90 mg/m(2) on days 1 and 2 combined with 375 mg/m(2) rituximab on day 0 of the first course and 500 mg/m(2) on day 1 during subsequent courses for up to six courses.

RESULTS: Overall response rate was 88.0% (95% CI, 80.7% to 100.0%) with a complete response rate of 23.1% and a partial response rate of 64.9%. Ninety percent of patients with del(121q), 94.7% with trisomy 12, 37.5% with del(17p), and 89.4% with unmutated IGHV status responded to treatment. After a median observation time of 27.0 months, median event-free survival was 33.9 months, and 90.5% of patients were alive. Grade 3 or 4 severe infections occurred in 7.7% of patients. Grade 3 or 4 adverse events for neutropenia, thrombocytopenia, and anemia were documented in 19.7%, 22.2%, and 19.7% of patients, respectively.

CONCLUSION: Chemoimmunotherapy with BR is effective and safe in patients with previously untreated CLL.

PMID:22869884

Devil is in the details..

The conclusion stated in the abstract is pretty blunt:  ”Chemoimmunotherapy with BR is effective and safe in patients with previously untreated CLL.”  

I suppose one can say that.   That is surely one way of looking at these results.  But just as sure as death and taxes, there is also a different perspective – one that you should be aware of before you make that all important frontline therapy decision.  So, let us dig just a bit deeper and see what is really going on here.

As the abstract points out,  starting in March 2007, 117 previously untreated patients were recruited for this trial.  In keeping with modern criteria for start of therapy, slightly less than half of these guys were Binet stage C (same as Rai stage 3-4).  Median age was 65 years, but about a quarter of the patients were older than 70 years.  This is an important point, since bendamustine is being touted as the kinder and gentler chemotherapy agent, likely to be better tolerated by older patients for whom FCR may be contra-indicated.  That is the claim.  Further down in this analysis we will see how well that claim holds up.

How about prognostics?  Only 7% of patients had the dreaded 17p deletion, and the other high risk FISH defect of 11q deletion was seen in 19% of patients.  16% were positive for ZAP70 expression.  Far higher percentage (88%) had the poor risk CD38 expression.  62% were unmutated IgVH (higher risk group).  Median B2M was 3.4.   All in all, I would classify these guys as sort of middle of the pack in terms of prognostics.  They were by no means toughest patients to treat.   For starters, each and every one of them is a chemo naive patient, no relapsed or refractory folks in this group.  They are kind of patients that could reasonably expect to get a pretty good remission from FCR, if that had been the the therapy they opted for.

The protocol called for  the present day standard of 6 courses, administered over 6 months.   Drug dosages are pretty standard for bendamustine and Rituxan.  Notice, unlike FCR that uses a purine analog (fludarabine) and alkylating agent (cyclophosphamide) along with Rituxan, in this combination bendamustine is the only chemo agent.  That is because it is often suggested bendamustine acts in ways that are similar to both alkylating agents and purine analogs.  That remains to be proven rigorously.  From where I am sitting, bendamustine looks and acts a lot more like alkylating agents (chlorambucil, cyclophosphamide etc) – with a very similar toxicity profile. More on that later.

The abstract is a little skimpy on the safety and adverse effects, you have to read the full text article to gt the juicy details.  Over a followup period of 27 months, the following were noted:

• 11 patients died during this time period.
• There were 3 patients who suffered Richter’s transformation.
• Three patients died within the first five months, due to treatment related infections.
• All in, roughly two thirds of the patients (64%) experienced grade 3 – 4 level adverse effects.  In case you are not familiar with the grading of adverse effects, grade 1 is nothing to write home about, grade 2 is a bit tougher but considered tolerable (given these guys have cancer!), but grade 3-4 is serious business.  There is another level, grade -5.  That is just a euphemism for the patient died.  So, I suppose you can say 11 patients had grade -5 adverse effect during the 27 months.

What did our guys get for their troubles?  We are all grown-ups here, we understand a certain amount of adverse effects are baked into the chemo cake and we are willing to tolerate them, provided – and this is an important condition – there is good news to be had at the end of it all.  And the good news we are looking for boils down to just three things:  length and quality of remission and overall survival.  Here is how that panned out.

• The overall response rate was 88%, but only a measly 23% got a “CR” response.  Bulk of the remissions were partial (64.9%) and stable disease in 9.4%.  Bummer!  Since you and I know very well that chances of a partial response or merely stable disease holding the line very long are not all that good, the low rate of CR responses is indeed a disappointment.  Sure enough, as you can see in the graph below, the rate of relapse was pretty steep right from the get go.  Half the patients needed to start new therapy, had progressive disease or died by about 34 months.  (Follow the red lines I drew in, to see how long it took for exactly half the patients to have relapsed). If anything, the relapse rate was even steeper after that point.

• How about quality of life during and after this therapy regimen?  I wish researchers would make that part of their data collection, ask folks how they rate their quality of life.  But that does not happen too often.  So, you and I have to do our best to guess at how life might have been for these guys.  Hematological toxicities such as anemia and neutropenia take their toll.  The former can cause deep fatigue, the later can precipitate infections and mandate party pooping “social distancing”.  Thrombocytopenia (reduced platelet counts)  increases risk of bleeding and bruising.  In this context, 64% of the patients had one or more high grade (3-4) hematological toxicity.  Don’t know about you, but  this does not sound like a “kinder and gentler” therapy regimen to me.
• As discussed in the adverse effect section above, 11 patients died during the observation period of 27 months.  I found it frankly difficult to sort out how many of these deaths were attributable to the therapy under discussion, and how many were due to unrelated causes.  Write to me if you wish to read the full text article and try to figure this out for yourself.

An expert comparison

Usually, when discussing these single arm trials I have to scramble around to find a good comparison without too much researcher bias built into it. In this case, my life is made a lot easier since the JCO article above is accompanied by an editorial that does a detailed comparison.  The author of the editorial is no less than Dr. Bill Wierda of M. D. Anderson, one of the lead researchers of the FCR regimen.  He has a wonderful table summarizing the results of this study and comparing it to a bunch of other studies using FCR, PCR, FR and a lot of single agents as well.  I have picked through his table and made the comparison much simpler for you.  Here it is.

Let us put this information into proper context.  The Fischer study is the present study of frontline B+R that we are discussing.  The FCR study from M. D. Anderson is the pivotal study that got chemoimmunotherapy into the limelight several years ago.  Dr. Wierda was closely associated with that whole effort and we can cut him some slack for perhaps feeling a bit more love towards that particular study.  But the third column is the clincher of the argument.  It is the “CLL 8″ report of the justly famous German CLL Study Group, a very large scale study conducted at many different institutions.  Heck, the present B+R study was also conducted by the same prestigious group! No one can complain about researcher bias when we compare results from the same group of researchers.   It is about as credible as it gets and I think the results are pretty solid.

Looking over the chart, I am truly taken aback by the differences, especially in the percentage of complete responses and the length of remission (also called PFS, progression free survival).  B+R suffers in the comparison.   Choosing FCR instead of B+R seems to  double the chances of getting a CR (23% versus 44%) and increasing the remission length by a year and a half, even if I take the GCLLSG results as the representative ones. 

Sure, this is not an apples to apples comparison since we are not talking of a double arm trial where every other variable is held constant.  But as Dr. Wierda points out, “Although the patient populations included in the trial may be different, it is difficult to conclude that the BR efficacy outcomes are consistent with FCR in the (GCLLSG) CLL-8 trial.”

It must be pointed out that incidence of grade 3-4 neutropenia was lower with B+R, compared to FCR in the GCLLSG study.  But making up for this, incidence of anemia and thrombocytopenia (reduced platelets) was higher in the B+R study.  Not a whole heck of a lot to point to, if you are trying to sell B+R as being kinder and gentler, compared to FCR.

One of the adverse effects that I worry about with “super” alkylating agents such as bendamustine is the long term risk of myelodysplastic syndrome and secondary acute leukemias down the road.  Researchers tend to be rather coy in discussing this risk, I find.  Longer term monitoring has shown even FCR has a certain percentage of patients who go on to develop myeloid cancers.  Richter’s transformations and  myeloid cancers are the proverbial second shoes yet to drop when considering bendamustine combinations – in the opinion of this layperson patient advocate.

Do send me a personal email if you want to read the rest of Dr. Wierda’s well reasoned and pithy editorial.  I enjoyed reading it.  It clarified the picture a great deal.

Editorial

Not much to add to what Dr. Wierda had to say, just tying a few loose ends to finish the job.  As you can see from the author list, this is a pretty heavy hitting team of German CLL experts.  Also as you would expect, majority of them had financial support from the pharmaceutical companies involved (Mundipharma, Roche), in terms of paid consultant or advisory role, or honoraria – not unexpected, that is how most clinical trials get funded these days.

So, does this important paper succeed in replacing FCR with BR as the new gold standard for chemo naive patients?  We  have to wait a bit more to see one-on-one comparison in terms of two arm trials, but what we have seen thus far suggests we may want to hang on to FCR for a while longer.  Is BR the kinder and gentler version of FCR style chemoimmunotherapy we were hoping for?  I am not sure that has been shown to be the case either, not in view of the high percentage of grade 3-4 adverse effects.  Is it good to have  this drug combination thoroughly tested in clinical trials?  You bet.  It is always good to have choices, and bendamustine combinations are important choices to have.  At this stage of the game, if there is no reason to rule out FCR, would I choose BR as frontline therapy?  I do not think so, the case has not been made to my satisfaction.  I would stick with the “better known devil” of FCR, until and unless more positive results of BR are demonstrated in future studies.

For a change, there was a clear acknowledgement “We thank all patients and physicians for their participation in the study“.  Wow.  I appreciate that.  We must be doing better getting our message out.

ASCO 2012

ASCO (American Society of Clinical Oncology) is a big “F” deal.  Every year, oncologists from around the world gather together to hear about the latest news in the cancer industry.  It is an industry event, with lots of money, reputations and glory riding on the results disclosed at these annual meetings. Unlike ASH (American Society of Hematology – the industry group for blood cancers and diseases), ASCO caters to all cancers.  As you can guess, much of the news pertains to the big solid cancers – breast cancer, prostate cancer, lung cancer etc.

But this year we have more than a smattering of important presentations dealing with the new crop of targeted kinase inhibitor trials.  While the information is very interesting and I for one am keeping my fingers crossed for the success of these trials, these are all early stage trials – which makes the results not quite something you can hang your hat on.  We will have to wait another year or two before we get to see Phase -3 trial results with larger groups of patients.

There were three papers on PCI-32765 (formal name ibrutinib, you might as well start getting familiar with it). After discussing the three abstracts, I decided to write a longish editorial section on stuff I am hearing as anecdotal stories from members.  Since some of my concerns arising out of member feedback are not based on official clinical trial results, these are best discussed in an editorial section.  As you may have noticed, companies are quick to highlight positive results, not so eager to publicize potential adverse effects.  

Single agent PCI-32765 in chemo naive patients

The importance and quality of these papers is to be judged by the high profile researchers who are on the authors list.  In this trial, patients who were older than 65 years and who had active CLL that had never been treated before but now needing therapy for the first time were recruited.  This is an early stage study trying to determine the right dosage.  26 patients got 420mg per day, while 5 patients got double that, 840mg per day.  It seems the higher dose did not show any better response and while they were not clear about it, there may have been some concerns about safety at the higher dose.  Whatever, the higher dose was soon discontinued and now the standard dose for PCI-32765 is 420mg per day.

I would describe this patient group as somewhat long in the tooth – you know, the young-at-heart-crowd.  Three fourths of the patients were more than 70 years old.  Reflecting the need for start of therapy, there were significant percentage with poor platelet counts (less than 100K) and hemoglobin levels not quite in the pink (less than 11.0).  A tad under 50% had unmutated IgVH (bad prognostic indication).

Adverse effects reported are moderate.  only 10% had Grade 3 or higher infections or cytopenias (drop in platelet counts, red blood cell parameters, reduced neutrophil counts etc).  More worrisome, non-blood related adverse effects – Grade 3 or higher – that could have been due to PCI-32765 were seen in 19% of patients.  That is roughly one in five, with high grade adverse effects of one kind or another, not even counting the blood related adverse effects.  I wish they had spelled out the exact nature of these high grade non-blood related adverse effects.

However, there is no question that PCI-32765 is a relatively easy drug to tolerate, especially when it is compared against chemoimmunotherapy combinations such as FCR or bendamustine combinations.  Since a large percentage of CLL patients fall into over 70 crowd, and high impact therapy options such as FCR and B+R may be contraindicated for a variety of reasons, the kinder and gentler nature of PCI-32765 is a huge plus.  For that reason, the age group of this particular study cohort is important to note. The researchers were wise in their inclusion criteria choices.

How well did the drug work?  After all, kinder and gentler does not impress us unless it actually managed to bring about a good response.  These are early days.  We have results based on a mere 11 months of patients on the drug.  There were 65% partial responses, 8% complete responses with no indication of CLL in the bone marrow either.  Another 12% had reduction in the size of their lymph nodes, even if they still showed elevated counts in their blood. Doing the math, that leaves 15% out in the cold.  Did these unlucky guys have stable disease or did they have progressive disease while on PCI-32765?  We do not know.  See what I mean about these abstracts not quite volunteering information about the more squishy side of the results?

The Bruton’s tyrosine kinase (BTK) inhibitor PCI-32765 (P) in treatment-naive (TN) chronic lymphocytic leukemia (CLL) patients (pts): Interim results of a phase Ib/II study.

ASCO 2012. Abstract No: 6507

Author(s): John C. Byrd, Richard R. Furman, Steven E. Coutre, Jan Andreas Burger, Kristie A. Blum, Jeff Porter Sharman, Ian W. Flinn, Barbara W. Grant, Nyla A. Heerema, Amy J Johnson, Tasheda Navarro, Danelle Frances James, Eric Hedrick, Susan Mary O’Brien; The Ohio State University Comprehensive Cancer Center and Arthur G. James Cancer Hospital and Solove Research Institute, Columbus, OH; Weill Cornell Medical College, New York, NY; Stanford University School of Medicine, Stanford, CA; University of Texas M. D. Anderson Cancer Center, Houston, TX; The Ohio State University, Columbus, OH; Willamette Valley Cancer Institute and Research Center, Eugene, OR; Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN; University of Vermont College of Medicine/Fletcher Allen Health Care, Burlington, VT; Pharmacyclics, Sunnyvale, CA; Pharmacyclics, Summit, NJ

Background: Fludarabine based therapy, while effective, carries significant risk of morbidity and mortality in the elderly pts. As such, older CLL pts represent a high priority for new therapeutic approaches. PCI-32765 (P) an oral, selective, irreversible inhibitor of BTK inhibits CLL cell proliferation, migration and adhesion. A multi-cohort Phase Ib/II trial evaluated 2 doses of single-agent P in both TN and relapsed/ refractory (R/R) CLL/SLL pts. Mature follow-up of the TN pts is reported. Methods: Pts >65 yrs old with active CLL requiring Tx by IWCLL guidelines were treated with oral P at doses of 420 mg or 840 mg administered daily for 28-day cycles until disease progression (PD). Response was evaluated according to 2008 IWCLL criteria. Results: 31 pts were enrolled- 26 pts (420mg) and 5 pts (840 mg). The 840 mg cohort was terminated after comparable activity and safety between doses was shown in R/R pts. Median age 71 yrs (range 65-84) with 74% of pts >70 yrs. 19/31 (61%) had baseline cytopenias (Hgb < 11g/dl or plts <100,000). Unmutated IgVH was present in 43% of pts. The majority of AEs have been Gr<=2 in severity, most commonly diarrhea, nausea, and fatigue. Gr >3 non-heme AEs potentially related to P in 19% of pts. 10% of pts experienced Gr >3 infections or cytopenias. With a median follow-up of 10.7 mos on 420 mg cohort 73% (19/26) achieved a response by IWCLL criteria with 65% partial responses (PR) and 8% complete remissions with no morphologic evidence of CLL on marrow. An additional 12% (3/26) of pts achieved nodal responses (NR) with lymphocytosis. Median follow-up in the 840 mg cohort is 4.6 mo, at 2 cycle assessment 2/5 achieved a PR and 1 pt with a NR. ORR was independent of high risk factors. 84% of pts remain on study, reasons for discontinuation = AE (3), investigator decision (1) and PD (1). There have been no deaths. Estimated 12 mo median PFS for the 420 mg cohort is 93%. Conclusions: PCI-32765 is highly active and well tolerated in elderly TN CLL pts. The high ORR, including marrow clearance and very low PD rate with the single agent suggests that P warrants further study as a first-line treatment approach in elderly pts.

Combination of PCI-32765 with ofatumumab

This too is an early stage study, looking to see if combination of PCI-32765 with a second generation monoclonal antibody such as ofatumumab works better; interesting and logical extension of single agent PCI-32765 studies of the type reviewed in the abstract above.

We know now that this kinase inhibitor (similar to the other kinase inhibitor in the news, CAL-101) works by disrupting the signaling pathways of B-cells, thereby kicking them out of their protected niches in swollen lymph nodes, spleen etc.  In fact, patients often see higher white blood counts in their blood work soon after start of ibrutinib therapy.  So, it makes sense to pair this kinase inhibitor with another drug that does a good job of killing CLL cells once they are out in open blood circulation.  Flush the little buggers out of their protective homes, then kill them while they are vulnerable and exposed – that is the game plan.

Many of you are familiar with ofatumumab (also known as Arzerra, or the earlier name Humax-CD20).  Think of it as the next generation version of Rituxan. It too target CD20 marker present on all mature B-cells (not just CLL cells).  Fortunately for people who develop allergic responses to the mouse component of Rituxan, ofatumumab is fully humanized monoclonal, mo whiff of mouse protein.

Unlike the previous abstract, this study recruited previously treated patients. In fact, all the patients had 2 or more prior therapies under their belt, all of them had exposure to stuff like fludarabine.  In addition to garden variety CLL, they also recruited patients with SLL or PLL (prolymphocytic leukemia).  There were even 3 patients with the dreaded Richter’s transformation.  10 out of the 27 patients had the high risk (FISH) deletion of 17p deletion, while another 9 had 11q deletion.  More than half had bulky lymph nodes, and 11/27 patients were refractory to fludarabine.  All in all, about as tough a crowd as one can gather, with not too many good therapy options open to them outside of clinical trials such as this.  That must be kept in mind while evaluating results and adverse effects.

Ibrutinib was given at the now standard dose of 420mg daily.  Each cycle consisted of 4 weeks.  Ofatumumab was initiated in the second cycle, with 2000mg of the monoclonal infused start of each week for the  second and third cycles.  (The very first infusion of ofatumumab in the first week of the second cycle was a reduced dose of 300mg).  After these initial 8 infusions of ofatumumab, infusions were given only once each cycle, on the first day of the cycle.

Impressively, after completion of 6 cycles (24 weeks) all of the CLL/SLL/PLL patients had responded, and even 2/3 Richter’s transformed patients responded.  This is truly encouraging news, given the advanced disease status of these patients and their poor prognostic indicators.  For the majority of these guys FCR would have been contraindicated and would have done precious little in any case.  After 6.5 months, fully 23/24 CLL/SLL/PLL patients are still in the study.  Unfortunately, two of the three Richter’s transformed patients had disease progression. Bummer indeed. There were moderate number of high grade (3-4) adverse effects, 11% anemia, 11% pneumonia, 7% urinary tract infections.  All in all, encouraging news in a patient cohort with few better options.

A phase Ib/II study evaluating activity and tolerability of BTK inhibitor PCI-32765 and ofatumumab in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and related diseases.

ASCO 2012. Abstract No: 6508

Author(s): Samantha Mary Jaglowski, Jeffrey Alan Jones, Joseph M. Flynn, Leslie A. Andritsos, Kami J. Maddocks, Kristie A. Blum, Michael R. Grever, Susan Michelle Geyer, Jennifer Ann Woyach, Amy J Johnson, Nyla A. Heerema, Erin Molnar, Mona Stefanos, Susan Devlin, Tasheda Navarro, Danelle Frances James, Ann M. Lowe, Eric Hedrick, John C. Byrd; The Ohio State University, Columbus, OH; Pharmacyclics, Sunnyvale, CA

Background: Bruton’s tyrosine kinase (BTK) is a non-receptor kinase that is critical for B-cell receptor (BCR) signaling in normal and malignant B lymphocytes. PCI-32765 (P), an oral, potent and irreversible BTK inhibitor, antagonizes BCR signaling in CLL cells and abrogates protective features of the microenvironment. P is highly active as a single agent in CLL/SLL patients (pts), and this phase Ib/II study builds upon single-agent experience by combining P with ofatumumab (O), an anti-CD20 monoclonal antibody. We present initial safety and efficacy data from cohort 1. Methods: Pts with relapsed/refractory (R/R) CLL/SLL following ≥2 prior therapies (Tx), including a purine-nucleoside analog (PA), are treated with 420 mg P daily, in 28-day cycles, until disease progression. O is added at a dose of 300 mg on day (D) 1 of cycle 2, followed by 2000 mg on D8, 15, and 22 of cycle 2, D1, 8, 15, and 22 of cycle 3, and on D1 of cycles 5-8. Results: As of November 2011, 27 patients with either CLL/SLL/PLL (n=24) or Richter’s transformation (RT, n=3) have been enrolled and have received at least 6 cycles of treatment. The median age is 66 (range 51-85), 9 were Rai stage III/IV. Median number of prior Tx is 3 (range 2-10), 15 pts had bulky disease (> 5 cm); 11 pts were PA refractory. Poor-risk molecular features were common (del(17p) 10 pts, del(11q) 9 pts). No grade (G) 3 or 4 infusion reactions, neutropenia, or thrombocytopenia have been observed. The majority of adverse events (AE) were G1/2. G3/4 AE included anemia (11%), pneumonia (11%), UTI (7%), hyponatremia (7%). 24/24 CLL/SLL/PLL pts have achieved PR (100% ORR) within 6 cycles; 2/3 RT pts had PR. With median follow-up of 6.5 mo (range 5.3-10.2 mo), 23 CLL/SLL/PLL pts and 1 RT pt remain on study; 1 CLL/SLL pt went to transplant in PR; 2 RT pts progressed. Conclusions: PCI-32765 combined with ofatumumab is well tolerated and highly active (100% ORR) in pts with heavily pre-treated R/R CLL/SLL. Rapid onset of response, low relapse rate, and favorable safety profile make this combination worthy of further study. Cohorts evaluating other Tx sequences are currently underway.

Combination of PCI-32765 with bendamustine and Rituxan

You could almost have predicted some one would start this clinical trial.  If PCI-32765 is good alone, better with a monoclonal thrown in for good measure, would it best when served along with a conventional chemotherapy drug such as bendamustine?  True, this would take away some of the “easily tolerable” cachet – since bendamustine packs as much of punch as any other chemotherapy drug out there – but I think most oncologists just cannot resist the temptation of piling on more drugs to increase the impact of their favorite drug regimens.  I think  FCR + PCI-32765  and similar alphabet soup combinations will soon come to an expert center near you.

Since this article is getting longer and longer, I will not belabor the details – which are highlighted below in the abstract anyway.  Basically, the cohort is an older and relapsed or refractory group of patients with late stage CLL with few good therapy options left to them.  In addition to the now standard dose of 420mg daily dose of PCI-32765, patients also got the usual doses of bendamustine and Rituxan.  Response rate was impressive.  But so too was the adverse effect profile, as would be expected from this bendamustine containing regimen. Of  note, two out of the 30 recruited patients suffered tumor lysis, an indication of the rate of cell kill with this aggressive therapy combination.  ”Adverse events (AE) have been consistent with that expected with BR” say the researchers.  What else is new.  Frankly, addition of BR makes this drug combination not-so-patient-friendly.  If you are contra-indicated for BR to begin with, PCI-32765 + BR is not going to be right for you either.

Combination of the Bruton’s tyrosine kinase (BTK) inhibitor PCI-32765 with bendamustine (B)/rituximab (R) (BR) in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): Interim results of a phase Ib/II study.

ASCO 2012. Abstract No: 6515

Author(s): Susan Mary O’Brien, Jacqueline Claudia Barrientos, Ian W. Flinn, Paul M. Barr, Jan Andreas Burger, Tasheda Navarro, Danelle Frances James, Eric Hedrick, Jonathan W. Friedberg, Jennifer R. Brown; University of Texas M. D. Anderson Cancer Center, Houston, TX; Long Island Jewish Medical Center, Hyde Park, NY; Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN; Case Western Reserve University School of Medicine, Cleveland, OH; Pharmacyclics, Sunnyvale, CA; Pharmacyclics, Summit, NJ; Hematology/Oncology Division, James P. Wilmot Cancer Center, University of Rochester, Rochester, NY; Dana-Farber Cancer Institute, Boston, MA

Background: BTK is an essential mediator of B cell receptor signaling and a critical kinase for lymphoma cell survival. PCI-32765 (P), an oral, selective, irreversible inhibitor of BTK, inhibits proliferation, migration and adhesion in CLL cells, and is highly active as a single agent for the treatment of R/R CLL pts. (O’Brien ASH 2011). BR produces an overall response rate (ORR) of 59% in R/R CLL (Fischer JCO 2011). We report interim data on P combined with BR. Methods: R/R CLL pts received P 420 mg orally daily for 28-day (D) cycles (C) until disease progression (PD). B was administered 70 mg/m2 on D1 and D2 combined with R 375 mg/m2 on D0 for C1 and 500 mg/m2 on D1 for subsequent courses for a maximum of 6 cycles. Response was evaluated according to IWCLL criteria. Results: 30 pts were enrolled. Median age of pts was 62 yrs (range 41-82). 46% of pts were Rai stage III/IV and the median # of prior therapies was 2 (range 1-4). 37% and 13% were considered refractory (treatment free interval <12 mo) to a purine analog containing regimen or BR, respectively. Bulky disease was present in 52%. Adverse events (AE) have been consistent with that expected with BR. Gr 3/4 neutropenia and thrombocytopenia have been noted in 47% and 10% of pts, respectively. Grade >3 non-hematologic AEs potentially related to P included rash (3 pts) and fatigue and tumor lysis reported in 2 pts each. There were no Gr 3/4 infusion reactions. There have been no discontinuations (D/C) due to AE and no deaths on study. At a median follow-up of 4.9 mos (range 2.7-8.3 mo) 16 pts have completed BR and 14 pts are still receiving BR. The ORR is 90% (27/30 pts) (CR 10%, PR 80%). 2 additional pts achieved a nodal response with residual lymphocytosis. Responses appear independent of high-risk clinical or genomic features. 90% of pts remain on study; reasons for D/C include PD (n=2) and 1 pt pursuing SCT. Conclusions: PCI-32765, in combination with BR, is highly active. The high ORR, low rate of PD, and good tolerability compares very favorably with historical controls, warranting additional investigation of this combination.

Editorial

Let us give this new drug its due credit.  It has shown remarkable activity in older patients, high risk patients, relapsed and/or refractory patients with bulky disease that is hard to treat.  This is precisely what our patient community needs right now, drugs that work well in segments of our community that have run out of other, more conventional therapy options.  I have no doubt that PCI-32765 and future generations of other kinase inhibitor drugs will change the paradigm for treating late stage and elderly CLL patients, increasing both quality and quantity of life for this segment of the patient population.

That said, I would like to share some concerns with you.  It seems that once the drug is discontinued, relapse happens pretty darned quickly.  We are not talking of remissions that last months if not years.  People who quit taking the drug start to see their lymph nodes popping back and making their presence felt within a mere week or two.  So, basically we are looking at taking drugs such as this daily, on an indefinite basis.  Best as I can tell, this is the case both for PCI-32765 as well as CAL-101.

So, that brings us to the next couple of questions. How safe are these drugs as long term maintenance drugs?  I will not even attempt to address a very real life concern about the dollar cost of being on these drugs daily, for years and years.  We do not know exactly how much they will cost, but I think it is a safe bet they are not going to be cheap.  Another question I will not attempt to answer is the long term efficacy of these drugs, since we do not have enough information on which to base even a guess.  Cancer cells have a way of learning new tricks, giving them the ability to become drug resistant after some time.  Will CLL cells learn to scoff at these new kinase inhibitors?  I do not know, I hope that is not the case.

Since I cannot talk about affordability or long term efficacy (yet), I will restrict myself to the safety issues.  I have already highlighted the issues recorded in the published abstracts.  Let me now focus on one specific concern that has not been talked about much, but one that has caught my attention based on feedback from my members.

Here is the skinny, without a lot of complicated science to confuse things.  PCI-32765 is a BTK (Bruton tyrosine kinase) inhibitor.  This kinase is important in the way B-cells communicate.  Messing up their ability to talk to each other as well as their environment makes the cells isolated and vulnerable, easier to kill.  That is the good news.

Now for the bad news.  BTK pathways are important not just in B-cell communication, they are are important in a number of crucial other functions of the body as well.  We will focus for now on one particular pathway that needs proper function of BTK.  It seems platelets need functioning BTK before they can do their job properly.  In a nutshell, healthy platelets are able to respond to any injury to blood vessels, seal off the cut with a tiny smidge of clumped platelets or ‘thrombus’.  This ability of platelets forming a little clot is essential for the cessation of bleeding.  If you nick yourself while shaving, even if you do nothing to stop it, most often the bleeding will stop on its own; that is, it will do so if you have healthy number of platelets and they are functioning properly.

Many of our guys have problems with inadequate numbers of platelets to begin with, courtesy of the underlying CLL.  Now on top of that, if there is worry that daily dose of PCI-32765 inhibits BTK function across the board (as it is supposed to do), and this interferes with platelets being able to do their job, we may well have bit of a problem.  I am not talking of slightly longer time bleeding when you cut yourself shaving.  How about internal bleeding that goes unnoticed?  This can happen in your GI tract, in your lungs and throat if you cough violently and last but by no means least, in your brain.  Micro ruptures of this sort pose no problem when people have well functioning platelets.  But what about the situation when this crucial function is degraded due to BTK inhibition?  Most of you are smart enough to keep an eye on platelet counts.  But now, we are talking of people with reasonably OK platelet numbers, but who may still be at risk if the platelets they do have are not able to do their job properly, on account of BTK inhibition.

The role of proper BTK function in platelets ability to form necessary clumps and thereby stop bleeding has been reported before, in prestigious journals.  I have attached one such report below – there are many others.  The science gets a bit hairy, but do read if you are inclined to do so.  Importance of BTK pathway in platelet function is sufficiently important that researchers have suggested BTK inhibitors can be used to protect folks from excessive blood clotting and therefore thrombosis risk!  Too much clot formation is not a good thing.  But so is too little clot formation capability – the ever-present Goldilocks dilemma.

Blood. 2006 Oct 15;108(8):2596-603. Epub 2006 Jun 20.

Bruton tyrosine kinase is essential for botrocetin/VWF-induced signaling and GPIb-dependent thrombus formation in vivo.

Liu J, Fitzgerald ME, Berndt MC, Jackson CW, Gartner TK.

Department of Biology, University of Memphis, Memphis, TN 38152, USA.

Botrocetin (bt)-facilitated binding of von Willebrand factor (VWF) to the platelet membrane glycoprotein (GP) Ib-IX-V complex on platelets in suspension initiates a signaling cascade that causes alphaIIbbeta3 activation and platelet aggregation. Previous work has demonstrated that bt/VWF-mediated agglutination activates alphaIIbbeta3 and elicits ATP secretion in a thromboxane A2 (TxA2)-dependent manner. The signaling that results in TxA2 production was shown to be initiated by Lyn, enhanced by Src, and propagated through Syk, SLP-76, PI3K, PLCgamma2, and PKC. Here, we demonstrate that the signaling elicited by GPIb-mediated agglutination that results in TxA2 production is dependent on Bruton tyrosine kinase (Btk). The results demonstrate that Btk is downstream of Lyn, Syk, SLP-76, and PI3K; upstream of ERK1/2, PLCgamma2, and PKC; and greatly enhances Akt phosphorylation. The relationship(s), if any, between ERK1/2, PLCgamma2, and PKC were not elucidated. The requirement for Btk and TxA2 receptor function in GPIb-dependent arterial thrombosis was confirmed in vivo by characterizing blood flow in ferric chloride-treated mouse carotid arteries. These results demonstrate that the Btk family kinase, Tec, cannot provide the function(s) missing because of the absence of Btk and that Btk is essential for both bt/VWF-mediated agglutination-induced TxA2 production and GPIb-dependent stable arterial thrombus formation in vivo.

PMID: 16788103

Several cases of intra-cranial bleeding in patients taking PCI-32765 have come to my attention.  Scary stuff. As you would expect, the risk is highest in people who are on BTK inhibitors such as PCI-32765 as well as blood thinner such as heparin, coumadin etc for other medical reasons.  So much so that newer PCI-32765 clinical trials are making this an exclusion factor.  If you have an artificial heart valve, for example, that needs daily dose of coumadin, you are likely to be ineligible for PCI-32765 therapy.  If  you need heparin to treat DVT (deep vein thrombosis), you must wait until the heparin therapy is complete and it can be assumed to be safely out of your system. How about less dramatic blood thinners?  How about the daily aspirin, fish oil or green tea extract capsules?  All of these are known to decrease – to various degrees –  platelets ability to come together and clot as needed, when there is a blood vessel rupture and bleeding starts.

While there is no official word on it, I have begun to encourage members to discontinue (or discuss discontinuing) over the counter supplements such as daily aspirin, green tea and fish oil capsules. How about stuff like Plavix, a drug that is often prescribed to patients at risk of stroke?  It too is a “blood thinner”, it is used precisely because it reduces the ability of platelets to clot.  Should you be on Plavix if you are going to be on PCI-32765 as well?  Talk to your doctor and your clinical trial researcher, before you make decisions on important stuff such as this.  I am doing no more than bring the worry to the surface, I am by no means qualified to give you medical advice.

For now, here is my two cents of advice, cheap at the price.  Talk to your doctors about each of the blood thinners identified above, if you are taking any of them.  Second, try and avoid bruising yourself.  You might notice that the bruises are much more dramatic while you are on PCI-32765, since it takes longer for the platelets to stop the bleeding under your skin and the pooling blood forms a bigger and more colorful bruise.  This may not be a good time to get truly deep tissue massage.  I am not an expert on this since I have never had one, but I would worry about potential micro tears it may cause to blood vessels deep inside.  If you do bang yourself up and are inclined to use any of the off-the-shelf potions and ointments on the bruise to ‘make it go away’, please don’t.  Most of these ointments work by trying to dissolve the clot – thinning the blood.  Who knows if this would make the situation worse, if you already have low platelet counts, and you are on PCI-32765 therapy to boot.  (I have heard from one member who did precisely this, you know who you are.  Please feel free to kick yourself in the rear-end,ever so gently – so you do not cause additional bruising.)

All in all, I am beginning to be concerned about this – mainly because the value of BTK kinase inhibition by drugs such as PCI-32765 rests with their use on a long term basis.  We just don’t know enough about the adverse effect profile of all the things that can go haywire with long term BTK inhibition.

As always, it is important not to throw the baby out with the bathwater.  This new generation of kinase inhibitors have given us much needed hope in treating older patients, patients with poor prognosis.  I hear people with 17p deletions are responding much better than can be expected to PCI-32765.  That is truly wonderful news.  But we also need to keep in mind these are early days.  We do not know the full adverse effect profile.  Degraded platelet function is a serious concern for me, especially if it is enough to trigger significant internal bleeding. Does this adverse effect become worse over time, as patients take the kinase inhibitor drug for longer and longer periods?  Do higher doses make the problem more serious?  How about people who must be on blood thinners for other medical conditions?  How low can the platelet count be before it becomes a real contraindication to take BTK inhibitors?

Keep your eyes peeled, your mind open to both the positive news and reasonable adverse effect concerns.  Your best protection is credible information.   At this point, they are just my concerns and they have not been officially reported yet in any papers that I am aware of –  hence my decision to report them in the editorial section of this article.  I will let you be the judge of the credibility of my concerns.

Breakthroughs in T-cell therapy

Some of you may have read about the University of Pennsylvania researchers treating a very small number of CLL patients with very advanced disease, using a novel T-cell therapy.  All of the lay-press carried reports of this new development and for a change the hype was almost justified.  We reported on it as well in an earlier article, hopefully with a more readable and balanced description of the technology and its potential value to us down the road.

While the approach was indeed an exciting development, there were some clear problems associated with it as well.  Now we are beginning to see modifications that may get around the potential pitfalls.  Combining potent therapies such as the new family of kinase inhibitors such as PCI-32765 with T-cell immunotherapies such as this may indeed make chemotherapy obsolete in the lifetime of patients reading this review. This is important stuff – and therefore, I hope you will bear with me as I walk you through the logic of how it is all supposed to work.  As always, I will attempt to make the science and jargon a lot less heavy-handed and therefore more user friendly.  In the process, I know I will be sacrificing some of the technical detail.  Those of you who are up to it are always welcome to read the professional articles for yourselves.

Limitations of conventional chemotherapy

Before we discuss the benefits of T-cell immunotherapy, it might help to highlight the short-comings of conventional chemotherapy.

While different chemotherapy drugs have different mechanisms, by and large they work by damaging and poisoning cancer cells to such a extent that the cells die.  Sounds good, but for a small fly in the ointment.  The toxicity of chemotherapy drugs is not strictly restricted only to cancer cells.  A certain percentage of perfectly healthy cells are also damaged in the process.   The differential between the toxicity of the drug on cancer cells versus healthy cells is called the therapeutic window.  A good chemotherapy drug is one that has a wide therapeutic window, in that it kills a lot of cancer cells while damaging and killing only a small number of healthy cells.

It always boils down to balancing risks and rewards.  Unless the chemotherapy drug kills most or all the cancer cells, relapse is likely.  Higher doses generally achieve more cell kill.  But if the dosage is increased to improve the percentage of cancer cells killed, it is very likely the toxicity to healthy cells will increase too.  In the extreme case, it is possible to give such a high dose of chemotherapy drug that almost all of the CLL cells are killed -probably at the expense of killing the patient too – a case of death by therapy.  We cured the CLL, but unfortunately the patient died.

Another limitation of chemotherapy is that very often the drugs are ineffective against CLL cells that are nicely tucked away in enlarged lymph nodes, infiltrated bone marrow or enlarged spleen, liver.  Larger percentage of CLL cells in such protected locations survive chemotherapy – one reason why it is relatively easy to clear the blood of CLL cells, but it is a lot harder to eradicate them in enlarge nodes or bone marrow – and these survivors can not only grow back to trigger a full-fledged relapse, the survivors are also likely to have learned how to avoid getting killed the next time around.  Drug resistance is a major problem with most chemotherapy drugs.  We see it all the time in CLL patients.  Over time, patients develop resistance to most of the major drugs available to us, resulting in ever shorter list of therapy options.

Autologous T-cell Immunotherapy

The label given to this kind of therapy is important.  It is immunotherapy – suggesting it is therapy based on your own immune system – and therefore very different from standard chemotherapy.  It uses T-cells as the smart troops, hopefully on a house-to-house search for cancer cells where ever they try to hide in the body.  It is autologous, meaning the T-cells used are harvested from the patient himself.

You have probably heard of another T-cell based therapy that has the ability to cure CLL patients, one that has been around for quite some time.  I am talking about mini-allo transplants.  In that case, the T-cells are allogeneic, meaning they are derived from the stem cells of the matched donor.  The killing of CLL cells by the newly grafted T-cells (and other components of the donted immune system) is called “graft-versus-leukemia” effect.  Sometimes, when the GVL is not sufficiently potent, the patient is given an extra dose of donor T-cells to get the job done (DLI – donor lymphocyte infusion).  While GVL is very much the desired effect since it is the lynch-pin that brings about the hoped for cure, there is another side to this coin – graft-versus-host disease (GVHD)  - which can be potentially dangerous.  In fact, GVHD contributes major share of sickness and death in mini-allo transplants.  We have yet to figure out exactly how to preserve and increase the GVL effect, but not at the expense of increased GVHD.  These two effects, GVHD and GVL, are two sides of the same coin.

All that becomes a moot point when we talk of using autologous T-cells.  Since the T-cells are obtained from the patient himself, there is little reason to expect that they would find the patient’s body “foreign” and therefore there is every reason to hope GVHD is no longer an issue. Unlike conventional chemotherapy, it is hoped that autologous T-cell therapy would spare healthy tissue, killing only the cancer cells and thereby toxicity to healthy tissue should be vastly decreased.  But how to get the patient’s own T-cells to go after the CLL cells, when clearly they had been sleeping on the job up to that point – the reason why CLL had a chance to establish itself in the first place? That is the million dollar question of all autologous T-cell therapy approaches.    Last but not least, it is hoped that the modified T-cells will stay vigilant and on the job for a long time.  We need these vigilant smart troops to survive and hang around long enough to finish the job, get the patient into a 100% cure with no CLL cells left behind to trigger relapse.

The game plan boils down to this:

1. We need to harvest sufficient number of T-cells from the patient.  This is not hard to do.
2. The next step is to vastly increase their number in the lab by encouraging them to grow and have lots of babies.
3. We need to tweak the armies of T-cells so that they are now monomaniacal killers fixated on killing CLL cells – and nothing else.
4. As with the University of Pennsylvania study, it is probably necessary to treat the patient with some chemotherapy regimen ahead of injecting back the doctored T-cell troops.  This is necessary to reduce the number of cancer cells in the body to manageable levels.  If the newly engineered T-cells infused back into the patient face an overwhelming army of cancer cells that outnumber and outgun them, chances of success become that much slimmer.
5. There is another reason for this high impact chemotherapy ahead of infusing back the engineered T-cells.  As most of you know by know, chemotherapy damages the immune system.  In this case, that is what we want the preconditioning chemotherapy to do.  We do not want the patient’s immune system still feisty enough to try and kill off all the newly engineered T-cells when they come back.  Same logic is used in mini-allo transplants as well, pre-transplant chemo conditioning is an essential feature.  Without it the new graft is quickly killed and the patient is back to square one.

There have been earlier autologous T-cell therapy experiments that met with scant success.  Some of you old timers may remember a company called Xcyte.  They too grew huge armies of the patient’s own T-cells in the lab and infused them back into the patient.  The problem was these were not specially trained to seek and kill CLL cells.  Nor were they given sufficient self-protection capabilities.  All too soon, the precious new comer T-cells were quickly killed off by the host immune system. The over hyped early phase clinical trials at UCSD (and elsewhere) came to nothing and the company went bankrupt.

University of Pennsylvania – a genuine breakthrough

So, what has changed from the prior generation T-cell attempts?  What the U. Penn folks were able to demonstrate is new technology that gave the engineered T-cells the ability to survive – even thrive and grow their numbers once they are infused back into the patient.  The prior heavy duty chemotherapy was important too, by softening up the host immune system.  For the first time, the engineered T-cells were still around and doing their job months after their infusion back into the patient. The other important thing they were able to do is channel the killing power of the new T-cells into a narrow focus.  They were able to graft a specific search / identify tool onto the T-cells, such that they could identify all cells carrying a particular marker, and kill them on the spot.  This identification tool is called a chimeric antigen receptor (“CAR”) and the hope is that CARs technology will allow us to engineer T-cells to target different cell types by appropriately chosen tumor markers.

U. Penn folks chose CD19 as the marker on which to focus the T-cell killers.  All B-cells carry the CD19 marker; not just CLL cells but  healthy B-cells as well.  As expected, once they are infused back into the patient  the CD19 targeted CARs T-cells killed every CD19 carrying cell they found in the body.  As hoped for, the new T-cells not only survived but even increased their numbers over time – a first step if this therapy is to work at all.  And they did indeed kill each and every cell they came across that carried the CD19 marker.  A couple of patients with very advanced and refractory CLL saw almost miraculous clearance of their CLL tumor load.  That is the good news, and it is indeed very encouraging news.

But there were problems as well.  Since the new CD19 targeted CARs T-cells killed all B-cells, pretty soon there were no B-cells of any kind.  B-cells are an important part of the immune system.  They also go on to become plasma cells, which manufacture immunoglobulins.  The constant and continuing surveillance of the killer CARs T-cells kept B-cell counts close to zero –  which meant no plasma cells down the road, and therefore no immunoglobulins either.  Ig levels plummeted and patients undergoing this therapy are committed to a life time of dependence on intravenous immunoglobulin (IVIG) therapy.  Immunoglobulin therapy is based on careful collection of these precious bits of protein from huge quantities of donated blood – not a cheap process.  IVIG therapy is quite expensive and the product is often in short supply.  Long term, this is not a viable approach for large groups of patients, since there is no way we can maintain all of them on regular IVIG therapy for the rest of their lives.

Building upon success

Any number of research groups are looking to see how to tweak the U.Penn CARs approach so as to keep the good parts going but fix the problem areas.  Using a different target for the T-cells – something other than CD19 – so that they kill only the cancerous B-cells and spare the healthy B-cells is very much desired.  A number of options are being considered and I have no doubt that we will build on the success of the ground breaking success of the U. Penn team.

M. D. Anderson and others are looking at something called ROR1.  What makes this marker hugely attractive is that it is expressed by CLL cells – but not healthy B-cells.  IF everything goes according to plan, the hope is that ROR1 targeted T-cells will survive long enough in the body to kill each and every CLL cell in the body, but not damage the healthy B-cells.  In other words, the patient is cured of CLL and yet healthy B-cell populations can recover and go on to produce plasma cells, immunoglobulins etc.  By using ROR1 as the target of the killing power of the engineered T-cells, we can hope for avoiding the IVIG dependence baked into the cake of the U. Penn approach.

Blood. 2010 Nov 25;116(22):4532-41. Epub 2010 Aug 11.

The B-cell tumor-associated antigen ROR1 can be targeted with T cells modified to express a ROR1-specific chimeric antigen receptor.

Hudecek M, Schmitt TM, Baskar S, Lupo-Stanghellini MT, Nishida T, Yamamoto TN, Bleakley M, Turtle CJ, Chang WC, Greisman HA, Wood B, Maloney DG, Jensen MC, Rader C, Riddell SR.

Clinical Research Division, Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. mhudecek@fhcrc.org

Monoclonal antibodies and T cells modified to express chimeric antigen receptors specific for B-cell lineage surface molecules such as CD20 exert antitumor activity in B-cell malignancies, but deplete normal B cells. The receptor tyrosine kinase-like orphan receptor 1 (ROR1) was identified as a highly expressed gene in B-cell chronic lymphocytic leukemia (B-CLL), but not normal B cells, suggesting it may serve as a tumor-specific target for therapy. We analyzed ROR1-expression in normal nonhematopoietic and hematopoietic cells including B-cell precursors, and in hematopoietic malignancies. ROR1 has characteristics of an oncofetal gene and is expressed in undifferentiated embryonic stem cells, B-CLL and mantle cell lymphoma, but not in major adult tissues apart from low levels in adipose tissue and at an early stage of B-cell development. We constructed a ROR1-specific chimeric antigen receptor that when expressed in T cells from healthy donors or CLL patients conferred specific recognition of primary B-CLL and mantle cell lymphoma, including rare drug effluxing chemotherapy resistant tumor cells that have been implicated in maintaining the malignancy, but not mature normal B cells. T-cell therapies targeting ROR1 may be effective in B-CLL and other ROR1-positive tumors. However, the expression of ROR1 on some normal tissues suggests the potential for toxi-city to subsets of normal cells.

PMID: 20702778

As expected, the abstract above reports ROR1 is nicely expressed by CLL cells, mantle cell lymphoma cells and fetal embryonic cells – but not healthy adult cells.  (In other words, this approach is a definite no-no if you are pregnant or likely to be pregnant in the near future).  Healthy B-cells do not express it.  In fact, the only group of cells that express it other than CLL cells and MCL cells are adipose cells (fat cells) and pancreatic cells.  The expression of ROR1 on fat cells and pancreatic cells is lower than its expression on CLL cells.

Potential risks

That ROR1 gene is expressed to any level by adipose cells and pancreatic cells may pose a problem with this technology.  In fact, one of the Canadian doctors at the conference asked Dr. Keating this question.  Is he worried that administration of ROR-1 targeted CARs T-cells will not only attack CLL cells, but pancreatic cells as well?  I thought this was a clearly relevant question.  And I was very chagrined that Dr. Keating brushed off the question with a joke.  He said that since ROR1 is also expressed by fat cells, a side effect of the ROR-1 based CARs technology may be that heavy patients with a few pounds to lose may find themselves getting slender, since their adipose cells express ROR1 as well and therefore targeted.

Well.  He was kidding, of course.  But the prospect scares the heck out of me.  One of the major (and I mean life threateningly major) risk factors of the U. Penn study was tumor lysis syndrome.  When too many cells are killed at a rapid pace, the quantity of debris created by the dead and dying cells can become a huge problem.  Eventually, all this stuff must be handled by the body’s garbage handling systems.  TLS can become life threatening if the load becomes more than the kidneys can handle.  Even with urgently initiated dialysis, kidney failure can kill patients a whole lot faster than CLL.

So, how would you like to get slender at the risk of TLS? Notice, the U. Penn researchers deliberately set out to reduce the tumor load in their patients by means of pre-conditioning chemotherapy.  The idea was to decrease the number of CLL cells left over for the CD19 targeted CAR T-cells to kill.  Even with that precaution, TLS was an issue with their patients.  Each and every one of us has adipose tissue – fat cells – in our bodies.  Some of us have more than others, but there is no way of taking adipose tissue to zero levels ahead of CARs therapy.  Is there a risk of TLS as the engineered T-cells go after fat cells, even though they express only low levels of ROR1?  This would not be my chosen way of losing a few pounds.  Along the same lines, pancreatic inflammation if the ROR1 targeted T-cells go after pancreatic cells would not be a trivial matter either.  The question asked at the conference  was quite valid and I wish Dr. Keating had chosen to answer it seriously.

Mol Ther. 2010 Apr;18(4):843-51. Epub 2010 Feb 23.

Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2.

Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA.

Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. rmorgan@mail.nih.gov

In an attempt to treat cancer patients with ERBB2 overexpressing tumors, we developed a chimeric antigen receptor (CAR) based on the widely used humanized monoclonal antibody (mAb) Trastuzumab (Herceptin). An optimized CAR vector containing CD28, 4-1BB, and CD3zeta signaling moieties was assembled in a gamma-retroviral vector and used to transduce autologous peripheral blood lymphocytes (PBLs) from a patient with colon cancer metastatic to the lungs and liver, refractory to multiple standard treatments. The gene transfer efficiency into autologous T cells was 79% CAR(+) in CD3(+) cells and these cells demonstrated high-specific reactivity in in vitro coculture assays. Following completion of nonmyeloablative conditioning, the patient received 10(10) cells intravenously. Within 15 minutes after cell infusion the patient experienced respiratory distress, and displayed a dramatic pulmonary infiltrate on chest X-ray. She was intubated and despite intensive medical intervention the patient died 5 days after treatment. Serum samples after cell infusion showed marked increases in interferon-gamma (IFN-gamma), granulocyte macrophage-colony stimulating factor (GM-CSF), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and IL-10, consistent with a cytokine storm. We speculate that the large number of administered cells localized to the lung immediately following infusion and were triggered to release cytokine by the recognition of low levels of ERBB2 on lung epithelial cells.

PMID: 20179677

Editorial

As you can see in the discussion and abstract above, CARs technology is immensely powerful.  It has the ability to cure, but it also has the ability to kill just as quickly.  We are in early stages of developing this technology, we need to build careful understanding of the science, so that we can benefit from the curative potential but avoid its lethal power that can cause mayhem.  Full fledged late stage clinical trials using ROR1 marker (and other target candidates being explored by other researcher groups) are several years out.  I have no doubt that down the road high powered immunotherapy regimens using this and similar approaches will finally cure CLL and many other presently lethal cancers.  Will we get there in the next 2-3 years?  Will chemotherapy become passe and CLL patients cured in droves in the optimistic time frame Dr. Keating mentioned at the conference?  I am willing to bet several dollars to a single high fat donut that the vast majority of CLL patients will still have to deal with less than perfect chemotherapy options for many years yet.

When pressed on the time horizons, Dr. Keating said we as patients and patient advocates can help the process by getting regulatory agencies off his back.  He said, and I quote, the only animal experiments he wants to do are in human animals .  I beg to differ, humbly but quite vehemently.  Without proper pre-clinical work in the lab and appropriate animal studies, in my layperson opinion it would be highly unethical to recruit “human animals” for the studies.  A couple of well publicized disasters where patients died as a result of poorly vetted technological errors can also set the whole field back for years.  All of us want success, all of us want it yesterday.  But there is good reason for the checks and balances in place to protect human subjects volunteering for such cutting edge technologies.  When is it OK to sacrifice the lives of early volunteers, cut corners on safety concerns so that we can speed up the process for folks further back in the line?

Never, not on my watch, not if I have to say anything about it.  There are these little things called the Helsinky Accord and the Nuremberg Code that were established soon after the second world war.  In 1948, German physicians who conducted deadly or debilitating experiments on concentration camp prisoners underwent criminal proceedings in the Nuremberg Trials. That same year, following the Nuremberg Trials, the Nuremberg Code was established. The Nuremberg Code was the first international document that supported the concept that “the voluntary consent of the human subject is absolutely essential”. The emphasis that was placed on individual consent in the Nuremberg Code was aimed at keeping participants informed of the risk-benefit outcomes of experiments.  No, I will not support “human animal experiments”, not without due diligence to scope out the risks and rewards through well conducted pre-clinical work and animal studies.  Not one of my members is expendable, not in this way.

You know my thoughts about patient volunteers who participate in cutting edge clinical trials.  Progress is not possible without their courage and generosity.  But precisely for that reason, it is our sacred duty not to sacrifice their lives without doing what needs to be done to protect them as well as possible.  Informed consent is the at the heart of human clinical trials.  How can consent be informed if we do not have a good handle on the possible risks and rewards?  I doubt ROR1 based CARs technology will ever get FDA approval as a way of controlling obesity.  The flip comment may be OK as a one-liner to lighten a speech and introduce a bit of humor to spice up a talk to cancer patients, but dismantling regulatory and ethical oversight in order to speed up development of a pet theory – that may or may not pan out – is not something I will support.  There have been plenty of other sure-fire sounding medical theories that have not done so well in actual practice.  Trust but verify, be hopeful but don’t buy every pig in a poke, be generous in volunteering for clinical trials but be damned sure you have a pretty good handle on the risks involved – this is my advice.

What say you?

Role of positive mental attitude

I am not sure exactly where this concept comes from, but it is quite common among cancer patients.  If one can practice truly positive thinking, not give way to any negative thoughts of any kind, eventually the cancer will be defeated.  ”Mind over Matter” is often cited as the irrefutable logic behind this concept.  I regret to inform you, there is no shred of evidence that positive thinking influences how cancer cells behave.  They are mindless little beasts, their behavior governed by the mangled DNA  that made them cancerous in the first place.  The Medscape article below goes into great detail debunking this myth.  No reputable psychologist or oncologist will support the magical power of positive thinking in curing cancer.  And I agree with them.

Does positive thinking do anything for us?

There is another reason why positive thinking is important.  Actually, I think it is easily the most important thing in life – whether or not you have cancer.  It is quite simple.  We are all born with a finite amount of life in our account.  When that runs dry, we die.  Some will die sooner, some will live long lives.  But die we must.  It seems to me that the important thing is not how long we live, but how we live the lives we do have.

Let us take an average CLL patient, with middle of the road prognostics.  It is not unreasonable that such a patient will be in Watch & Wait for several years (say, 4 years).  Assuming he has access to the present day drug regimens only and no breakthroughs occur during his life, he may have another 6 or so years alternating between therapy and remissions.  A full ten years or more from the dreaded day of CLL diagnosis to when he may kick the bucket.  Take a minute to think about it.  Ten years is a long time!  Much can be achieved, much can be experienced in all those years.  The choice rests with the patient. Make the ten years he does have a living hell because he is so depressed and angry about not having more than the ten years. Or he can make them the best ten years of his life.  Positive thinking will not change the quantity of his life. But it surely will change the quality of his life.

There is a small caveat even when it comes to the influence of positive thinking on cancer outcome.  None of us live on a desert island, dealing with our CLL in total isolation.  All of us interact with others – our families, our physicians, the nurses in the infusion room, the insurance company representative, the pharmacist that fills your prescription.  Each and every one of these people can influence your CLL outcome.  Most of us have heard of the book “How to win friends and influence people” – I must confess I have not actually read it.  The short version of the book is quite simple.  Your personality, how you approach a given situation, how you negotiate your way through complex situations, all of these are important when it comes to influencing people.

If CLL was a simple disease with well defined guidelines for treatment, it may not be that important.  But we know better than that.  CLL is complex, varied and bewildering.  Options are not crystal clear.  Even experts don’t always agree.  You really want your doctor to go the extra distance, really stretch his brain before making a therapy recommendation. You want the nurse to be extra careful in getting the dosage right, get a good vein the first time she pokes you with a needle.  Family support systems are very important for all the crazy hurry up & wait stuff.  It is a lot harder to avoid infections if your family does not cooperate.  Inclusion criteria for clinical trials are not always cast in concrete.  Sometimes they can be interpreted and bent just a tad to fit a specific patient’s situation.  Will the researcher making the call go the extra distance for you?  I guess it depends on how good you are at winning friends and influencing people.

A good thing gone bad

But there is a truly dark side of this whole business of positive thinking.  We hear such glowing stories of brave cancer patients fighting against insurmountable odds. The smiles never leave their faces, they never admit to a moment of self doubt.  Nothing scares them, they are serene and powerful in their positive thinking.  Wow.  Now that is a true hero.

I am not one of them.  I remember plenty of nights being scared silly as I watched my husband sleep.  No decision was ever made without going back and forth, agonizing over minute details that really did not influence the decision in any way.  I would not be surprised if the majority of the human race is more like me and less like the cancer patient hero that reporters gush about.  Does that make you feel less than adequate?  A nagging sense that somehow you failed to live up to the expectations of others?  Trust me, you are not alone.  We have built such a huge edifice to the myth of the brave patient warrior that we have lost all sense of proportion.  It is OK to be human, worry about your health, feel scared, even shed a few tears if you are so inclined.  The important thing to remember is not to expect perfection, even from yourself.

I am curious to know what you guys think about all this stuff.  Faith, a positive mental attitude, a gentle philosophy of accepting what is after all inevitable for all mortal beings – all of these are important in making life worth living.  They make us better human beings, better parents, spouses and patients. But none of them will actually make us immortal.  Some diseases are influenced by brain chemistry and stress levels – high blood pressure for example.  In a stretch, I suppose one can make the case that mental attitude influences how immune system functions and that in turn influences how CLL behaves.  It is a stretch, and I have seen no evidence that it actually makes enough of a difference that can be measured, defined.  But I have no doubt at all that a positive attitude gives patients the empowerment they need to take better care of themselves, make smart therapy decisions that will help improve both the quality and quantity of their lives.

What say you?

 Personality Does Not Influence Cancer; Hypothesis Should Be Retired

Zosia Chustecka

August 27, 2010 — Personality has no effect on cancer risk or cancer survival, concludes a new study based on the largest and most relevant dataset to date. Other recent studies have also found no link or have been inconclusive.

It is time to finally retire the hypothesis that personality has an effect on cancer, say psychologists reporting and discussing these findings in the August 15 issue of the American Journal of Epidemiology.

In the study, Naoki Nakaya, PhD, and colleagues from the Institute of Cancer Epidemiology at the Danish Cancer Society in Copenhagen, analyzed data from more than 4500 cancer patients and found no effect of personality on either risk or survival.

“Cancer patients should not think that their personality traits may have affected their cancer or cancer prognosis,” the researchers conclude.

Given the evidence, we think that it is time to retire the hypothesis.

“Given the evidence, we think it is time to retire the hypothesis that personality — as it has been studied until now — is causally related to the onset of and survival from cancer,” said Adelita Ranchor, PhD, professor of health psychology at the University of Groningen, the Netherlands.

“Studies so far have failed to find any epidemiological evidence,” she told Medscape Medical News.

Dr. Ranchor coauthored an editorial that accompanied the study with Robbert Sanderman, PhD, also from the University of Groningen, and James C. Coyne, PhD, professor of psychiatry at the University of Pennsylvania in Philadelphia.

Dr. Nakaya, principal investigator of the study, told Medscape Medical News that he agrees that it is time to retire this hypothesis, and urges physicians to tell cancer patients about these findings so that they can stop worrying.

“Many patients worry that their own personality has made their cancer develop, or that their personality shortens longevity,” Dr. Nakaya said. “But our research shows that this is not the case, so cancer patients need not worry about this,” he reported.

“The notion that personality is related to cancer onset and its course might cause turmoil for the patients and their families because there might be some pressure on the patient to fight the cancer,” Dr. Ranchor added. If doctors see that the patient and family are struggling with this issue, then providing relevant information can bring some peace of mind, she explained.

Strongly Held Cultural Beliefs

The hypothesis that personality influences cancer can be traced back to the times of the Ancient Greeks, the editorialists note. The idea resurfaced in the 1960s after a few positive studies — which have since been severely criticized — led to the idea that some personality traits lead to an increased risk for cancer, and that once cancer has developed, optimism and a fighting spirit can extend survival.

Some of these ideas have now become “embedded in a matrix of strongly held cultural beliefs,” the editorialists note.

Many of the theories on personality and cancer were proposed by Hans Eysenck, who was involved in some of the early studies and who developed the personality test that was used to measure extraversion and neuroticism in many of these studies.

The personality test itself is “well validated and widely accepted,” the editorialists point out, “but Eysenck’s views on the relation of personality to cancer are not.”

He was “one of the most vigorous proponents of personality as a risk factor for cancer,” and even though much of his work in this field has since been discredited, his ideas are still influential because not everyone is aware of the criticisms surrounding his controversial work, which continues to be cited, Dr. Ranchor said.

On the basis of a small study, published in 1962, that found that lung cancer patients were more likely than control subjects to score high on extraversion and low on neuroticism, Eysenck proposed that these personality traits affect an individuals’ risk for cancer because they affect stress, which in turn affects the immune and endocrine systems. His explanation for this was that people who scored high for extraversion would seek out stimulation and would therefore experience high levels of stress, and that people who scored low for neuroticism (which measures emotional instability) would tend not to express their feelings and would therefore experience a high level of emotional stress.

Some of these theories were extended to cancer patients, with the idea that the accumulated repression of emotions would cause stress, which again, through an effect on immune and endocrine functions, would have a negative effect on cancer progression.

This led to the idea that psychological factors such as optimism and fighting spirit can have a positive effect on cancer. “These views are still widely held, even though evidence from high-quality studies does not support these theories, and no reasonable mechanisms to explain how the effect can be mediated have been identified,” Dr. Ranchor explained.

Although the idea that a fighting spirit prolongs survival offers a sense of hope, it can also cause turmoil in the lives of cancer patients and their families, which is very sad when patients have only a limited time left, Dr. Ranchor said. Patients might be accepting of the disease, but the family thinks that they should fight because they want the patient to recover. And of course, patients themselves can become seriously disappointed if they think it is possible to fight the disease when it “turns out that it is not,” she added.

If the doctor sees that the patient and/or family are struggling with such issues, providing relevant information might help, she said.

Latest Study Largest So Far

This study by Dr. Nakaya and colleagues — which is “undoubtedly the largest relevant dataset ever assembled” — found no association between personality traits and all-cancer incidence or mortality, the editorialists write. These null results should be given a weight that takes into account not only the study’s superior sample size but also its methodological strengths, they explain.

We can now be reasonably confident.

“We can now be reasonably confident that the overall effect size for a personality–cancer causal association is much too small to have clinical and public health implications, if it exists at all,” the editorialists write.

The hypothesis that personality can influence cancer should “quietly pass into oblivion,” they suggest. However, they acknowledge that it is not likely to disappear because of “strongly held cultural beliefs and ideology.”

Conducted in Scandinavia

The study was conducted while Dr. Nakaya was at the Danish Cancer Institute — he has since returned to Japan, and is now at the Kamakura Women’s University. The team was headed by Christoffer Johansen, MD, PhD, DMSc, head of the department of psychosocial cancer research at the Institute of Cancer Epidemiology at the Danish Cancer Society.

They analyzed data collected in twin studies conducted in Sweden and Finland, in which all participants completed personality questionnaires, and linked it to data collected in the national cancer registries of both countries.

For the analysis of the association with risk for cancer, data from both Sweden and Finland were used. It involved 59,548 individuals who had completed questionnaires and 4631 cases of cancer, with a maximum of 30 years follow-up.

For the analysis of the association with cancer survival, only data from Finland were used. It involved 2733 cancer cases and 1548 subsequent deaths, with a maximum of 29 years of follow-up.

Neither analysis found any association between extraversion or neuroticism and the risk for cancer at any site or the risk for death from cancer at any site.

“Our findings are in line with those of recent prospective studies, which provide no support for the hypothesis that personality traits are direct risk factors for cancer at all sites,” the researchers conclude.

They note, however, that their own study found a significant positive but very weak association between extraversion and neuroticism and the risk for lung cancer; this has also been seen in previous studies. They explain this by suggesting that this effect is mediated through smoking — people with a certain personality are more likely to smoke, increasing their risk for lung cancer.

The team also found a significant negative association between neuroticism and the risk for liver cancer, but they suggest that this might be a chance finding. There was no mediation by alcohol consumption, and the numbers were small, they add.

The editorialists discuss both of these findings, and agree that smoking might explain the increased risk for lung cancer, but “no plausible biological pathway can be mustered” to explain the reduced risk for liver cancer. “We might concede that both are due to chance, rather than embrace one finding but not the other,” they add.

Am J Epidemiol. 2010;172:377-385, 386-388.

Medscape Medical News © 2010 WebMD, LLC

Richter’s Transformation

We don’t quite know why or how it happens.  But in a certain percentage of patients, their erstwhile indolent CLL suddenly morphs into a far more aggressive disease, a fast growing and far more dangerous lymphoma.  The classical therapy for such patients used to be CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone).  Now the standard of care is R-CHOP (R for Rituxan).  There is a lot of clinical evidence that R-CHOP gets far better responses and remissions than plain old CHOP, making this scary transformation a lot less dangerous.

Nevertheless, for most patients this transformation comes as a totally unexpected bolt from the blue.  There is a growing concern that combination of alkylating agents and purine analogs (as in cyclophosphamide and fludarabine, for example) increase the risk of Richter’s transformation.  Some research published by M. D. Anderson raises the possibility that prior history of mononucleosis (“glandular fever”) may increase risk of subsequent Richter’s transformation.  There is still a lot of research that needs to be done before we can hope to understand all the underlying risk factors.

Many of you know Diane Mackinnon as our patient advocate on the FDA drug advisory panel.  She is also a dear friend of mine.  Last year she joined the ranks of CLL patients whose disease underwent Richter’s transformation. I am delighted to tell you Diane is doing well right now.  Below is her story.  We are all stronger when our members share their experiences with the rest of the patient community.    Please join me in wishing her continued good health.

                   Notes from a Richter’s Transformation Survivor

I have discussed my Richter’s transformation with Chaya extensively which lead to her suggestion that I write up my experience.  First I recommend reading her excellent overview of Richter’s transformation to provide context for my saga:

Background

At age 58 in 1997 I was diagnosed with stage 0 CLL and subsequently followed by an NIH study and a local hem-onc.  No history of mononucleosis or other EBV exposure.  I had a 13q deletion (good) but high cd38 and unmutated IgVH (not good).  My lymphocyte doubling time was about 13 months so within 5 years I needed treatment; marrow impacted, spleen enlarged, adenopathy, and blood counts, other than WBC at 256k, trending down. I was and continue to be under the care of Dr. Bruce Cheson at Lombardi Cancer Center, Washington DC.  1^st treatment was 6 cycles Fludara/Rituxan (FR) Jan 2003 which gave me a good nPR which lasted four years.  2^nd treatment, this time with a mediport for infusions and blood tests, was a repeat of FR which again gave me a good PR but not the sought after CR.  In 2009 I started periodic IVIG as IGg was falling below 300.  I was stable until October 2009 when my counts all crashed precipitously.  3^rd treatment was 6 cycles Bendamustine/Rituxan which was difficult each week after treatment (nausea and fatigue) but again provided a good PR after which I felt great.  Up until this point I had managed my disease and treatment with minimal impact on my husband (other than psychological) since being an independent cuss I prefer to do it myself.  That approach would soon become impossible.

Transformation onset

Spring of 2011 I experienced gastrointestinal upsets which were consistent with my history of Irritable Bowel Syndrome (IBS) but more troublesome.  I coincidently had a colonoscopy for which I was due; it came back clear.  I saw Dr. Cheson in May with no obvious problems.  In June I started to feel lousy, fatigue, periodic fevers, very bloated stomach, low appetite. It all happened rather quickly with my initial symptoms masked by my IBS problems.  Dr. Cheson advised going to the ER for admission.  They were quite responsive: Chest x-ray, CT scan abdomen, echo cardiogram, BMB, EKG, ultrasound of abdomen indicating greatly increased nodes and fluid drain of acites in abdomen.  Lots of blood tests of course with low platelets and high LDH.  Within 2 days the diagnosis was made of Richter’s transformation into aggressive Diffuse Large B Cell Lymphoma (DLBCL).  I knew that was a bad turn of events (survival 5-8 months) so I immediately agreed to the gold standard protocol of R-CHOP which was initiated on the third day.   

Treatment Cycle 1

I was inpatient for Cycle 1 on June 24, 2011.  I was given IV Rituxan, cyclophosphamide (cytoxan), vincristine (oncovin) and doxorubicin (adriamycin which is cardiotoxic)) on day 1 and oral prednisone for days 1-5.  I was also given a new drug rasbericase to help prevent Tumor Lysis Syndrome (TLS) as well as allopurinol and Claritin (as opposed to Benedryl to which I am over sensitive) premeds.  Those days in the hospital are a bit of a blur but I do remember 2 nights when I had hallucinations during which I could not tell dreams from reality for a few hours.  My husband visited daily, my daughter came after work each day and my son flew in from Boston for 4 days. I was finally discharged on June 27, day 4. I had to come back on day 5 outpatient for a Neulasta injection to control neutropenia. (Could not be done while I was hospitalized due to Medicare rules which allow only Neupogen for inpatient).  I was sent home with a variety of oral medications: allopurinol for TLS (2 times a day), prednisone for last cycle day, zofran for nausea every 8 hours, metroprolol to prevent hypertension, protonix to prevent ulcers, compazine for nausea every 6 hours, and percocet for pain (used seldom).  I was a walking pharmacy and felt awful. My son made up a spreadsheet for the medication schedule.  My children and husband were devoted but terrified caregivers.

July 1, I was back in the hospital with febrile (102F) neutropenia. Given neupogen injections and IV cefeprin antibiotic.  July 3 given 2 units red blood cells as hemoglobin was down to 7.5 and the addition of vancomycin antibiotic. Fever finally broke so I was discharged after yet another scary inpatient week.

2nd, 3rd and 4^th cycles

One day every three weeks were outpatient followed by Neulasta injection Day 2. I went in for blood tests each week. I was miserable most of the time, barely fighting off nausea/vomiting with two medications (Zofran and Compazine), impressive fatigue, loss of hair, weight loss of 15 pounds.  My daughter insisted on keeping me company on the infusion days.

Aug 31 – admitted via ER for high fever.  Given chest x-ray, EKG, 2 units red blood.  Continued spiking fever and neutropenia.  Given IV cefepine and vancomycin.  Sep 3 fever breaks but platelets were way down at 21.   Heard later that there was a high level of concern for my condition … me too. Platelets rebound enough to discharge me on Sep 6 with prescriptions for cefdinir at 300mg twice a day for 7 days and ciproflaxin at 500mg for 10 days.  There must have been no bacteria alive in me after that regimen.  Fortunately I did not get diarrhea or a yeast infection from all those antibiotics.

When I next saw Dr. Cheson he noted that I was seriously struggling with the regimen and that 2 more cycles with incremental gain were not worth the real risk to my health so we stopped after 4 cycles.  I was relieved to stop but of course also concerned that we had stopped short of the standard recommended 6 cycles.  CT scan showed marked improvement and BMB indicated no Richter’s in the marrow (it is in the lymph nodes and usually not in the marrow) with 30% CLL involvement.  Not clear how well I had responded.  As a hedge, I entered a clinical trial at Lombardi for both DLBCL (Richter’s transforms into this) and CLL patients.  I qualified on both counts.

In October my ENT discovered a sinus infection for which he prescribed Augmentin and nasal spray.   Cough which I had for months (nobody could hear any lung involvement) continued.  CT scan report mentioned something on right lung so I see my pulmonologist.  He takes a chest x-ray which he compares to a previous one.  Definite pneumonia diagnosis.  End up on 750mg Levaquin for 10 days then 5 days more before x-ray determined infiltrate was resolved.  Was almost hospitalized again but I resisted.  Note to patients to be forewarned:  only symptom was coughing, nobody ever could actually hear this pneumonia, no high fever, it was apparent only on the x-ray.

Clinical trial

Infusions of Rituxan and DCDT2980s experimental drug every 3 weeks. Neutropenia was the only bad side effect which was controlled by Neulasta.  My platelets took a bit of a hit but remained above 50 and rebounded each cycle.  An easy regimen all things considered.  After 8 cycles a CT scan indicated an increase in adenopathy, i.e. some disease progression, so I had to leave the trial in April.  Not clear what effect the trial drug had.  Good news was that a PET scan Feb 29,  requested by me with Dr. Cheson’s concurrence,  indicated no active DLBCL disease.  It would have been nice to have this test earlier but there may have been a medical reason to delay.

My nursing care at Georgetown University Hospital was excellent.  Since it is a teaching hospital I did have to deal with some inexperienced stressed out post residency fellows which was mainly just an annoyance.  That hospital has a terrific special unit (2 Bles) for immune compromised patients.  The unit is sealed off from the hospital with an airlock and has a special air filtration system; each patient has a single room with bath and a lower nurse to patient ratio.  All nurses on the unit are infusion certified and oncology trained.  Hospitals are by definition stressful, replete with miscommunication where nothing happens when or exactly how they tell you but at least everyone was pleasant, competent and concerned with my care.

So I seem to have dodged the Richter’s transformation bullet.  I have not bounced back to my pre-Richter’s level of energy and well being but Dr. Cheson was clearly pleased with the PET results.  I am functional on a day-to-day basis but cannot handle exertion such as hikes or much stair climbing.  I still have CLL which may need treatment again in the near future.  Will I have another Richter’s transformation?  I have not asked that question because I am certain nobody really knows.  Grueling as my experience was it ought to give hope to any other patient who has a Richter’s transformation. 

Changing names, ownerships

Just when you were getting used to CAL-101, it is time to re-file this drug under a new acronym.  Calistoga Pharmaceutical has been bought out, lock stock and barrel, by Gilead Sciences.  Rumor has it CAL-101 was considered one of the crown jewels.  With new ownership comes the new name, GS-1101.  No doubt they will have a much more sexy brand name once the drug gets FDA approval and available commercially.  In the meantime, don’t get confused by this proliferation of drug titles.  CAL-101 is the same exact thing as GS-1101.

Below is my review of the design of their latest clinical trial.  Results of the trial itself will not be available for many moons.  This article reviews the design of the trial, because I think there are a couple of details here that may trip up patient recruitment.  Earlier on, I had several serious concerns about the trial design and my review would have been quite a bit more negative.  Fortunately, the company was willing to discuss my concerns in a detailed phone conversation.  It is a little bit complicated and you really need to understand your options before you sign up, but now I believe this trial is worth considering if you fit the inclusion criteria and you are looking to participate in this kinase inhibitor trial.

Trial Design

You can read the official description of the trial by clicking on the link to the clinicaltrials.gov citation.  I strongly urge you to read it.  It has inclusion criteria, contact information etc. Right now they are recruiting at four centers in the USA, including the prestigious Long Island Jewish Hospital.

Basically, they want to recruit 160 patients.  These guys will be randomly assigned to either of two arms, 80 in each arm.  One arm will get 8 infusions of Rituxan over a 24 week period, along with 150mg of CAL-101 pill, to be taken twice daily.  The other arm will be the control arm.  These guys will get the 8 infusions of Rituxan too, but instead of CAL-101 pills they will get placebo pills for the duration of the 24 weeks.  So, it boils down to comparing CAL101 + Rituxan versus Rituxan alone.

As you can see below, the study wants to recruit pretty advanced CLL patients.

1. You must have been previously treated for CLL.  In other words, they do not want chemo virgins.
2. You must fit the criteria for needing therapy to control the CLL now.
3. They are looking to recruit patients whose disease is aggressive enough that they got only a short remission (less than 2 years) from their previous round of therapy.
4. Patients must have other health problems (co-morbidities) or sufficient bone marrow damage from prior therapies that they are not considered fit to undergo additional chemoimmunotherapy.
5. Patients should not be refractory to Rituxan.  (I wonder how they determine that?)

I will be the first to admit, this is going to be a pretty tough crowd.  That makes the trial design all the more important – as I attempt to explain below.

Late stage patients such as these guys do not have time to waste, their window of opportunity is rather limited and they need to be smart in their therapy choices.

The experimental arm (which uses CAL-101 + Rituxan) makes lots of sense.  As we have seen before, CAL-101 has the ability to flush CLL cells out of their comfortable and safe niches in the lymph nodes, where they are hard to reach and even harder to kill.  Patients treated with CAL-101 in earlier studies have seen remarkable and rapid shrinking of their swollen lymph nodes.  Of course, all those CLL cells driven out of the lymph nodes have to go somewhere and that somewhere is blood circulation.  A spike in peripheral blood lymphocyte counts (WBC, ALC) have been observed upon treatment with CAL-101.  This is not something that should freak you out.  It is not only expected, it is to be desired.  CLL cells out in open blood circulation are a lot more vulnerable and easier to kill.  Combining CAL-101 with Rituxan may give us the capability of (1) flushing out the CLL cells out of lymph nodes (2) killing them dead once they are out in the open.  This one-two punch is what makes this combination so interesting.  Incidentally, the new generation of kinase inhibitors such as CAL-101 and PCI-32765 do not seem to care about prognostic indicators.  In other words, even guys with poor prognostic indicators – including the dreaded 17p deletion – seem to respond nicely.

But since this is a two arm, randomized study, you do not have any guarantee that you will indeed end up in the CAL-101 + Rituxan arm.  You have a 50:50 chance of being placed in the control arm.  Patients in the control arm will get 8 infusions of Rituxan over a period of 24 weeks (6 months). The trial is also supposed to be “blind”, in the sense that the control arm folks will also get pills to swallow each day but in their case the pills are bogus – placebo pills.   I doubt the “blind” part of the trial will work out quite that way; I expect most patients will be able to tell whether or not they are getting CAL-101, based on how their nodes (and blood counts) behave. No shrinking of the nodes, no increase in blood lymphocyte counts means you are probably in the control arm.

I am willing to bet most patients will volunteer for this trial because they hope to be in the experimental arm.  It pays to be realistic.  Exactly half of you will be in the control arm.  As I discuss below in the editorial section, that poses some risks and questions.

As a single agent, Rituxan is not all that effective even under the best of circumstances (chemo naive and good prognosis patients) and it is not likely to do a whole heck of a lot for this crowd.  So, my concern prior to discussions with the company was simply this:  are the folks in the control arm being sacrificed with less than optimum treatment just so they serve as a reference point?  If that had been the case, I would have had real problems with this trial.  Why would anyone in the control arm hang around for 24 weeks if they experience disease progression while being treated with single agent Rituxan?  I hope you know by now, patients have an absolute right to walk out of any clinical trial, vote with their feet as it were.  I had visions of the researchers retaining most of their 80 patients in the experimental arm, while a large percentage of the control group dropped out of the trial.

As it turns out, there is an important loophole to finessing this dilemma. The company is also initiating a follow-on trial, an extension of this trial.  Here is the citation link to the extension trial.  Anyone in the original trial who is tolerating therapy but whose CLL progresses while being treated can switch over to this extension trial.  This too is a two arm trial, but everyone in it gets CAL-101.  The difference is that some of the patients will get the “standard” dose of 150mg twice daily, while others will get a heftier 300 mg twice daily.  In other words, the safety net for the control group folks is that if your CLL progresses while you are on single agent Rituxan, you can switch over to the extension trial and get put on CAL-101, without having to wait to complete the 8 infusions and the 24 week period.  Phew.  You can see why this is an important detail.

I have no doubt the results of this large scale and double arm trial will be of great importance in future FDA approval considerations.  If you decide to volunteer for this trial, my heartfelt thanks.  Your generosity and courage will pave the way for development of this and other kinase inhibitor drugs for other CLL patients.  But I want you to remember this:  informed consent means just that, your consent, after you are fully informed.  We do not yet know all the pros and cons of this new drug.  That is the whole point of doing this study, to learn more about it.  But there are other details that do impact your risk exposure and these are things you should know about. Volunteering without knowing what you are signing up for is a sucker’s game.  You may want to browse through my earlier articles on CAL-101 for additional details about this drug.  Much of the commentary below that I would like you to consider is my own layperson opinion.  As such, it is best presented under the editorial section.  I try hard to distinguish between official details and my own opinions, but sometimes the distinction is hard to make.

Editorial

Mini-Allo Stem Cell Transplants

Imagine if you are 75 years old, newly diagnosed with CLL.  And your oncologist told you that based on your prognostic indicators you have a life expectancy of 10 years or so.  NOT quite the death sentence, is it?  If indeed your oncologist’s crystal ball is perfectly clear and his guesstimate of how long you have to live is bang on target (between you and me, I would take such pronouncements with a very large pinch of salt – but then, I am a recently minted cynic) and you live to the ripe old age of 85, what is not to like?  The only guarantee we have is that each and every one of us will eventually die.  85 is not a shabby number of years to have spent in this world.

Now flip the scenario on its head.  What if you are in your early forties or fifties, with a whole lot of things to do and a lot of life to live?  What if the same incredibly wise oncologist read the tea-leaves and gave you a ten year life expectancy?  Aha. There is the rub. Dying before you can even hope to retire, dying before you get to see your children / grandchildren grow up, dying before you have a chance to do all the zillion things you told yourself you will do one day – now that has all the makings of a real tragedy.  CLL is definitely not a good cancer in this scenario.

Let us be very blunt.  As of today, we do not have a strictly curative drug therapy for CLL.  Curative as in really, truly curing you of CLL, once and for all.  Guys, that is why they call it an incurable cancer.  The only hope of curing CLL lies in something a lot more complicated than “simple” (duh!) drug therapies.  We are of course talking of a mini-allo stem cell transplant, where your buggy, cancerous immune system is yanked out by its roots, tossed into the garbage, and replaced by healthy stem cells from a well matched and willing donor.  The hope is that the new immune system will like its new home, grow roots and settle down, and start making all the various cells of your blood and immune function that will keep you alive for the rest of your natural life expectancy.  Since the new immune system is not corrupted by cancer, it has no love lost for CLL cells.  The new T-cells, neutrophils, macrophages etc go on a killing rampage, hunting down and killing any CLL cells lurking in your body with no mercy.  This is what we call “Graft-versus-Leukemia“, the magic that makes it possible for us to hope for a complete – and I mean complete – CURE.

Unfortunately, mini-allo stem cell transplants are anything but simple procedures.  There are many hurdles along the way.  First, there is the little problem of finding yourself a perfectly matched and willing adult donor.  Not as easy as you would think, if your parents forgot to give you lots of siblings since this is the first place you would look for a matched donor. If you are also an ethnic minority not well represented in the volunteer stem cell donor banks, your chances of finding a matched unrelated donor (“MUD”) are slim to zero.  I know all about that.  My husband PC was one such.  My man was undoubtedly one of a kind, but I thought he took this business of being unique a little too far.  We could not find a single matched adult donor for him in all the donor banks in the world.  In his case the only option was to use stem cells for umbilical cord blood – an experimental procedure with still high chances of mortality.  You can read all about his transplant journey in Harvey’s Journal.  Make sure you are feeling strong before you read it.  I promised the truth and the whole truth when I started that journal, and I spare no detail of the roller coaster emotional ride. I can no longer bear to visit that journal.

Last but by no means least, is the toxicity inherent in stem cell transplants.  True, “mini” allo transplants have reduced the mortality risk significantly, which is why they are considered kinder and gentler stem cell transplants, compared to the bad old days of full myeloablative stem cell transplants.  But another aspect of transplant morbidity still plagues us.  Graft-versus-Host Disease (GVHD) is the single biggest cause of sickness and death in post transplant patients.  In a nutshell, the new immune system is not quite used to its new home and cannot tell the difference between friend and foe.  Perfectly healthy cells (such as the cells of your skin, liver, or any other part of your body) can be attacked.  The picture is not pretty.  In an attempt to damp down this over-the-top immune function, transplant patients are frequently on immune suppressant drugs for quite  long time.  The other side of trying to control GVHD is that the patient is left vulnerable to opportunistic infections.  If it is not one thing, it is another.

So, transplant decisions are not easy ones to make.  I try to steer younger patients with high risk disease towards transplants, since they do not really have much of a chance of running out the clock by piece-meal and sequential therapy choices.  In high risk cases, all the bullets available are spent too soon for comfort and the patient faces massive loss in both quality and quantity of life. There is a school of thought that if a transplant is the way to go, it may be a good idea not to wait until the last bitter moment before making that decision.  You may run out of options, if you cut it too close.  Also, your body may no longer be able to handle the tough ride of a transplant, after going through every CLL drug therapy known to man.  Some day, transplants may get so safe that the decision can be made with less angst.  Or, newer and truly curative drugs may be discovered that make stem cell transplants unnecessary.  We can hope. But we are not there, yet.

With that rather wordy preamble, please allow me introduce you to Jane.  ”Jane” is not her real name, we try our best to protect the privacy of our members.  ”Harvey” was my husband’s pseudonym while he was alive, a salute to Jimmy Stewart’s wonderful movie of that title.  His privacy as a patient does not seem as important now, since he passed away – almost four years ago.  ”Jane” and I exchanged several emails, a couple of which are reproduced below to set the stage.  The story that follows is in Jane’s own words.  She tells me this is her “donation” to the cause, sharing her experiences so that others may learn from them.  I cannot think of a more generous gift.  I have kept my cotton pickin’ mitts off of her story, so that you can hear her “voice” and not mine. Please join me in giving her a nice hand of applause.

Since we are talking of happy endings, here is a totally unrelated happy ending of my own.  After suffering acute dog-withdrawal when my beloved Aussie Jasper passed away a couple of months ago, I accepted I was hopelessly addicted to dogs and got myself another Aussie.  Please say hello to “Buddy“, the new love of my life.  He is 11 weeks old, all energy and no sense, a one-puppy wrecking crew.  I could not be happier.

====================================================================================

Dear Chaya,

I still have this note you sent me two years ago, because I was so impressed with your gracious response. I did ultimately pursue the recommendation to undergo a stem cell transplant, which is why I am writing to you now.

Prior to and during the stem cell transplant process, I relied almost exclusively on the clltopics website (and my doctors at Mayo, of course) for learning everything I could. I purposely stayed away from the acor list and blogs because I really didn’t want any more detail on how miserable I could be, and it is human nature to want to write more about about the negatives.

Since I relied so heavily on clltopics for information, it was scary for me that while there were statistics from articles on good outcomes from sct, the only outcomes that are chronicled are tragic ones.If you think it would be appropriate and could be helpful, I would be happy to provide you with my journal about my sct process (attached) on clltopics. I am very aware that each person’s situation is unique, and I would be representative of only myself. I am also very aware that at only 15 months post-transplant, I am by no means “out of the woods”. But if you think it could be helpful, feel free to use this as another case study, but with a positive outcome.

Whether you choose to use this or not is certainly up to you, and my feelings won’t be hurt if you don’t. If nothing else, I hope you find this a day brightener for all the wonderful work you do.

Jane

On Tue, Apr 6, 2010 Chaya Venkat wrote:

Jane:

Thank you for writing, and thanks for the kind words about my efforts. CLL Topics and Updates survive and thrive only because of our grassroots support in the patient community. I hope soon you will feel comfortable participating in our discussions. In the meantime, you are doing exactly what I would do in you shoes – learn as much as you can about this disease.

Your family background is all too familiar to me. I am sorry you have an aggressive form of CLL. But given that, you have made wise choices in your medical team as well as frontline therapy. Mayo Clinic (Rochester, MN) is my favorite expert center. I know all the folks there very well and think very highly of them. Campath is one of the few drugs (along with Revlimid and flavopiridol – still an experimental drug) that are known to work on 17p deleted cases. At 54 you are very young to try and let the clock run out on this disease. When the time is right I hope you will explore the option of a mini-allo transplant with a suitably matched donor. We have a lot of articles on the subject both on Updates as well as our flagship website www.clltopics.org

If there is anything I can do to help you personally, please do not hesitate to write. Working one-on-one with our members is the best part of this “job” and at any given point in time I have dozens of patients that I try to help.

Best wishes,

Chaya

From: Jane

Sent: Tuesday, April 06, 2010 9:47 AM

To: Chaya Venkat

Subject: Re: [CLL Topics Updates] New Article: “Case History of a Relapsed CLL Patient”

Chaya,

I am a newly diagnosed (last Dec) SLL/CLL patient, and still too timid to post to your site, but do feel compelled to let you know how amazingly helpful your website is and how much I appreciate all your work on it.

I was stunned by this case history… I am a 54 yr female, Ashkenazi jewish descent, strong history of multiple cancers from both parents (my dad had cml leukemia, among other cancers, my one brother was diagnosed 2 yrs ago with follicular lymphoma)… I am currently in a trial at Mayo using Campath, pentostatin, and low-dose rituxan after I learned I have the 17p deletion…

I’m sure this is a story you are very familiar with, much more so than I am, as I try to come up to speed on as much as I can. Mostly, I just wanted you to know that there is one more person out here in cyber-land that very much appreciates your perspective, advocacy, and hard work you put into this site.

Thank you!

Jane

Jane’s Happy Ending 

(Fingers crossed!)

Background

January 1, 2011

Getting a stem cell transplant is a leap of faith. While it’s faith in science rather than religion, it’s still a leap of faith, and faith is not one of my strong suits…

Since being diagnosed with small lymphocytic lymphoma in December of 2009, I have felt almost completely fine and normal and certainly fully functional. With rapidly growing lymph nodes in my armpits which were a bit uncomfortable, a decision was made to start treatment in February 2010. At that time, FISH analysis was performed which showed I had 70% 17p-deleted SLL/CLL.  At that time, my local Minneapolis oncologist made contact with experts he knew from the University of MN and Mayo Clinic.

Dr. Clive Zent from Mayo responded to my local oncologist that he had a trial using pentostatin, alemtuzamab (Campath), small doses of rituxan three times / week (PAR), and GM-CSF, and his recommendation was to get me into a good remission and quickly into transplant. I headed to Mayo and started this protocol the end of March, 2010. I sailed through this regimen without much problem. (I developed fevers from the GM-CSF and possibly from Bactrim, so I was switched to GCSF and pentamadine. The fevers never recurred. Even though I tested CMV negative before the treatment started, I was still tested weekly for CMV throughout treatment and continued to be tested monthly until I was turned over to the transplant team.) I was able to be treated in Minneapolis for the three times / week Campath shots and Rituxan, with bi-weekly trips to Mayo. At the end of the 12 weeks of treatment, I was feeling good, and in August (two months after treatment was completed), was declared in “complete clinical remission”. I was not tested for MRD, as Dr. Zent felt that was not useful for me. But all palpable and abdominal lymph nodes were gone, and bone marrow was clean (had been 50% infiltrated).

[A side note: I am not a “normal” CLL case. The decision to treat me was based on my rapidly growing lymph nodes throughout my abdomen, groin, armpits, and neck, and infiltration of my bone marrow, and the fact that I was 70% 17p-deleted. All of my blood counts prior to and throughout all treatments have stayed in a “normal” range, and, as far as I can tell, the Rai and Binet stages do not apply to me(?).]

Going into my stem cell transplant, one of the things that made me most leery was that on the clltopics website, my main online information source, there were no case histories of good outcomes, only tragic ones. And it was hard to convince myself that I should not only voluntarily go make myself sick with the transplant, but the likelihood of ever feeling as good as I’d been feeling again was pretty slim, given the probability of GVHD.

My initial decision was to wait and closely monitor, and see how long this good remission lasted. I was aware that the possibility of this good a second remission would be lower, and I was healthiest now for transplant. I had no intention of going through multiple therapies for a long time and throwing away a good transplant opportunity. But, I just wasn’t willing (yet) to put an end to what felt like a normal, healthy life! I was aware of the studies which showed going into transplant healthy were so much more successful than “hail Mary’s”, but I wanted to just wait a little bit, and I just felt so darned good…

While the transplant doc I saw for consultation at the University of MN strongly recommended against this approach, Dr. Zent felt it was “reasonable” to closely monitor and use high-dose steroids if needed to get me ready for transplant, and that it wouldn’t greatly increase my transplant risk (my words, not his). So we agreed I would be closely monitored…

After my declaration of “complete clinical remission” at the end of June, I almost immediately developed an assortment of dermatitis’s with mildly itchy skin in various places, which were treated adequately with an assortment of steroid and anti-fungal creams, lotions, shampoo, etc. Dr. Zent attributed this to my recovering immune system being overly “frisky” and looking for something to attack.

At one of my dermatology visits to Mayo after my entire face had swollen up over night (diagnosed as hives), Dr. Zent saw me and found a palpable lymph node under my arm. When he saw me for my regular monthly visit a week later, it was bigger, and he found one under my other arm. This occurred in September – clearly NOT a durable remission! I decided at that time I really had no choice other than to go for a stem cell transplant, and questioned my decision to wait… Once the decision for transplant was made, (I had previously met with Dr. Hogan from the transplant team at Mayo), HDMP+Rituxan was scheduled for the following Monday, and a meeting with Dr. Hogan was scheduled. (As an aside, Dr. Hogan commented that it was probably a good thing that I did wait a little while for transplant, since my tumors returned so quickly and aggressively. I seemed to get a more durable remission from the HDMP+R than I had from the PAR.)

I again sailed through treatment, this time with five days of HDMP (1600mg/day!) and four weeks of regular dose Rituxan, and was again declared in “complete clinical remission”.

I just read the clltopics update, and I feel bad that I am unable to donate very much to support this website, which has been a godsend to me. The one thing I think is lacking on the site is a story of someone who goes through a mini-HSCT and has a good outcome! I keep checking back to Harvey’s Journal to get an idea of what I might expect, but I just can’t read to the end right now… Because of our medical expenses, I can’t give what I would like to the website. What I can “donate” to clltopics, is a good success story, and I hope (and dare plan?) to do that a year from now…

For now, I will document my experiences before they hopefully become fuzzy in my mind due to passing time…

Pre-Transplant

I only have one brother, and he was diagnosed with follicular lymphoma (he’s in stage 1 watch and wait), so obviously not a donor candidate. I was very lucky to have a MUD donor found relatively quickly. There was a big push by Dr. Hogan to get the transplant done before the Christmas and New Year holidays, so the process wasn’t prolonged. I had been scheduled to receive a second round of HDMP+R, but with the push for a quick transplant and my continuing good remission, the decision was made to forgo the treatment.

Dr. Hogan wanted the transplant scheduled for Dec 14^th, but the donor was unavailable that week, but was available the week before, so a scramble was on to get the pre-transplant evaluation done in a hurry. We headed back to Mayo on November 17^th to start a week of pre-transplant evaluation. (One thing I’ve learned is Mayo only wants to use fresh, not frozen stem cells, if at all possible. I’m sure it’s to eliminate all the infusion side-effects associated with the preservatives, but for whatever reason, it definitely makes scheduling a little more challenging!) I got through the pre-transplant evaluation, prodded and poked as never before, and was declared physically and mentally healthy.

Because my insurance requires the pre-transplant evaluation be complete before they will give final approval, we had a week “off” between pre-transplant evaluation and transplant. We headed home (which is at the edge of the Boundary Waters Canoe Area Wilderness, 3 miles from Canada, and almost 400 miles from Rochester) on the day before Thanksgiving.

We enjoyed an improvised, last minute Thanksgiving, and loved having a chance to be home again for a week. The following Tuesday, we “winterized” our house, which meant draining all the pipes and filling drains with anti-freeze, and moved anything that could possibly freeze into the basement, which we planned to keep at 40 degrees with electric baseboard heaters. It was very sad leaving the home that we loved, and we headed into the nearest town 40 miles away, where we were dropping off dog #1 with friends. (The absolute hardest part for me to this point was and is having to “re-home” our two Labrador retrievers – our only children – in “foster” homes for a few months!)

We got to our friends’ who were keeping the first dog, walked him into their house, and were saying our goodbyes, when my cell phone rang. It was Mayo clinic, telling me that my donor had failed final clearance! They did say I had a backup donor who was also a perfect match (!), and they would call in the next couple of days with some news…

We were definitely in a bit of shock as we took both dogs and headed back home, un-winterized the house, and settled in for a completely unknown period of time.

I got a call the next day that Dr. Hogan was pushing hard for a new transplant date of 12/20, and the donor was available to donate on that date. They put an “urgent” rush on getting the new donor’s final clearance. I got a call the next day that I was to be at Mayo on Dec 13^th. Unfortunately, the donor wouldn’t have final clearance until the 14^th. We just had to assume and hope all would be good.

We went through the house winterizing, dog drop-off routine again on the 11^th, got the other dog “re-homed” in Minneapolis on the 12^th, and headed to Mayo the morning of the 13^th. As we were pulling into Rochester, I got a call that my new donor was cleared.

The Transplant

The transplant conditioning (Fludarabine and low dose radiation) was mostly uneventful – just nerve-wracking because it was all unknowns to me – nothing I’d ever experienced before. It was the same kind of nerve-wracking as initiating treatment last March, or getting the HDMP in October.

I am totally happy with the people and care I’m receiving at Mayo, and would recommend them to anyone in my situation, but I do have one small complaint…  I learned that while reduced intensity conditioning (the mini in mini-allo) is the norm for HSCT for SLL/CLL, it’s not the norm in the BMT ward at Mayo. So we went through a lot of “education” and coaching and were told again and again how sick I would be by around Day 6, and that my neutrophils would be down to near zero. I hadn’t expected that from the research I’d done, and hadn’t expected it from talking with Dr. Hogan. But after umpteen nurses, dieticians, nurse practitioners, and physician’s assistants continually told us how sick I’d likely be, I gave up arguing with them and started to believe it. I may be the only patient they’ve had who began getting very worried because I was still feeling fine by Day 10…

One thing about Mayo is that they take total patient care very seriously, and whenever I expressed anxiety about anything, they would take it very seriously, and would explain to whatever level of detail we wanted and required exactly what was happening and why, until we were completely satisfied and my mind was at ease.

Mayo keeps transplant patients out of the hospital as much as possible. Their rationale is that in their experience, infection risk is no higher or more likely to occur outside of the hospital than in it. Plus, we were told that the infections that patients tend to acquire in the hospital tend to be the nastier variety. One of the doctors also told us they do it to be “mean”:  He said one of the best things for transplant patients is to have them be up and moving around, and by keeping patients as outpatients, that forces us to get up in the morning, get dressed and go through normal morning routines, get to the hospital, walk the block or more in the tunnels of the Mayo complex to the hospital… I’d already figured that part out, and am not minding at all that I need to live a more “normal” life.

I was in the hospital for three days prior to transplant for IV tacrolimus (what Mayo uses instead of cyclosporine), and getting motivated to get out of bed and walk the halls of the hospital with an IV pole was not easy… Where I’m staying in Rochester, getting up and out of our room is a necessity, so I am much more active than I’d be in the hospital.

My transplant was scheduled on Dec. 20^th, and that was the day for stem cell donation. It was also the day another Winter Storm Warning was forecast for Rochester. The nurses all assured me the stem cells would get here, but I spent a fair amount of the day on my pc, watching the weather and checking the Rochester Airport for cancellations and delays… The stem cells were scheduled to arrive at 10:30 that night. The next day I learned that all the nurses also kept checking the airport info online.

The stem cells arrived at 10 p.m. on Dec. 20^th. Several nurses were unable to report in because of the snow, so one of the nurses who was scheduled to leave planned to stay with me and my new stem cells until someone else could come in. The actual transplant occurred at 2 a.m., and I mostly slept. As others have said, it was a non-event. I was released from the hospital on 12/21/2010, Day 0.

The only hiccup between then and now was a small hole discovered in my Hickman catheter, so the catheter had to be replaced. I was in a bit of a panic about that, both due to my very high infection risk, and because the first one was sore for a few days. I was afraid, in my weakened state, it would hurt more, be slower to heal, and I’m not allowed to take Tylenol because of the possibility of it masking fever… Again, a nurse practitioner spent an hour explaining the replacement procedure, which is less invasive than putting in a new line, and addressing all my concerns about infection risk and pain. The line was replaced last Monday, and hasn’t been a problem…

That brings me to today: Day 11, 1/1/11. I’m not much of a believer in omens, but the binary-looking date looks like it should have some significance, though I have no idea what…

Everything is still fine. I feel OK except I feel like I’m getting a cold. (I was told as long as the nasal mucous is clear and I don’t have a fever, it’s not unusual and they don’t worry about it.)  My blood counts seem to have bottomed out and may be starting to rise? My neutrophils never went below 0.9, which necessitated another long explanation from the doctor as to how the new stem cells are surviving if my own blood counts never went as low as I thought they would. (The explanation was that the chemo/radiation was still killing off “my” stem cells, and what was showing in the counts was remaining blood cells that hadn’t died off yet, most likely not new ones produced by “my” old stem cells…) As long as he was happy with how I was progressing, I chose not to question it anymore.

I feel like getting a stem cell transplant is a little like a very prolonged, ultra-slow motion surgery. I feel pretty good, and there are times when I’d just like to say I changed my mind, I want to go home now… But it’s like I’m in the middle of surgery with my insides lying all over the table and there’s no turning back…. We were told that the standard protocol is to check for chimerism at Day 30, so we wait, hope nothing bad happens along the way, and try to just appreciate feeling good!

Day 15:

So far, the only really bad thing I’ve experienced was what felt like horrendous menstrual cramps last night. I’m peri-menopausal, so that could have been the case. The problem was the restriction that I not take any pain meds that might mask a fever related to infection. I called the BMT ward last night, told them my temp. was 96.3, and asked if I could take Tylenol. I took 2 Tylenol plus 1 ibuprofen (with permission) and was fine and asleep by midnight.

All my blood counts dropped today. Neutrophils down a point to 1.6, hemoglobin down to 9.6, and platelets below normal for the first time to 130. I’m a little nervous, but waiting to see what the next couple of days bring.

Day 18:

Here’s the email update I sent to family and friends this morning:

I’m still doing OK, and we “graduated” from the BMT outpatient ward of the hospital over to the clinic yesterday, where we met with my transplant doc. The good news is that I’m progressing quite nicely. The tedious news (nothing bad, just tedious) is that my neutrophil count seems to be plateauing or heading down a little bit. Dr. Hogan explained that that’s what he would expect to see, and he wouldn’t be surprised if the count keeps going down for a while before heading up, and I’m still at risk of becoming neutropenic. He did say they won’t check for chimerism until day 28 or 30, because the results before that aren’t very reliable, and will likely result in discouragement without any reason to be discouraged. In the meantime, we’re only going into the clinic twice a week now for blood checks, I can relax my restricted diet a bit, and brush and floss normally! All good stuff…

Dr. Hogan definitely wants us staying in Rochester – i.e. not staying in Mpls and driving down twice a week. We’re talking about starting to look for an apartment or townhouse in Rochester, one that would allow dogs(!) We’re not planning on making any sudden moves until my white counts turn the corner and start heading up again, but we’re getting anxious for that to happen :-) The transplant house is very lovely and nice and provides a very supportive environment, but I’m looking forward to being able to snack while watching t.v. without my mask on :-)

While we don’t have another appointment until Monday, we are heading back to the BMT ward this morning so John can learn how to flush my Hickman catheter, which needs to be done daily. As long as I was going in everyday, we weren’t responsible for that, but now John will have to do it. It doesn’t look like a big deal, just one more thing that needs to be tended to.

Other than that, we’re still in thumb-twiddling mode, waiting for counts to head up and be otherwise boring. I can’t believe we’ve been in Rochester for almost four weeks!  Definitely a simultaneous feeling of not believing I’ve been here that long and it seems like we’ve been here forever…

That pretty much says it all. Except the truth is, we’re both starting to go pretty stir crazy. I’m really happy I’m progressing as well as I am and feeling as good as I am. But I think this is really the hard part. I’ve always considered myself a very patient person, but “watch and wait” has never been this hard before…

January 21, 2011 – Day 31

A couple of highlights from the past couple of weeks:

First, a decision was made to check for chimerism a week early. We were surprised by that, and when we met with Dr. Hogan after the fact and asked why it was ordered early, he sort of waffled and it sounded to us like it was a miscommunication and he did not really want it done that early. We did find out yesterday that the results were “aberrant”. Dr. Hogan said the results showed my cells, my donor cells, and a third set of cells! (I jokingly asked if I was part alien?) He said that since they’d never seen this before, they were just going to throw out the whole thing and do another test when I go in for my blood draw next Tuesday. Only if it still shows those results will they start working on figuring out what’s going on….

The second incident of note was that last Monday my hemoglobin dropped to 7.9. I was barely able to function as I was so weak and tired, so was relieved they ordered a red blood transfusion for that afternoon, my first ever. At the end of the two units of blood, my blood pressure, which is normally 110/70, shot up to 187/90. My chest was tight, I was having a hard time catching my breath, and couldn’t get comfortable. The infusion center paged the emergency response team, where they determined my heart and lungs were fine, and my blood pressure was starting to drop back down. There was blood in my urine and diarrhea however. Even though I was improving, they sent me to the ER at St. Mary’s hospital, where I was continually monitored and gradually improved. They sent me back to Methodist hospital to spend the night for observation. By Tuesday, I was weak and tired, but basically back to normal. The lab was unable to track down a reason for a hemolytic reaction, so their diagnosis was “probable overload”. When we met with Dr. Hogan yesterday, he said he wasn’t convinced that that was the entire story based on the physical reactions I had, and thought there may have been a combination of overload and some obscure antibody or something in the blood that my system didn’t like. Hopefully I will not need another transfusion. My hemoglobin is back up to 9.0, so I obviously was able to process at least some of the two units I received. According to Dr. Hogan, at this point in the process, my hemoglobin may level off, or may drop again…

My neutrophils are back up to 1.8, after dropping to 0.79 (a new low) on Day 20. When asked if neutrophils should have leveled off and start heading up by now, we were told that for my protocol, there is no normal at this point. They may still go down again or may not. So we are back to watch and wait…

January 29, 2011  Day 39

My hemoglobin has stayed up above 9 so far, so at least I don’t have to worry about more transfusions for a while anyway. My blood is only being checked weekly now, but based on my energy level, I feel like it’s staying reasonably high enough. Unfortunately, I’ve developed a bad case of frequent, watery diarrhea, and was diagnosed with c.diff. a couple of days ago. The only symptom is the diarrhea – no nausea, fevers, or otherwise feeling unwell, so that part’s good. But add 6 flagyl tablets to my daily meds…

My biggest problem right now is that I’m going stir-crazy – especially because I’m feeling so well. I’ve always been very independent and come and go as I please. It’s really starting to bug me that I can’t just hop in my car and go shopping or driving around or whatever. I go for walks outside, but it is mid-winter in Minnesota, so that’s somewhat limited. While I love being with my husband, who’s doing an amazing job as my caregiver, I just want to have time on my own again – and not just in the apartment! It’s really starting to get me down… hopefully when we bring one of our dogs down to Rochester my mental health will improve. But I hate the forced dependence. I keep trying to remind myself that the good news is, if I wasn’t feeling as well as I am, this wouldn’t be a problem, so I try to stay positive with that…

February 11, 2011  Day 52

Not much has happened with me, though the past week has been a whirlwind…

I had another blood transfusion last Thursday, after my hemoglobin fell back to 8.0. It went just fine with the help of Benadryl and Tylenol premeds, plus the Ativan I took to calm my nerves about it… A couple of magnesium infusions, since that level just won’t stay up, and I’ve been dealing with a bad case of diarrhea so they don’t want me to take more magnesium pills. I also had a mild bout of c. diff., which tested negative after a 10 day course of flagyl. Hopefully that will stay away…

Last weekend we were given permission to spend the weekend at our house in Minneapolis. We were dragging and reluctant to go, just to spend two days somewhere else. But it was a mental godsend. I got to feel healthy and relatively normal. I even could drive myself to do some grocery shopping, which felt great.

We picked up our dog that was staying in Mpls and brought him back with us. Unfortunately, on the way back to Rochester, we learned that our dog that was staying with friends up north was diagnosed with bone cancer, was in severe pain, and should be euthanized. We went back to Mpls on Weds and picked him up. We were able to spend the night and next morning with him before taking him in to end his pain. Coming back to Rochester felt surreal. We have no memories of our dog being in Rochester, but I keep wanting to call his foster home up north and see how he’s doing…

I’m being good about going through the motions of taking all my meds at the right time, eating when I’m supposed to, and taking Benadryl so I can sleep at night. With all the pills I’m taking, I wish there was one they could prescribe for a broken heart…

We got the results of my chimerism test today, and like much about me, the results were “weird”. Dr. Hogan said he’s not concerned; that there’s definitely some level of engraftment though he can’t be sure how much, and my blood counts are all doing very well. My neutrophils are back into normal range and my hemoglobin is up to 11.8, so all is good that way. He gave us permission to move back to Mpls and make the weekly 2 hr. commute to Rochester once per week. Moving back north is still out of the question until after Day 100, but just being in Mpls. feels like huge progress. It will be a very bittersweet homecoming with Eddie gone from our house, but it will be a win none-the-less, and I think will actually help us through the process of losing him. Of course, I wish he would be there so we could be our happy two-dog family once again, but it’s just not to be.

So overall, everything with me is good, except for a broken heart….

Friday, March 4 Update Day 73 (from emails to family and friends):

Sorry I haven’t sent any updates for awhile, but nothing really to report – which is a good thing. We’ve settled into living in Mpls, and counting days until we can go north. Day 100 is March 31st, which is in sight, so I’m getting antsy to get north! Sounds like quite a few tests at that point, so I’ll probably head north early in April.

I’ve been feeling good. I had an early bone marrow biopsy last Tuesday. It’s normally done around day 100, but because my chimerism tests have been so “weird”, they wanted to check and make sure everything is good, because they don’t have a good sense of how much I’ve engrafted. We saw the doctor today and the bone marrow and blood tests showed no sign of CLL/SLL, which is what we hoped for! Unfortunately, they didn’t shed any new light on engraftment, so we just have to go with “all appears good” without an official test to confirm it. (The Mayo labs are still working on my chimerism test DNA, and if they ever do figure it out, it’ll probably end up as a case study somewhere…) Also, still no signs of GVHD, which I certainly appreciate. I’m weaning off of one of the anti-rejection drugs, but still on another one full strength, which is likely keeping any possible GVHD in check at this point.

My blood counts are dropping again, but the doctor didn’t seem concerned about that. He said that it’s pretty normal with reduced intensity conditioning transplants for CLL. So it feels a little discouraging, but not so bad… My hemoglobin is still dropping without transfusions, but I’m not quite low enough to require another one quite yet. I did ask and if needed, I can have that done in Mpls, so that would be a lot more convenient, since it takes around 6 hours.

March 25, 2011 Day 94

Today was Mayo day, and we’ve been in countdown mode – one more week…

My blood counts were pretty much the same as they’ve been for the past several weeks: hemoglobin low (8.5) but not enough to need a transfusion; white counts low – but not enough that the doctor seems overly concerned. We got the chimerism results and they still show 50% me and 50% donor – lower than they want to see at this point, but no lower than they’ve been…

The doctor came in and said that we were “close enough” to Day 100 and said we could go home and come back in two weeks!! I still get teary thinking about it :-) They will continue to do chimerism tests monthly and monitor engraftment percentages closely. They really want to see 100% donor, and if the per cent starts to trend down instead of up, they will consider giving me more donor cells. Dr. Hogan explained that their studies show that to combat CLL, 50-50 is not good enough… But at this point, I feel great and they will just monitor closely. I’m almost off of one anti-rejection/anti-gvhd drug (cellcept), and will now start slowly tapering off the other one (tacrolimus). They want to see what happens to the donor cells and watch out for possible GVHD as I get off these drugs.

In the meantime, this news caught us a bit by surprise, so we’ll still be in Mpls another week doing all that we need to do before moving back, but I’m still overwhelmed by the freedom of being allowed to leave – both elated and a little nervous…

April 23, 2011 Day 123

From my email to family and friends:

I haven’t been sending any updates because not much has been happening and all is progressing well, for the most part. You’ve probably noticed by now that a stem cell transplant is not at all like a solid organ transplant. Instead of a surgical procedure that you heal from, a stem cell transplant is a “process” that continues for a long time… But I’ve been getting lots of questions and again can’t remember what I’ve said to whom, so here’s all the news since my update a month or so ago…

As planned, I headed north on March 31st, Day 100. John went the day before to warm up the house and clean, and when I got there it was heaven!! There was still two feet of snow on the ground, and when I got inside, there was a Christmas card sitting on the dining room table where we’d left it when we left on December 12. I felt like I hadn’t really been gone and Christmas was right around the corner :-) Very surreal… It was very easy to quickly get back into normal life at home up north!

We went back to Mayo the following week for my bi-weekly check-in. That was my “official” Day 100 check (even though it was Day 108), and I had nine or so appointments, starting at 7:45 a.m. with pulmonary function test, followed by bone density scan, chest xray, ct/scan, and I can’t remember what all else. Then my normal blood draws and bmt doctor visits, and finally, when all checked out good and I was pronounced “ok”, removal of my Hickman catheter at 4:15. They’d done a bone marrow biopsy a few weeks early so didn’t need to do that again. It was one very exhausting day, but really good, with no signs of cancer. My blood counts all seemed to have plateaued at a low level, but not low enough to cause much concern.

I’m tapering off my last anti-rejection drug (tacrolimus), they’re looking for how that affects all my other blood levels, looking for signs of GVHD, and they’re doing monthly chimerism tests since I’m not at 100% donor.

Anyway, it was a quick weekend down then back north. A few days later, we got a call from Mayo that my latest chimerism test was down to 30% donor cells, which caught us off guard. I guess we were expecting them to hang out around 50% for the foreseeable future, since nothing else was changing. That’s what the doctor said he expected. But since the drop to 30%, they wanted to do another chimerism test before I came back, to do a test with finer detail. (I think, though am not positive, that the 30% was the blood chimerism that Mayo does in their lab. The chimerism “sort”, which checks specifically for T cells – the most important ones for the transplant, is what they send out to Seattle and takes a week or two for results.) So they mailed a kit to me up north, so I could bring it into the local clinic and have them send it back to Mayo. They really want to see close to 100% donor cells by now, so we’re definitely nervous about the possibility of the new cells being rejected…

After a couple weeks up north, we were back in Mpls this week, with our bi-weekly Mayo trip yesterday. Overall, it was good. We’re still waiting on the results of the latest chimerism test that was drawn in the local clinic and mailed back to Mayo last week. Yesterday they drew blood for another chimerism test while we were there, since there’s a couple weeks lag time for results. (It was pretty exciting to get poked for a blood draw like a normal person, instead of getting blood through my central line! I’m sure that novelty will wear off fast, but it was nice…)

What we did learn yesterday was that my hemoglobin was up to 9.5 – it had been hanging around 8.5 for several weeks, so that was really good news. My white counts were also up a bit. The doctor was encouraged that that was due to the donor cells kicking in. He was very clear that he does not want to prematurely infuse more donor cells if they aren’t absolutely needed, because of the increased possibility of bad graft vs host disease. As he said, even if the graft goes to zero, we can deal with that. Once the new cells are there, if I do get bad GVHD, they can’t remove the new cells and GVHD can be really hard to treat. So he sounded like he wanted to be very conservative and go slow and see what happens, which makes a lot of sense to me. He did say, it’s not impossible, but highly unlikely that my increased blood counts are due to my old cells kicking in – chances are the new cells are kicking in as I’m tapering off the anti-rejection drugs, so he’s remaining optimistic that all is good until he sees otherwise.

The bottom line is, I’m feeling great and all is ok until we hear otherwise :-) Just like the last several months have been, an exercise in patience while we wait and see what happens. As long as I’m feeling good, I’ll take it and enjoy being up north, which is where I’m headed tomorrow morning :-)

From my email to family and friends, Thursday, June 16, 2011:

It’s been almost two months(!) since I’ve sent an update, and you can assume that no news is good news… I don’t have bad news to share at this point, just iffy….?

I’ve been on 4-6 weeks between visits to Mayo, with weekly blood draws in our local clinic. We even took a “mini” vacation to St Louis to see the Cubs play baseball.

Last week I was at Mayo where I got a basal cell skin cancer removed from my scalp on Tuesday (a mere annoyance in the scheme of things!) and my regular transplant follow-up visit on Weds. My blood counts were markedly down from just the previous week, so with a little trepidation, drove back home up north on Friday… John was called out for work in Arizona, so I was home alone.

Anyway, I got my blood tested in our local clinic again on Monday, and my hemoglobin was down to 8.6 and neutrophils down to 0.4. Definitely neutropenic and at high risk of infection… again! My neutrophils are now lower than they ever became post-transplant… I stopped my last anti-rejection drug the week before, and got to be off all food restrictions, mask wearing, etc., for four whole days! I did get to eat lox and bagels, and had a big salad for dinner before the food restrictions were back on :-)

After chatting with one of my nurse coordinators at Mayo, I reluctantly agreed it was prudent for me to be in Mpls. with my high infection risk, rather than hanging out by myself out in the boonies, over an hour away by ambulance from our basic community hospital. So on Tuesday, my dog and I headed back down to Mpls, where we have close-by neighbors and quicker access to emergency medical care if needed – which hopefully it won’t be…

The fear with my blood counts crashing is that I may be rejecting the new donor cells now that I’m off the anti-rejection drugs. My doctor has said that he’s also seen blood counts go way down as the new cells take over, so that’s still a possibility. I just received results of peripheral blood chimerism which is showing I’m still 40% donor, so I take that as a guardedly positive thing…?  I’m still waiting to see if I get results from the sort chimerism that checks for t-cell donor %, and is more significant. Sometimes I can get results and sometimes I can’t… :-) And, blood tests last week show my cancer is still in remission. Dr. Hogan sounded fairly certain that that’s the effect from the transplant itself, rather than the pre-transplant chemo and radiation. Another positive…

In the mean time, I still feel basically fine, just a little less energy with the low hemoglobin. Just back in my “sort of bubble” to try to not get sick… As the doc said, yes, discouraging, but not disastrous… I’ll still get weekly blood tests, now in Mpls, will head back to Mayo for follow-up after the 4th of July, and still waiting to see what happens next…. I don’t remember hearing that one of the most important requirements for getting a stem cell transplant is patience…

From Email,  Monday, June 20, 2011:

Quick Update… good news…

Today’s lab work shows my counts have all jumped up back to “safe” range! I’m not sure I trust them quite yet… I’ll feel better after a repeat showing in another week. In the meantime, I was told it was now ok to go home back north, but will stay in Mpls for a few more days to do routine doctor appointments and get the garage door fixed. I feel a little whip-sawed… I was just starting to get used to food restrictions and mask wearing again, and suddenly it’s determined they’re not needed. We’ll see…. :-)

Oh, and another chimerism test that came back “non-diagnostic”… Sigh… Dr. Hogan wants to try it again and will send me a kit. At least he’s persistent! My current dilemma is which address to use for them to mail the kit…

From Email,  Monday, June 27, 2011:

Another quick update with good news…
Weekly blood tests in the local clinic this morning resulted in my counts being even higher than last week. I was pretty nervous waiting for the results, since I wasn’t convinced that last week’s uptick hadn’t been an anomaly.

Still waiting to see what happens next, but for now at least, doing the waiting in a better mood :-)

From Email,  7/13/11: All, or at least mostly, good news…

My bloods counts have continued to rise, and are now within sight of “normal” ranges. Chimerism results are still “non-diagnostic” – Dr. Hogan is clearly getting annoyed with them and is trying to get the lab to double-check the donor sample. He’s not optimistic that will get anywhere because of donor confidentiality and inability to get another sample… But, all appears good, so he said to assume that it is until we learn anything to the contrary.

The plan moving forward is to check my blood bi-weekly for a month, then monthly. I don’t have to return to Mayo for “2-3 months”!! At that time, they’ll do another ct/scan to check my remission status.

So for now, all is good. Assume no news is good news…

And, not emailed:

My fatigue seems to be getting worse instead of better. I think that may be because I feel “fine” so expect to be able to keep going at the same pace I did pre-transplant. Last Weds. I spent 10 hours in Rochester at appointments and visiting friends. After getting back to Mpls. at 8:00, had to go grocery shopping for my trip back north the next day. I was so exhausted I was in bed by 9:30. I had to push getting up Thursday morning, to get to a meeting at 9:30, prior to the 7 hour trip north.

Duluth is the halfway point on the drive, and I stopped to visit a friend in the hospital there. Looking for a shady place to park because I had my dog with me and it was hot out, ended up hitting a parked car! I’m sure it was because I was so over-tired, and should have waited a day to head back north.

I’m also experiencing “chemo-brain”, which I mostly laugh off, but is starting to get to me. (Between chemo-brain and peri-menopause, my brain has turned to mush!) But I’m nervous that was a contributing factor in my accident also. I’m trying to stay up-beat, but I think the stress of waiting to see what happens due to the lack of chimerism information, combined with my other cognitive issues, is definitely starting to get me down. I need to remind myself that I’m still only six and a half months post-transplant, and I need to pace myself and keep from getting over-tired.

Saturday, July 16, 2011

I think I’m finally starting to feel caught up as far as not as tired. I just think I was over-did it and it took almost a week. I definitely need to learn to pace myself….

Thursday, October 06, 2011

Yesterday was my three month follow-up at Mayo. I’m definitely feeling better – no longer counting “days post-transplant”. It’s approximately nine and a half months since I got my stem cells.

I was nervous getting the ct/scan… Dr. Hogan has completely given up on chimerism testing for me. I haven’t had any palpable lymph nodes that I could find, so was “cautiously optimistic” but definitely not convinced I was cancer-free. The ct/scan came back negative for any sign of enlarged nodes!! Dr. Hogan is convinced I’m engrafted, missing chimerism test results notwithstanding. My blood counts are mostly in the normal range – hemoglobin was down to 10.4 and lymphocytes are still only up to 0.9. But other counts, and liver and kidney function are all totally normal.

In addition to my usual appointment with Dr. Hogan, I saw Dr. Zent for the first time since last fall. When I saw him last, he said, “see you in a year…”. What was left unspoken was, “if I make it that long…”. It was so good to see him yesterday, I wanted to cry. And I know it made him happy to see how well I was doing… He did thank me and mentioned that I was a “pioneer” for getting PAR followed by HDMP/R to achieve a really good remission prior to transplant. Nice to know I could help :-)

My energy level has been improving and my chemo brain has been resolving a bit. As long as I walk at least a mile a day, I have reasonable energy. Last week, I went on longer hikes a couple of days. Hiking trails over rocks, roots, and up and down hills is a lot more work than walking along a dirt road, and it was work. But I accomplished a 2 mile trail hike on Tuesday, and a 3 mile hike on Friday. Dr. Zent smiled and said, “I’ll put you down as performance level 0…”. Life is good!

Tomorrow is Yom Kippur eve. It is the day that God seals the entries in the “Book of Life” for the coming year. “Who will live and who will die…” Last year this was especially poignant for me, knowing I was heading to transplant. I feel so lucky and blessed that I’ve made it IN GOOD HEALTH to this time.

L’ Shana Tova.

Saturday, March 31, 2012, fifteen months post-transplant

I have remained remarkably well and healthy. Some very minor GVHD experienced mostly as dry mouth and dry eyes, which have mostly resolved. I did go through a period of not being able to eat any food that was the least bit spicy, but after a course a dexamethasone mouth wash, that has mostly gone away. Now, I use biotene toothpaste and drink a lot of water, and that’s about it. I continue on penicillin and valacyclovir prophylaxis, but am off all other meds. My energy is almost back to normal. If I get over-exhausted, it does take several days to recover, and I find I now need 9 – 10 hours of sleep at night.  There are no side effects that I can’t easily live with.

I never was able to get a conclusive chimerism test, and they’ve given up trying. Dr. Hogan describes this as akin to losing an instrument on an airplane. The pilot can see that everything is fine, but it would be nice to have the reassurance of a conclusive test. In other words, as long as everything is fine, don’t worry about it! The thought that GVHD, relapse, other cancers, and who knows what all else can crop up at any time always remains in the back of my mind. The positive side of this is that I’m able (often – not always) to use this knowledge to help me appreciate life and try to make the most of each day. At the age of 56 and after 20 years off and on in a graduate program, I will be getting my Ph.D. next month. For now, I am more concerned about politics, the threat of wildfire, and what to cook for dinner, than I am about any health issues…

We will be discussing two separate but related articles today.  The first is a detailed assessment of skin cancer risk in CLL patients.  The second is an intriguing paper that links Vitamin A supplementation to reduced risk of aggressive melanoma.  I am sure this is not the last word on the subject and I do not want you to rush out and take massive amounts of Vitamin A without consulting your physicians.  But anything that gives a bit more protection to our guys and reduces the risk of having to fight a two front war with CLL and skin cancer is definitely worth a second look.

Expert Review: Skin Cancer Risk in CLL Patients

In case you were a skeptic, here is a detailed “Best Practices” article from no less than the Mayo Clinic that talks about skin cancer in CLL patients.  There is no doubt our guys are more at risk of skin cancer.  And garden variety squamous cell carcinoma (SCC), basal cell carcinoma (BCC) are more likely to be aggressive in immune compromised patients (read, CLL patients) and therefore require more extensive Moh’s surgery.  The Mayo article goes beyond that and discusses the impact of malignant melanoma (MM) and Merkel Cell Carcinoma (MCC)  (see image alongside) on overall survival in CLL patients.  As you would expect, it is not a good idea to have to fight melanoma or merkel cell carcinoma, while you are also struggling with the “good” CLL cancer.

Merkel Cell Carcinoma

Since Merkel cell carcinoma may be a new one to some of you, it may be worthwhile to get some details about this form of skin cancer.

• Merkel cell carcinoma is often observed as a fast-growing, painless nodule on your skin. The nodule is often shiny and may be skin colored or shades of red, blue or purple.
• The majority of Merkel cell carcinomas appear on skin surfaces frequently exposed to UV radiation (sun exposure, tanning beds etc) but they can develop anywhere on your body, even on areas where the sun don’t shine.
• People with weakened immune systems — such as those with CLL, HIV infection or those taking drugs that suppress the immune system — are at increased risk of Merkel cell carcinoma.
• Other risk factors are: people with pale skin, older individuals (risk increases after 50, though even younger people can get it), those that have already had basal cell or squamous cell carcinoma.
• Merkel cell carcinoma has a nasty habit of metastasizing quickly, even while it is under treatment.  often, it travel first to nearby lymph nodes and then may spread to your liver, bone, lungs or brain.
• Recently, it has been shown that Merkel cell carcinoma may be triggered by a virus, the Merkel cell polyomavirus.  As immune compromised people, CLL patients are more at risk of all sorts of viral infections, including this polyomavirus.  Here is the link to a detailed article discussing MCC and viral connections.

Below is the abstract from Mayo.  If skin cancer is something you worry about (and in my humble opinion every CLL patient should be aware of increased skin cancer risk), the full length article is something you should read and file away for future reference.  Send me a personal email and I will help you locate it.

J Clin Oncol. 2012 Feb 21. [Epub ahead of print]

Chronic Lymphocytic Leukemia Is Associated With Decreased Survival of Patients With Malignant Melanoma and Merkel Cell Carcinoma in a SEER Population-Based Study.

Brewer JD, Shanafelt TD, Otley CC, Roenigk RK, Cerhan JR, Kay NE, Weaver AL, Call TG.

Mayo Clinic, Rochester, MN.

PURPOSE: To delineate outcomes of malignant melanoma (MM) and Merkel cell carcinoma (MCC) in patients with chronic lymphocytic leukemia (CLL) or non-Hodgkin’s lymphoma (NHL).

PATIENTS AND METHODS: We identified patients with MM or MCC reported to the Surveillance, Epidemiology, and End Results program and analyzed the effects of history of CLL/NHL on overall (OS) and cause-specific survival after MM or MCC. Expected survival was derived from patients with MM or MCC without CLL/NHL.

Results: From 1990 to 2006, 212,245 patients with MM and 3,613 patients with MCC were identified, of whom 1,246 with MM and 90 with MCC had a prior diagnosis of CLL/NHL. Patients with MM and a history of CLL/NHL had worse-than-expected OS as measured by standardized mortality ratio (SMR; SMR for CLL, 2.6; 95% CI, 2.3 to 3.0; SMR for NHL, 2.3; 95% CI, 2.1 to 2.6). MM cause-specific survival was worse than expected for patients with a history of CLL (SMR, 2.8; 95% CI, 2.2 to 3.4) or NHL (SMR, 2.1; 95% CI, 1.7 to 2.6). Among patients with MCC, OS was worse than expected for those with a history of CLL (SMR, 3.1; 95% CI, 2.2 to 4.3) or NHL (SMR, 1.9; 95% CI, 1.3 to 2.8). MCC cause-specific survival was worse than expected for patients with a history of CLL (SMR, 3.8; 95% CI, 2.5 to 5.9), but no difference was observed for NHL (SMR, 0.9; 95% CI, 0.4 to 2.1).

CONCLUSION: Patients with CLL before diagnosis of MM or MCC have significantly worse OS and MM or MCC cause-specific survival than those without a history of CLL/NHL.

PMID: 22331952

The bottom line is quite clear.  In this large retrospective study with more than a thousand patients with malignant melanoma and another 90 patients with merkel cell carcinoma – all of whom also had CLL / NHL, patients with CLL diagnosis before diagnosis of MM or MCC had significantly worse overall survival.  And conversely, CLL / NHL patients were more likely to die of these two types of skin cancers than people who did not have CLL / NHL.

The first graph above shows overall survival of CLL and NHL patients from the time of diagnosis of malignant melanoma (MM).  Notice how much steeper the colored lines are (gold for NHL, blue for CLL) when patients had to fight a two front war complicated by melanoma.  The black lines are for reference, where the CLL / NHL patients did not have melanoma.  Likewise, the second graph shows the same information but with reference to merkel cell carcinoma (MCC).  These two skin cancers – MM and MCC – are the two most deadly form of skin cancers and something I would not wish on any of  you.

Below is the take-home quote from the Mayo experts that is worth its weight in gold:

 Our analysis provides strong evidence that patients with a history of CLL or NHL are at a higher risk of death as a result of MM (malignant melanoma) or MCC (merkel cell carcinoma) once one of these cancers develops.  When considered with the higher risk of and more aggressive behavior of other skin cancers (eg, basal cell carcinoma, squamous cell carcinoma) in patients with CLL and NHL, an annual dermatologic skin examination and patient education regarding sun protection and skin self-examination seem appropriate for patients with these lymphoid malignancies.

I have been preaching all these points for about a decade now.  It is good to have this kind of expert guidance clearly spelled out.

Link between Vitamin A and Melanoma risk

Now for the second article I want to discuss today.  It takes a more positive look at melanoma risk, namely at a potential way of reducing the risk.

J Invest Dermatol. 2012 Mar 1. doi: 10.1038/jid.2012.21. [Epub ahead of print]

Association of Vitamin A and Carotenoid Intake with Melanoma Risk in a Large Prospective Cohort.

Asgari MM, Brasky TM, White E

1] Division of Research, Kaiser Permanente Northern California, Oakland, California, USA [2] Department of Dermatology, University of California, San Francisco, San Francisco, California, USA.

Laboratory data suggest that intake of vitamin A and carotenoids may have chemopreventive benefits against melanoma, but epidemiological studies examining the association have yielded conflicting results. We examined whether dietary and supplemental vitamin A and carotenoid intake was associated with melanoma risk among 69,635 men and women who were participants of the VITamins And Lifestyle (VITAL) cohort study in western Washington. After an average of 5.84 years of follow-up, 566 incident melanomas were identified. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of melanoma associated with dietary, supplemental, and total vitamin A and carotenoid intake after adjusting for melanoma risk factors. Baseline use of individual retinol supplements was associated with a significant reduction in melanoma risk (HR: 0.60; 95% CI: 0.41-0.89). High-dose (>1,200 μg per day) supplemental retinol was also associated with reduced melanoma risk (HR: 0.74; 95% CI: 0.55-1.00), as compared with non-users. The reduction in melanoma risk was stronger in sun-exposed anatomic sites. There was no association of melanoma risk with dietary or total intake of vitamin A or carotenoids. Retinol supplementation may have a preventative role in melanoma among women.

PMID: 22377763

While this is an interesting study, I would like to caution you about massive doses of Vitamin A without first checking it out with your physicians.  Vitamin A is a fat soluble vitamin and unlike water soluble vitamins (vitamin C is a good example of a water soluble vitamin), it is not easily excreted from the body along with urine.  In other words, it gradually accumulates in your body, in the fatty tissues.  Too much of anything is not a good thing.

It is also worth noting that the results are not quite crystal clear.  The authors saw a reduction of melanoma risk only with high-dose supplementation with retinol, compared to to those that did not get the retinol.  Women seem to benefit more than men.  The benefit was also more pronounced in those parts of the body that were more sun exposed.  All in all, I found this study raised quite a few more questions than it answered.  For example, if retinol reduced melanoma risk, it is kind of hard to see why a similar relationship was not seen in the case of overall dietary intake of vitamin A.  Perhaps it has to do with the bigger oomph of high dose retinol supplementation.  As always, prudence is the better part of valor.  Send me a personal email if you want my help in locating the full article.

Imiquimod, anyone?

We have several articles on our websites regarding a topical cream called imiquimod (brand name in the USA is “Aldara”).  Imiquimod is thought to work through improving the patient’s own immune system via facilitating the release of several important cytokines.  Initially imiquimod was approved by the FDA for genital warts and actinic kertosis. More recently it has been seen to have benefits in a number of different skin diseases, including SCC, BCC, herpes skin lesions and even malignant melanoma. Here is the link to the article.  You can read it for free by just clicking on the link.  Even if the language is a little dense, there are a whole lot of before-and-after pictures of patients with malignant melanoma treated with topical imiquimod cream – pictures that will knock your socks off. Here is an example.

A, Right lower leg showing multiple papules and an ulcerated nodule of cutaneous melanoma metastases.

B, After 4 months of treatment with 5% imiquimod cream, complete remission with residual hyperpigmentation is seen.

We need your help

In a recent slew of articles we discussed the issue of potential for conflict of interest when important clinical trials are paid-for entirely by pharmaceutical companies that have a lot of money riding on the outcome of the trials.  There is a reason why prestigious professional journals now require authors to disclose their financial or other relationships with drug companies.  There have been enough scandals over the years to satisfy even the most ardent conspiracy buff!

Unfortunately, well conducted and large scale clinical trials cost a lot of money and effort.  Money is always in short supply, that goes without saying.  But increasingly, I am worried that even many of our expert centers and CLL experts are finding it easier to conduct research that is almost entirely paid for by the pharmaceutical industry.  Smaller trials conducted by lesser known institutions without this massive support of  industrial patronage suffer due to lack of funds, lack of visibility and ultimately lack of ability to recruit patients.

Literally a beacon of hope in this grim scenario are the excellent clinical trials conducted at the National Institute of Health (NIH), National Cancer Institute (NCI), National Heart, Lung, Blood Institute (NHLBI).  If you are not familiar with the excellent work done by these tax-payer funded research institutions, please check out the member comments that follow each of the articles where I reviewed clinical trials at the NIH / NHLBI.  Here are the links to the articles for your convenience.  To say these clinical trials and the researchers involved in conducting them get rave reviews would be a huge understatement.

A well designed PCI-32765 clinical trial

A clinical trial perfect for our times

I received a request for getting people to sign a petition authored by Dr. Meltzer of Johns Hopkins, for more robust financial funding for the NIH.  The request is attached below and pretty self-explanatory.  You may have to visit http://www.whitehouse.gov/ and  register to get an active account on the “We the People” website (if you do not already have one) before you can sign the petition.  May I add my voice to that of Dr. Meltzer.  As patients with an incurable cancer, as members of a community that is small potatoes compared to more lucrative “solid” cancers such as breast cancer, prostate cancer etc, we are at a huge disadvantage when it comes to new drug development and trustworthy analysis of clinical trial outcomes that are not at the mercy of commercial interests.  We  need a vibrant and well funded NIH / NCI / NHLBI.  Signing this petition is in our own self-interest.  The deadline is March 18th.  Please sign the petition yourself, and get the word out to your friends and family.

Stephen J. Meltzer, M.D.

The Harry & Betty Myerberg/Thomas R. Hendrix Professor

Departments of Medicine (GI Division) and Oncology

The Johns Hopkins University School of Medicine & Sidney Kimmel Cancer Center

1503 E. Jefferson Street, Room 112

Baltimore, MD 21287

smeltzer@jhmi.edu<mailto:smeltzer@jhmi.edu

I was on a recent conference call with White House officials, during which research funding was discussed. It seemed to me that these officials did not fully understand the central importance of NIH funding to our national research enterprise, to our local economies, to the retention and careers of our most talented and well-educated people, to the survival of our medical educational system, to our rapidly fading worldwide dominance in biomedical research, to job creation and preservation, to national economic viability, and to our national academic infrastructure. In response to a question from a participant, they staunchly defended the proposed flat $30.7 billion FY 2013 NIH budget as being perfectly adequate, remarking that “The NIH receives more funding than any other research entity; it will continue to be strong; it will do just fine.”

This statement is patently false. The proposed flat NIH budget will severely exacerbate a catastrophic crisis that has been ongoing since 2003, when growth in NIH funding fell (and has continued to fall every subsequent year) behind the rate of inflation. As a consequence of this deeply flawed public policy, promising careers have been cut short, amazing research projects have been aborted, hundreds of laboratories nationwide have shrunk or been shut down, established and accomplished senior researchers have been forced to abandon their programs, young scientists have departed from research of even left the country (even after many years of productive training), thousands of ancillary jobs have been lost, our worldwide medical research dominance has been eroded (ceded to China, India, and other nations), and a large support network of laboratory supply and biotechnology companies has been drastically attenuated.

I write to let you know about a recently created petition on “We the People”, a new feature on WhiteHouse.gov  , and ask for your support. If this petition gets 25,000 signatures by March 18, 2012, the White House will review it and respond!

We the People allows anyone to create and sign petitions asking the Obama Administration to take action on a range of issues. If a petition gets enough support, the Obama Administration will issue an official response.

You can view and sign the petition here:

http://wh.gov/81O

Here’s some more information about this petition:

Increase NIH budget to $33 billion dollars next fiscal year! A flat $30.7 billion will kill jobs and hurt research.

Increase NIH spending to $33 billion! The proposed flat NIH budget will close labs nationwide, kill good-paying jobs, damage our worldwide medical research dominance, and hurt state economies. NIH jobs cannot be outsourced. NIH funding created 350,000 jobs and contributed $50 billion to the national economy in 2007! In-source our jobs!!

Not all monoclonals are the same!

Sometimes I really have a hard time understanding the logic behind some of the clinical trial researchers choose to conduct.  It is not as if we don’t have enough open questions – lord knows there are a lot of interesting drugs and combinations that are still open to exploration.  But more often than not, it seems to me the decisions are made without first putting brain into gear, to the detriment of good scientific logic and patient safety.

You are all familiar (I hope!) with the success enjoyed by FCR (fludarabine, cyclophosphamide and Rituxan) as the present day “gold standard” in the treatment of of previously untreated (“chemo naive”) patients.  So, if FC + Rituxan is so good, how about substituting the other FDA approved monoclonal Campath in place of Rituxan?  If FC + Rituxan is good, would FC + Campath be even better – since Campath packs more punch and is also thought to work in 17p deleted high risk patients?

This might seem a good concept – for about 5 nano-seconds.  Then, if brain was properly in gear, you would start worrying about the fact that both fludarabine and Campath (also known as alemtuzumab ) are extremely immune suppressive.  Of all the drugs you are likely to encounter in your CLL journey, these two drugs are most justly infamous for destroying T-cell counts. And not having sufficient number of T-cells leaves people wide open to opportunistic infections and even secondary cancers – just think of the health issues associated with advanced AIDS patients and you get the picture.  Using both of these drugs (Campath and fludarabine) at the same time would be doubling down on the risk of extreme immune suppression. Patients would be at significantly higher risk of infections and even secondary cancers, when their immune defenses are down for a prolonged period of time.

It is not as if we have no information available on what combination of fludarabine and Campath can do.  We have published several articles on the topic of Campath consolidation.  When Campath was administered too soon after completion of FCR – as a way of mopping up remaining CLL cells and bringing patients closer to a MRD (minimum residual disease) negative status – there was a big spike in toxicity.  A German trial (we wrote about this one all the way back in 2004) using this approach had to shut down because of unacceptable number of infections and even deaths.  CFAR clinical trial at M. D. Anderson (combination of FCR+Campath in one massive drug combination) proved the point once more – very high toxicity when Campath is combined with fludarabine. You would think these lessons have been learned in many different ways and would not have to be learned all over again:

• Don’t use Campath consolidation too soon after fludarabine based therapy.
• Substituting Campath in place of Rituxan in regimens such as FCR or FR is not such a good idea, likely to result in heavy duty immune suppression and increased risk of infections, secondary cancers.
• Piling on Campath on top of FCR (as in the “CFAR” combination) may be more toxicity than most patients can absorb. You guys with me so far?

So, I have a hard time understanding why this group of researchers in France and Belgium  thought that using the same deadly combination – FC + Campath – in previously untreated patients is such a terrific idea.  Mind you, this is not a small scale clinical trial.  This is a full fledged phase-III trial, conducted at many centers in France.  Patients were randomized to get either FC + Rituxan or FC + Campath.  We are not talking about a small group of patients either – a whopping 165 patients were randomized to either group in this study.

Excess mortality following FCCam treatment in previously untreated patients with CLL: safety and efficacy in a randomized, multicenter, phase III trial

Stephane Lepretre1, Therese Aurran2, Beatrice Mahé3, Bruno Cazin4, Olivier Tournilhac5, Herve Maisonneuve6, Olivier Casasnovas7, Alain Delmer8, Veronique Leblond9, Bruno Royer10, Bernadette Corront11, Sylvie Chevret12, Roselyne Delépine13, Sandrine Vaudaux1, Eric Van Den Neste14, Marie Christine Béné15, Remi Letestu16, Florence Cymbalista16, and Pierre Feugier17

A French and Belgian multicenter phase III trial was conducted in medically fit patients with untreated chronic lymphocytic leukemia (CLL). Of 178 patients enrolled in the study, 165 were randomly assigned to receive six courses of oral fludarabine and cyclophosphamide (FC) in combination with rituximab (R; 375 mg/m2 in cycle one, 500 mg/m2 in all subsequent cycles) or alemtuzumab (Campath; 30 mg subcutaneously injected on cycle days 1-3); each cycle was 28 days. Recruitment was halted prematurely because of excess toxicity; eight patients died in the FCCam group: three from lymphoma and five from infection. Overall response (OR) rates were 91% with FCR and 90% with FCCam (P=0.79). Complete remission (CR) rates were 33.75% with FCR and 19.2% with FCCam (P=0.04). Three-year progression-free survival (PFS) was 82.6% with FCR and 72.5% with FCCam (P=0.21). Three-year overall survival (OS) was similar between the two arms at 90.1% in the FCR arm and 86.4% in the FCCam arm (P=0.27).These results indicate that the FCCam regimen for the treatment of advanced CLL was not more effective than the FCR regimen and was associated with an unfavorable safety profile, representing a significant limitation of its use. This study is registered with www.ClinicalTrials.gov, number NCT00564512.

I do not have the heart to summarize the full details of this study.  They are too shocking and depressing.  I described some of the details when this study was first discussed as an ASH 2011 abstract. If you are in the mood for it, or if you are considering the combination of FC + Campath and therefore need a swift kick in the backside to stop you from doing it, please send me a personal email and I will be happy to help you find the full text of this horrific article, just published in all its glory in “Blood”.

Here are the sad details / results in a nutshell.

• 165 patients recruited for this two arm trial.  Half got FCR, other half got FC + Campath
• While the patients recruited were indeed a relatively high risk group needing to start therapy of some kind, all of them were previously untreated.  Not what I would call the walking dead, by any means.
• Things got so bad that even this group of “brave” researchers halted recruitment prematurely.  I guess we have to be grateful for small mercies.
• Eight patients died in the FC + Campath group.  That is a massively large number!
• Cause of death was infection in five patients and secondary cancer (lymphoma) in three patients.  This should not come as a surprise to anyone even remotely familiar with the high risk of immune suppression associated with a combination of fludarabine and Campath.
• So, did the patients in the FC + Campath get a lot better overall responses compared to FC + Rituxan?  Did they get more bang for the very high price they paid for the FC + Campath combination?  You be the judge.  FCR got 90% overall response, while those in the  FC+ Campath arm got 91%.  Absolutely no difference in response rate.
• How about overall survival?  Once again, no difference between the two groups.
• Here is the bottom line.  Not my words, this is a direct quote from the article and the abstract above.  ”These results indicate that the FCCam regimen for the treatment of advanced CLL was not more effective than the FCR regimen and was associated with an unfavorable safety profile, representing a significant limitation of its use”.

Editorial

Where do I start?

Perhaps a good place to start is raise my concerns with mix-and-match style drug combinations, just changing the alphabet soup of drug combinations.  How about getting a bit more creative, something other than doing yet another me-too style clinical trial?

Is it reasonable to expect that there was sufficient data already available regarding the risks of combining fludarabine and Campath?  I think so.  Many patients had already paid dearly to prove that Campath consolidation too soon after FCR (or FR) was risky business, as far back as our review of it in 2004.  The same concerns were also evident in the results of CFAR combination. Which part of this immune suppression risk  did these researchers not get?

Guess who paid for this trial.  I will give you just one guess.  That’s right, the trial was paid for by Genzyme and Schering – the two pharmaceutical giants that own marketing rights to Campath.  Do you honestly think anyone else would have been interested in paying for this particular deadly combination?

I mourn for the 83 patients who were unfortunate enough to be randomized to the FC + Campath arm of this deadly trial.  Their participation in this clinical trial got them  higher rates of infection, secondary cancers and even premature death – with no increase in response rates or overall survival.  And here is the bit that really sticks in my craw.  The researchers thanked the pharma companies that own Campath and paid for this trial – but they had not one word of thanks for the patient volunteers.  Heck, in this case, thanks would not have been sufficient. How about abject apologies?

What blows my mind is that the terrible outcome of this clinical trial cannot even be dismissed as a case of 20:20 hindsight.  The lessons were there already, provided anyone was willing to look at the outcomes of similar trials in the past and willing to learn from them.  This trial provided nothing more than remedial education as it were, for researchers only too willing to conduct a trial just because they got the funding for it, not because it was a good idea to begin with or one that had high probability of helping the patients who participated in it.  I can (sort of) understand dug companies wanting to improve their market share by pushing the drugs they own.  But what is the excuse of researchers and physicians with a sworn duty to protect patients?  Whatever happened to the “Do no harm” pledge?

Last but not least:  where were the local oncologists who funneled patients into this trial?  On what basis did they guide their patients into this obviously flawed approach?  Is there an active patient advocacy effort available in France and Belgium that could have short-circuited this disasterous trial before it recruited even a single patient?

I guess that last point is the one that hits close to home for me.  We have thousands of members, all around the world.  But there is no question the vast majority of our members come from English speaking countries.  We have a few volunteers translating CLL Topics and Updates articles into German and other languages.  Not enough, it seems.  I am only too aware of the limitations of my own efforts.  Our reach is limited to computer savvy and English speaking patients.  An even bigger hurdle is mind-set.  Too many patients are still timid about getting personally involved in their own healthcare, too many doctors are offended / intimidated by patient advocacy or empowerment, too many inappropriate clinical trial designs getting approved based mostly on availability of funding rather than good science.  Until these mindsets changes, we will continue to have tragedies like this.

What can you do?  Please get the word out.  Preach patient advocacy and personal choice in therapy decisions and clinical trial participation.  If you “get it”, try and convince a few others who may not be quite as far up the learning curve as you are.  We are all our brothers’ keepers.

On a very different subject, my sincere and heartfelt thanks to all the kind readers who wrote and expressed their condolences on the death of my beloved dog Jasper.  Please forgive me for not writing back to thank you personally.  I am still having a hard time coping with this loss.

Skin cancer and CLL – a two front war you do not want to fight

That is the succinct message I have repeated dozens of times on this website.   It is now well documented that the single most common second cancer in CLL patients is skin cancer.  The little patch of actinic keratosis (pre-cancerous lesion) and basal / squamous cell carcinomas that are dismissed as relatively unimportant can become life threatening monsters in CLL patients – unless you pay attention and take care of the problem right away.

The first line of defense is avoidance.  Avoid skin damage by excessive exposure to UV radiation.  That means long sleeved shirts, long pants and a hat, if you are going to be out for any length of time.  Remember, just because it is cloudy does not mean there is no UV sleeting down.  Lack of sun exposure may mean vitamin D3 (“cholecalceferol”) deficiency.  Fortunately, it is easy enough to get tested for your level of this important vitamin and correct any insufficiency with oral capsules.  Please search for “vitamin D3″ and “BCC” to find all the other articles we have on these important topics.

Sometimes sun damage that happened way back in your mis-spent youth may come back to haunt you, especially if you have the skin type that burns easily.  Avoidance is no longer a choice, that train has already left the station. The second line of defense is getting early warning. That means full body skin examination from a well trained and qualified dermatological oncologist.  You do not want to get stuck with the guy who makes a specialty of curing zits in teenagers, or Botox injections for the anxious middle aged among us.  Or someone who does not understand the implication of your CLL – less than robust immune system – and its impact on your body’s ability to make short work of tiny skin cancer spots that healthy people can take care of with one arm tied behind their backs.

The third line of defense is offense.  It may not be sufficient to just freeze off the tiny skin lesions.  Moh’s surgery to remove basal cell or squamous cell carcinomas are simple affairs in otherwise healthy people.  Not so in the case of CLL patients.  Mohn’s surgery needs to be done with larger safety margins (bigger piece of your hide removed) in order to improve odds of the cancer not recurring at the same location.  People, vanity is all very well, but please do not second guess your surgeon when he says he needs to take a big bite out of your balding scalp or the tip of your nose.  On the contrary, be sure to ask him whether he is being prudent enough, taking out enough margin around the BCC to increase your odds of avoiding recurrence, given your history of CLL.

Surgery is not always enough and I have seen too many cases where the skin cancer recurs at the same location.  There has been a real need for better drug options to add as a backstop to the Moh’s surgery.  Far too often, the neglected or under-treated little basal cell carcinoma takes center stage, overtaking CLL in its impact on both quality of life and duration of life.

A much needed new drug

That is why I am pleased to hear about the FDA approval of vismodegib (trade name  ”Erivedge”) from Roche.  This is a new addition to the stable of “smart drugs”, targeting what is whimsically called the hedgehog pathway, a signaling pathway that is important in the spread of basal cell carcinoma. Is it completely safe and without side effects?  You want to take a guess at the answer?

No, it is not entirely without a risk profile.  If you are pregnant or breast feeding, forget about using it.  It has very serious risk of birth defects.  Fortunately, for the majority of our patients this is not an issue of concern, since we are more likely to be looking at welcoming grand-kids into this world than having kids of our own.  Sure, there are exceptions.  If you are pregnant or planning to get pregnant, don’e use this drug.  Period. The rest of the adverse effects (listed in the press release below) are not much fun either.  But they sure beat the alternative:  fighting a two front war with CLL and aggressive skin cancer.  That is a fight I would not wish on my worst enemy.

FDA approves Roche skin cancer drug Erivedge

(AP) NEW YORK — Federal regulators on Monday approved a pill that treats the most common type of skin cancer, basal cell carcinoma.

The pill is called Erivedge and is made by Genentech, a unit of Swiss drugmaker Roche. Erivedge is intended to treat locally advanced cancer for patients who are not candidates for surgery or radiation, and for patients whose cancer has spread to other parts of the body. The capsule is taken once per day.

Genentech said Erivedge is the first drug approved to treat advanced basal cell carcinoma. It said the drug will be available within one to two weeks.

The drug’s label will warn that it is linked to fetal death and severe birth defects when it is used by pregnant women. The most common side effects of Erivedge include muscle spasms, hair loss, weight loss, diarrhea, fatigue, changes or loss in sense of taste, decreased appetite, constipation, and vomiting.

Curis Inc. of Lexington, Mass., which collaborated with Genentech on the drug, is getting a $10 million payment from Genentech now that the drug has been approved.

The approval comes ahead of schedule, as the Food and Drug Administration previously said it would make a decision on Erivedge by March 8. The drug was given a fast six-month review because there are no approved treatments for basal cell carcinoma.

What do we know about the drug thus far?  In a phase II clinical trial of using this drug to treat basal cell carcinoma (two cohorts, one aggressive BCC and the other metastatic BCC – total of 104 patients), Erivedge  demonstrated it can shrink tumors or heal visible lesions in 43% of the patients with locally advanced BCC and in 30% of patients with metastatic (fancy word meaning the cancer has spread to other parts of the body) BCC.  Median progression free survival for both groups was 9.5 months. You may not think those results do not sound too peachy.  Trust me, it is a huge improvement over what we had going up to now in such advanced cases – especially with CLL thrown into the mix.  Based on this encouraging data, Roche decided to up the ante and asked the FDA for an early decision, even though the data was based only on a phase -II trial.  The all important FDA approval came well ahead of the company’s expected decision deadline.  I have no doubt this drug will be commercially available for prescription within short order.  I will keep an eye out for any additional information on it and report back to you.

Site News

I have had to pre-pone my trip back from India to the USA.  My beloved dog Jasper is very ill and in this serious emergency I am pulling out all the stops to get back home ASAP to be with her.  I am heading out of here tomorrow.  Please note I will be out of email reach for the next few days due to the travel, followed by downtime to take care of jet lag.  In other words, don’t get upset if I don’t respond to your emails with my usual promptness.  Sometimes life intrudes and prevents us from taking care of stuff.

Postscript

I am back home in the US –  exhausted and heart-broken.  Jasper passed away before I got here.  I got the news a few hours before I boarded the flight in India.

She was my best friend, my muse, my precious connection to the life I lived with my husband.  I am reeling with grief and loss.  In less than a week she went from perfectly fine through diagnosis of metastatic lung cancer, blindness, respiratory distress and death.  I am devastated that with my best efforts I could not make it back in time to say goodbye to her. Pete gave her a loving and gentle send off, for which I will always be grateful.  She went away, as she listened to Pete telling her how much she was loved, that mommy was coming back soon, and Papa is waiting to go on hikes with her again.  She could not see Pete, but she could hear him and smell him.  She gave him several gentle licks on his hand and died peacefully.  RIP, sweet Pup.  You gave much joy to our family and friends who got to know you.

“A Nuanced Approach to Autonomy, Culture and Paternalism”

The Cancer Network has an excellent and thoughtful article on the subject of communication between oncologists and their patients. I am glad to see the article is available free of charge to anyone who clicks on this link.  Good, this way we can hope a lot of ordinary patients get to read it too, not just medical professionals.

The article deals with problems of patient’s rights and autonomy, various levels of paternalism on part of the doctor (not always to be disdained), cultural differences in how human beings handle life-or-death situations.  I strongly recommend you read the full article for yourself, it just takes a click of your mouse and a little of your time.  Whether you are a patient or a caregiver, this is an article that I hope provokes a good discussion among our members.  For a change, you don’t have to read through my long-winded explanations, the article is easy to understand and speaks for itself rather well.

Here is an example from the article, just so you know the kind of issues it discusses.

Mrs. Kimat Met (pseudonym), a 37-year-old ultra-orthodox Jewish mother of two small children, presents with metastatic pancreatic cancer with extensive liver metastases. She is weak and cachectic. Given the very advanced disease and her poor performance status at presentation, the outlook is poor and the likelihood of substantial benefit from chemotherapy is small. The family, who were told of her diagnosis by the diagnosing surgeon, request that you not tell her how serious her condition is. They explain that in their culture any information should be given to her husband, and that he and his rabbi will decide what is best for her to know.

At times when her family has not been present, the patient has repeatedly remarked to the junior resident that she wants to be told what is happening to her.

You, the attending of record, sit by her bedside and take her hand. She turns on her pillow, looks you in the eye, squeezes your hand, and says, “I want to live! I need to see my children grow up! I need you to give me hope! I am the sick one here but I feel like no one is talking to ME.”

Questions abound:

• Are you going to tell her what is going on despite the explicit request of her family?

• How much will you tell her about the grim prognosis or the low likelihood of benefit and the potential for harm from treatment?

• Does her plea for hope demand that you hold back on disclosing the full scope of the impending tragedy?

• Without all of the information, how can she possibly make an informed decision about whether to receive what will probably be ineffectual and possibly harmful chemotherapy?

The article goes on to discuss various options that the oncologist can try.  Interesting reading, as I said above.

Editorial

My blood boils every time I hear of an arrogant physician who will not take the time to listen, who treats the disease or the lab numbers, not the human being in front of him.  Heavy handed paternalism does not work for me, however well intended it may be.  As I mentioned in a previous article, we do not sign away our unalienable rights of life, liberty and the pursuit of happiness just because we happen to be cancer patients.  Medical jargon may not be our forte, but that does not make us stupid or incapable of understanding issues that define our very existence. Damn it, as the consumers that pay for every single dollar spent on healthcare, the least we deserve is a bit of respect!  Whatever happened to “the customer is always right”?

But it takes two to tango, and in all fairness we cannot place the entire blame for botched communication on the shoulders of oncologists. There is another side to this problem of complicated communications.

The example from the article I cited may sound a bit extreme to you.  Believe me, it is not.  I am not an oncologist.  My role is far more limited – I am merely a patient advocate.  Yet, I too have seen my share of similar problems.

• What do I tell a newly diagnosed patient who writes to me, clearly looking for my validation of the latest nonsense herbal cure – and tells me in so many words that she cannot bear it if I tell her it is so much snake oil?
• Or how about the 75 year old desperately seeking optimistic survival odds for stem cell transplants for people his age?  And takes me to task for writing about poor survival statistics for people who have totally flunked FCR – as he has?
• How do I convince a patient deathly scared of dying of chemotherapy toxicity that she would die a lot sooner if she refuses necessary and sensible therapy – notwithstanding the adverse effect profile of chemotherapy?
• What do I do with all the lost souls who ask me to pray for them, rub the belly of the Buddha, cross my fingers, anything, just so long as I tell them pretty little lies?
• And where in my heart do I carefully wrap and tuck away the pain and hurt of patients who dropped me like a hot potato after my husband P.C. died – possibly because I have become a bad luck talisman in their eyes?
• What should I do with patients who insist on asking  me to make all the tough medical decisions for them because they cannot handle them and there is no one else?  In a sane world that is a level of responsibility that no patient advocate deserves.  Family, close friends, spiritual guides – these are the people that should be the ones handling such tough calls.  But it seems that sometimes our over-crowded world is also a very lonely place – especially for people who are sick or facing a patch of bad luck. And we all depend on the kindness of strangers.
• Last but not least, what do doctors (and patient advocates) do with patients who ask them to perform miracles – when they too are mere mortals?

Mind you, I am not complaining.  Very far from it. I am overwhelmed by the honor you do me – with your trust and affection.  Like many wonderfully hard working and sincere healthcare workers, I wish I was more worthy of it.

The very least I can do is fess up.  Here is the skinny my friends.  We are all human beings, all of us with  huge, ugly clay feet making a mess where ever we go.  That is built into the DNA of being human.  Don’t expect miracles of us.  And don’t expect miracles of yourself, you too are human. I see those ever so dainty clay feet poking out from under your pants.  If you need one character trait to deal with being a cancer patient, it is being able to make-do with less than perfect situations, families, therapies, doctors and yes, patient advocates and patients too.

They say talk is cheap.  I beg to differ – if by “talk” we mean an active effort at communication.  It takes two people to have a meaningful dialogue.  It takes a lot more than that to build a vibrant community that works well together.  We have thousands of registered members. Yet, only a few ever bother to log in and read member comments, or post comments themselves.  How can we hear you, if you neither talk nor listen to us talking?  It won’t be perfect symphony of empathetic communication – nothing ever is.  Remember what I just told you?  Don’t expect perfection!  Good enough for government work is good enough to get started.  We will work on perfection tomorrow.  You OK with that?

And while we are waiting for that perfect tomorrow, get out there and try to communicate.  Today. Imperfectly. Humanly.

From Israel, with love

 I continue to be impressed by the quality of CLL research being done in Israel.  Perhaps it has something to do with the higher incidence of CLL in Ashkenazi Jewish people.  While we have many members from Israel, to my chagrin I do not have too many contacts in the researcher communtiy there.  Oh well.  I can still read and appreciate their research papers.

The paper (abstract below) that I review today is detailed and well documented.  I will attempt to present some of the highlights.  But as always, if the topic interests you (it should, unless you are truly a spring chicken and plan to stay that way forever), do make the effort to read the original article in full.  Send me a personal email and I will be happy to help you locate the paper.

Blood Rev. 2012 Jan;26(1):15-23. Epub 2011 Sep 28.

Optimal management of older patients with chronic lymphocytic leukemia: Some facts and principles guiding therapeutic choices.

Tadmor T, Polliack A.

Hematology Unit, Bnai-Zion Medical Center, Haifa, Israel.

Chronic lymphocytic leukemia (CLL) is a disease of older patients and median age at diagnosis is 72years. This older group is under-represented in clinical trials, (median age 58-62years). Here we review background data on incidence, survival, definitions of older age, fitness criteria, frailty and co-morbidities. Issues influencing the choice of therapy in older patients are also addressed and different therapeutic options are highlighted based on recent available data. Fit older patients with less co-morbidities benefit most from the very effective chemoimmunotherapy (FC-R) given for younger patients today, but whether other novel drug combinations or new agents are more suitable for less fit patients is still unsettled. Based on careful evaluation of published data from larger clinical trials and major referral centers we present our concept of therapy as a guide to optimal management for subgroups of older patients with CLL.

PMID: 21955980

Our understanding of this confusing disease is growing by leaps and bounds, with direct impact on how best to treat patients in different risk buckets. For the first time, new therapy options using chemoimmunotherapy combinations have increased overall survival – perhaps the single most important criteria, along with quality of life, that matters most to patients and their families.  There is palpable optimism in the air.  But one shoe does not fit all.  Biological frailty, co-morbidities and age at diagnosis  - all of these play an important role in defining fitness of the patient and eligibility for various treatment options.  How best to treat elderly CLL patients in community based medical facilities is still not well understood.

Study Perspectives

This paper does a couple of things.  First, it does a better job of describing what we mean when we say “old” or “elderly”.  In the USA, the lazy man approach is to use 65 years as the defining criteria – possibly based on the age when people become eligible for Medicare.  This is hardly satisfactory.  It is refreshing to see a discussion of how frailty and co-morbidities play a role in decision making, rather than the slam-dunk chronological age.  Attitudes towards age have changed in the general population.  It is time that physicians get on the bus as well in this regard.

The second part of the paper discusses the therapy options available to us at this point in time, highlighting how older patients fared when these therapies are used either in clinical trials or at major expert centers.  Based on this hindsight knowledge, the authors attempt to define how best to serve the needs of this large sub-section of CLL patient population.

Here are some eye-popping statistics, pointed out by the authors:

• 75% of all CLL patients in the USA are over the age of 65.
• 50% are 75 years or older.
• At the time of diagnosis, about a third of patients (30%) are between 70 and 79 years old.
•  Roughly a quarter of patients are above 80 years of age.

If these statistics come as a surprise, you are not alone.  Part of the problem is that older patients tend not to be as vocal and assertive; they shy from participation in on-line forums such as this – both because they grew up in a different culture and because they may not be as computer savvy.  They are truly the silent majority of our community:  under-served in clinical trials, under counted in epidemiological statistics, generally under appreciated by all of us.

But a more insidious issue is that our societies and healthcare systems tend to take a rather condescending approach when it comes to dealing with the “old dears”.  I am all in favor of age-appropriate therapy, making decisions that take into account quality of life as well as quantity of life.  But that does not mean acceptance of indifference to the needs of our older patients or dismissing the intrinsic value of their lives.  Last time I read it, our Declaration of Independence still lists life as one of those unalienable rights.  It is your life. You do not waive your unalienable right to it, just because of the date of your birth. Or because you have this “good” cancer.

The authors point out that the statistics quoted above are probably an under estimation, because many doctors do not even bother to confirm diagnosis of CLL or report it to the family if the patient is elderly.  All too often, the death certificate lists cause of death as pneumonia with no mention of the underlying CLL and the resulting immune dysfunction that led to the pneumonia.  Easy, lazy and downright incorrect.  And it bugs the heck out of me.  Epidemiological statistics and accuracy of reporting are necessary before we can get our arms around this miserable disease.

Who is fit for therapy?

The authors discuss the approach taken by the well regarded German CLL Study Group.  They divide patients into three rough groups.  First, the young and fit patients, the so-called “Go – Go” group, who can benefit from aggressive therapy that can yield high quality remissions.  Second, the “Slow-Go” group, those with some medical problems in addition to CLL.  Unfortunately this group tends to be under-represented in clinical trials and we are not really sure how best to treat them. (Why are they under-represented?  Don’t get me started.  Ever hear of cherry picking trial participants in order to improve outcome statistics and bragging rights?).  The third group of truly frail patients is the “No-Go” group. These guys have multiple health issues, shorter life expectancy, physical dependency in every day activities – you get the picture.  Palliative therapy is generally the recommended option for this group.

This three tier approach sounds pretty reasonable, in so far as it goes.  The problem is how best to judge which group an individual patient belongs in. Here is an interesting example of why it is necessary to put brain in gear first before using scoring systems.  Patient presents with extreme frailty, deep anemia.  Is this because of a systemic problem, anemia caused by one of the many health issues that plague the elderly?  If that is the case, the patient is perhaps best treated as a “No-Go”.  But what if the so-called frailty is due to CLL induced anemia, which can be reversed nicely by treating the underlying CLL? You see what I mean?  Scoring systems need to be nuanced, taking into account clinical stage, prognostic markers, age at diagnosis, overall health, projected life expectancy.  And we need to work harder at the trickle down of these concepts to the local oncology healthcare providers.  You can do your bit to make it happen, a kind of trickle-up of information from you to your way-too-busy oncologist.

I would like to add one more factor that is missing, even in this thoughtful discussion:  patient’s own wishes and attitude towards cancer treatment.  We need to keep reminding physicians about our unalienable rights – to life, liberty and pursuit of happiness.  Anyone trapped in the oncology ward of a large hospital, hooked up to a zillion machines and drips can tell you this: cancer therapy decisions involve all three of these unalienable rights. At the other end of the spectrum, it is frustrating when the physician does not understand or take into account your zest for life – and gets fixated on your date of birth, to the exclusion of everything else.  Repeat this mantra everyone – it is your life.  You get to decide.

What therapy options are best suited for elderly patients?

Considering the massive statistics in their favor, you would think we know the answer to this question by now.  It is not the case.  Only a very small number of clinical trials and published papers report studies done specifically with elderly patients.  Most of the information used to make decisions comes from trials where the elderly were under-represented.  This needs to change!  This paper is a good place to start.  It does a very nice job of tabulating the existing information in detail, along with citations of the actual papers and clinical trials if one is inclined to chase them down.

Among the options discussed in detail are the perennial favorites, fludarabine based regimens (F, FC, FCR, FCR-Lite); chlorambucil based regimens get a lot of attention as well.  Here is direct quote from the Israeli paper:

“Catovsky and co-workers have publisheda retrospective analysis of data supporting the use of Chlorambucil in a paper entitled “Chlorambucil — still not bad: a reappraisal”, in which the UK CLL study group summarize the last 30 years experience with the drug. In the CLL3 and LRF CLL4 studies 33%, and 35% of the patients respectively were 70 years or older and results of Chlorambucil therapy in the elderly compare favorably with those obtained with Fludarabine and Bendamustine. They stress the fact that higher doses of Chlorambucil correlated with better overall response rates than lower doses, and in the light of these results, Chlorambucil used in the correct dose may well be a suitable choice for elderly patients with CLL”.

I have been fielding a flood or emails from patients asking about bendamustine, with or without other drugs.  It seems local oncologists are all anxious to road test this latest trendy (“Treanda -y”?) drug.  I have written enough times about the low dose chlorambucil “straw-man comparison” done in order to win FDA approval for Treanda (bendamustine).  It seems some of our best CLL experts share my concern – notice the special emphasis on using chlorambucil at the correct dose in the quotation above.

Does bendamustine have a role to play, perhaps in combination with Rituxan or other drugs?  Possibly so, “but longer follow up is still needed in order to determine the degree of myelosuppression seen as late toxicity”.  ”Myelosuppression” is just a fancy word for bone marrow damage that reduces its capacity to create new myeloid cells (red blood cells, platelets, neutrophils – to name a few).  Why is this of particular importance to older patients?  Because even in the young at heart patients who have led a blameless life, there is an inevitable toll in the amount of bone marrow reserves over time.  Stem cells living in our bone marrow gradually decrease in number and their ability to produce new blood cells diminishes as we age.  Younger patients may have less of a problem with drugs that have the potential for bone marrow toxicity, since they have a lot more resilient bone marrow that is able to take a hit and still recover quickly.

Alemtuzumab (Campath) is discussed in some detail – especially in the context of its ability to handle patients with 17p deletions and defects.

Also discussed is the use of  high dose pulse therapy with steroids such as prednisone, often in combination with Rituxan or other drugs.  R+HDMP (high dose methyl prednisolone) has been studied extensively at UCSD.  However, this and other reported studies have only small minorities of patients over the age of 65.  Bottom line, the Israeli authors conclude that “The efficacy of this regimen still needs to be evaluated in larger cohorts of elderly patients but taking inot consideration the toxicity and side effects profiles of this regimen.”

In keeping with the thorough discussion of all available options, this paper also includes a discussion of CAM and herbal medicines.  But to my relief, they are selective in their approach, choosing only those that have demonstrated promise in clinical research.  Most of you would be familiar with the list, we have discussed almost all of them on this website and CLL Topics: green tea; curcumin (from the spice turmeric); vitamin D; gossypol (from cottonseed oil); silvestrol (extract of the bark of Aglaia foveolata).

No discussion of CLL therapy options is complete without a discussion of new biologic drugs such as kinase inhibitors (CAL-101, PCI-32765), flavopiridol,  next generation anti-CD20 monoclonals similar to Rituxan but hopefully better (GA-101 and ofatumumab), an anti-CD74 monoclonal called milatuzumab that I have yet to research.  As I have said more than a couple of times, this is a detailed paper.  No stone left unturned.  No way I can do justice to all the lovely details, you really have to read the full paper for yourself.

Many of these drugs and therapy regimens have been reviewed by me in earlier articles.  The easiest way to find these is to type the key word or phrase into the search box at the top right hand corner of our home page. That easy.  I promise it will become second nature to you, after you have done it a couple of times.  Combining our flagship CLL Topics and the more recent Updates websites, we have many hundreds of articles.  Even I cannot remember all the articles I have written over the last 10 years.

Bottom line..

A picture is worth a thousand words. Here is how the authors bring together much of the information they discuss in their paper.  This is their paradigm on how best to treat elderly patients upfront.

Not too many surprises here.  It is by now well accepted that CLL patients who are trundling along minding their own business, no symptoms of the disease, these guys should not be treated.  The latest IWCLL (International Work group on CLL) has done a very good job of detailing who should be treated and who should be merely monitored in W&W.  Please refer to our earlier article to read about it.

Symptomatic patients who need therapy and who are not enrolled in clinical trials designed for the elderly (we hope you will have improved access to such trials in the future!) are divided into three groups, based on their level of physical fitness.  Therapy options are suggested for each group.  I don’t have much to quarrel with here.  My problem is still the old one we discussed earlier.  Dividing patients into the three groups is not a cut and dry process.  One man’s idea of a less than fit patient may be another man’s medically robust patient.  This paper does an excellent job of raising the question, but when push comes to shove, it is still a matter of the individual medical practitioner making the call on your ability to handle a particular drug regimen.

Editorial

As I reached the editorial part of my review I realized I have already done a lot of editorializing, all through the article.  Sorry about that – usually I try to keep a lid on things until I get to this part, where I can do my soap box stuff.  This time around the subject matter got to me, I guess.

All of us have a hard wired need for simple answers to complex questions –  sort of the whole universe and what makes it tick boiled down to a bumper sticker;  a road map clearly marked, with all congested areas avoided.  Any of you fans of Douglas Adams and the “Hitchhiker’s guide to the galaxy”?  Ask a silly question and we deserve a silly answer. It does not help to know the answer to everything is 42.

So, what to do?  Quit asking silly questions and looking for easy answers, for starters.  Take the time to read, come up the learning curve, think about what is important to you as a patient and as a human being.  Work with your physicians to come up with the best plan taking into account your medical history and your personal preferences.  Keep your eyes peeled for new therapy options, this is an exciting time when lots of new drugs are on the horizon.  Stay involved, stay motivated, take care of yourself.  Yeah, I know it is easy to preach and hard to do.

I worry about the lack of access to online information for many elderly patients unfamiliar with computers.  Fortunately, many of them have savvy family members who care enough to pitch in.  I hear many patient stories. The saddest one I have to tell you is about a member who corresponded extensively with me about her father’s CLL.  She said he was pretty much computer illiterate and therefore it was her job to learn as much as she could about CLL.  As we got into the nitty gritty details of disease complications and survival statistics, I discovered my member was just 12 years old!  It broke my heart, here was this kid trying to deal with bleak life and death issues – because there was no one else to do the heavy lifting.

None of us have crystal balls, but some folks (like the authors of this paper) have better information than most, and they bothered to pull it all together in a nice package.  It is definitely worth your time and effort, especially if you are heading into a higher age bracket like the rest of us.

Give it to me straight Doc, I can take it..

 You have seen the scene repeated in a zillion Hollywood movies. The hero has just been told he has cancer.  Somber music plays in the background. The wise doctor looks  worried and the beautiful young nurse assisting the doctor looks like she is about to cry.  The hero looks up as the camera goes in for a close-up, his eyes bleak but no tremor in his voice.  He delivers the heart wrenching line with appropriate pathos .. “Give it to me straight Doc.  I can take it.  How long do I have?”.  Pregnant pause as the audience holds its breath and a lone violin weeps gently in the background – then the doctor gives his verdict: “A few weeks, months at most”.  There is not a dry eye in the whole theater, no matter how many times we have heard this corny dialogue before.

That is so not going to happen to CLL patients.

Frankly I do not know of any examination rooms where they play weepy violin music, the doctor and nurse rarely fill the needs of Hollywood central casting, nurses are generally not inclined to cry every time they hear a cancer diagnosis.  You would be lucky if you got your doctor’s undivided attention for the full fifteen minutes of your consultation window.  Given that CLL is supposed to be the “good” cancer, it is much more likely that instead of corny pathos and empathy you will get flip condescension and told not to worry your pretty little head about it, go home and not bother the nice doctor.

If you are like many patients, you have probably felt a twinge or two of feeling sorry for yourself since your CLL diagnosis.  Here you are, dealing with the “big C” and after the first week or so, the universe does not seem to be paying much attention.  You look about the same, you are not wasting away, hair not falling out in tufts, you are not even going to have therapy for the foreseeable future.  Friends and family wander away – sort of bemused.  And you are left alone holding the bag, as it were.  Not quite alone, because we are here for you.

What can newly diagnosed CLL patients expect?

How long do early stage CLL patients have to live?  What can they expect, by way of quality of life? How soon will they have to start therapy? Here is the abstract of a very recent paper that sifts through a very large database of patient histories to come up with some guide posts.  I will do my best to review the highlights, but really, you have to read the full text version of the paper to get all the juicy details.  Send me a personal email and I will help you locate the paper.  This is article is a keeper for your personal files.  I recommend it.

Br J Haematol. 2011 Dec 15. doi: 10.1111/j.1365-2141.2011.08974.x. [Epub ahead of print]

Defining the prognosis of early stage chronic lymphocytic leukaemia patients.

Pepper C, Majid A, Lin TT, Hewamana S, Pratt G, Walewska R, Gesk S, Siebert R, Wagner S, Kennedy B, Miall F, Davis ZA, Tracy I, Gardiner AC, Brennan P, Hills RK, Dyer MJ, Oscier D, Fegan C.

School of Medicine, Cardiff University, Cardiff Medical Research Council (MRC) Toxicology Unit, University of Leicester, Leicester Institute of Cancer Research, Belmont, Sutton, Surrey CRUK Institute for Cancer Studies, University of Birmingham, Edgbaston, Birmingham, UK Institute of Human Genetics, University Hospital, Schleswig-Holstein, Campus Kiel, Kiel, Germany Royal Bournemouth Hospital, Bournemouth, UK.

Approximately 70% of chronic lymphocytic leukaemia (CLL) patients present with early stage disease, therefore defining which patients will progress and require treatment is a major clinical challenge. Here, we present the largest study of prognostic markers ever carried out in Binet stage A patients (n = 1154) with a median follow-up of 8 years. We assessed the prognostic impact of lymphocyte doubling time (LDT), immunoglobulin gene (IGHV) mutation status, CD38 expression, ZAP-70 expression and fluorescence in situ hybridization (FISH) cytogenetics with regards to time to first treatment (TTFT) and overall survival (OS). Univariate analysis revealed LDT as the most prognostic parameter for TTFT, with IGHV mutation status most prognostic for OS. CD38 expression, ZAP-70 expression and FISH were also prognostic variables; combinations of these markers increased prognostic power in concordant cases. Multivariate analysis revealed that only LDT, IGHV mutation status, CD38 and age at diagnosis were independent prognostic variables for TTFT and OS. Therefore, IGHV mutation status and CD38 expression have independent prognostic value in early stage CLL and should be performed as part of the routine diagnostic workup. ZAP-70 expression and FISH were not independent prognostic markers in early stage disease and can be omitted at diagnosis but FISH analysis should be undertaken at disease progression to direct treatment strategy.

PMID: 22171799

The statistics derived in this study are with reference to early stage patients – Binet Stage A is the equivalent of Rai Stages 0 and 1.  The cohort size is very large at 1,154 patients and therefore the conclusions drawn from this study are likely to be robust.  (In the editorial section I will have more to say about statistics derived from large groups of patients, and how they apply to a single patient).

As the abstract points out, the purpose of this study is to assess the value of prognostic indicators in predicting two important outcomes of crucial interest to us chickens.  First, how long will it be before “Watch & Wait” ends and therapy has to begin?  Because, much though we all like to gripe about the Chinese torture of W&W, believe me it beats the alternative by a mile.  This period, between initial diagnosis and the time when therapy must be undertaken, is called “TTFT” (Time To First Treatment). The second issue that is even of greater interest speaks to the Humphrey Bogart scenario above, how long are we going to live?  The acronym for this is “OS” (Overall Survival).

Who were these patients?

The inclusion criteria for participating in this study is that the patient has to have clinically documented CLL and be in Binet Stage A.  Here is a short list of the patient characteristics.  Notice the age range, all the way from 24 to 96 years!  24 is way too young to have this nasty disease, and I take my hat off to the brave 96 year old still game enough to participate in the study.  Not all the patients had all the prognostic tests done, and that is why the numbers don’t add up to 100% in each category.  I have highlighted the good prognostics in black, for your convenience.

Which Prognostic Indicators?

Over the last ten years a bunch of different tests and indicators have been suggested for defining prognosis.  I am glad to see the researchers stuck with the tried and true, the prognostic indicators that are rapidly becoming the standard set.

• Patient’s age
• Lymphocyte doubling time (LDT)
• IgVH gene mutation status (IGHV)
• CD38
• ZAP70
• FISH

We have discussed each of these in some detail in earlier articles but if you want a quick refresher course, I recommend an article based on one of our recent workshops: “Prognostic indicators: who, when, what and why”.  Most (but not all) of the participants in this study had these prognostic indicators tested and recorded at the time of diagnosis.

Results – Highlights

Given below are graphs showing how the time to first treatment (TTFT) and overall survival (OS) changed between patients who had mutated and unmutated IgVH.

The dark blue curve shows how many of the patients with (good) mutated IgVH stayed untreated as the years went by.  As you can see, even as far out as 25 years and more, fully half of them had not needed therapy.  For these guys, CLL is truly the “good” cancer to have.  Not so for the folks with (bad) unmutated IgVH.  Half of these guys had to have therapy by 4.6 years.  Quite a difference, you would agree.

The next graph looks at the crucial question of “How long do I have?” – namely, overall survival.  Once again the dark blue curve is for the lucky mutated IgVH guys and the red curve is for not so fortunate unmutated IgVH.  Drawing the horizontal line from the 50% mark, you can see that half of the mutated IgVH guys are still trundling along at 23.3 years, where as this milestone was reached much earlier in the unmutated IgVH folks, at only 12.6 years.

If you also take patient’s age into consideration, this difference between mutated and unmutated IgVH can make all the difference between dying with CLL versus dying because of CLL.  For a typical 65 year old CLL patient with mutated IgVH as prognostic indicator, a 50% chance of living beyond 88 years sounds pretty good!  But the scenario is not so rosy for a 40 year old patient with unmutated IgVH, looking at roughly even odds of not making it past 53 years.  Prognostics are important in how we think of overall survival, but so is the age of the patient.  Please remember that.

The authors have similar time to first treatment and overall survival graphs for the other prognostic indicators (CD38, ZAP70, FISH cytogenetics).  They also have differential projections for people whose prognostic indicators do not quite match up, where there is a discordance.  But rather than reproducing all those graphs here in my review, I strongly urge you to read the original paper for yourself.  As I said, it is one of those must keep articles.  Rather than just reproducing all the other graphs, I would like to highlight some of the interesting conclusions reached by the researchers in this valuable study.

Study Conclusions

This study is important not just because it looks at a large cohort, done at very prestigeous institutions and reports the results in great detail, but also because the authors looked at the results and came up with some interesting and important observations.  Here are some of them.

• While the Rai and Binet staging systems have been very useful in classifying patients, they both fail to identify which of the early stage patients (roughly two thirds of them) will have progressive disease requiring therapy at some point – and which one third are going to “smolder” on for the rest of their natural lives.
• Taken individually all of the modern prognostic indicators studied (IgVH gene mutation status, CD38, ZAP70, high risk FISH abnormalities) influenced time to first treatment.
• LDT (lymphocyte doubling time) was the single most important prognostic indicator for TTFT. (Figures, this is sort of like the proof of the pudding is in the eating. Patients with short doubling time have demonstrated an aggressive disease, for crying out loud. This is a bit like predicting the weather by looking out the window and ‘predicting’ it is indeed raining).
• When combined together, only this set of four prognostic indicators had the power to predict time to first treatment: LDT, IGVH, CD38 and the patient’s age.
• The researchers wondered whether the strong showing of LDT in predicting time to first treatment has something to do with doctors treating the numbers, getting spooked by high white blood counts even if the patient did not really need therapy right away.  Interesting indeed.
• The researchers noted a significant trend for younger patients to receive therapy sooner than otherwise – perhaps once again reflecting physicians’ bias towards treating younger patients more aggressively, while taking a more laid back approach to treating elderly patients.
• This last point is something to think about, if you are in the younger crowd. “Given the increasingly recognized association of CLL chemotherapy with development of secondary myelodysplastic syndrome / acute myeloid leukemia (8-10% of fludarabine combinations treated patients), this observation is very important and worthy of further study”. No kidding.
• Patients with 17p deletion (FISH abnormality) are widely accepted to have poor prognosis. But this study shows that only 53% of early stage patients with 17p deletion needed treatment over a 3 year period. Of note, patients with 17p deletion but mutated IgVH usually had stable disease.  Looks like the ‘good’ mutated IgVH takes some of the sting out of the 17p deletion.
• Only 5-7% of newly diagnosed and untreated patients have 17p deletion, and these guys may not have such a bleak future. The situation is very different when patients acquire 17p deletion as clonal evolution during the course of their disease.
• The researchers recommend that once disease progression happens, FISH analysis is necessary in order to develop appropriate treatment strategy. Presence of 17p deletion, for example, changes the ballgame and mandates different therapy options.
• Bottom line, using patient’s age, LTD, CD38 and IgVH mutation status for predicting time to first treatment, and adding FISH analysis when it is time to treat, the researchers believe will be sufficient to identify the two thirds of early stage patients who will progress and need intervention.

Editorial

Allow me to give you a simple example of how statistics works, and something called a normal distribution.  I promise I will make it clear why and how this applies to cancer patients like you.

You are out shopping for light bulbs. Obviously, you want a brand that has a reputation for lasting a long time without burning out. The manufacturer provides the following information about his light bulbs. He says his light bulbs have a mean life of 1000 hours and a standard deviation of 100 hours. Does this mean all the light bulbs made by the company will last exactly 1000 hours? No, it does not. It means that exactly half the light bulbs will last more than 1000 hours and the other half will last less than 1000 hours. That is precisely what a “mean value” implies. The majority of their light bulbs (68.2% of them) will last somewhere between 900 hours and 1100 hours.

Now, what are the chances that you get lucky and the particular light bulb you pick up lasts more than 1,200 hours? If you do the math using the standard deviation of 100 hours he quoted, it turns out you have a 1 in 45 chance (2.3%) of getting such a super bulb. But remember, there is an equally slim chance (1 in 45) that the bulb you got is a dud and lasts less than 800 hours before giving up the ghost.

So. The point to remember is this. While the vast bulk of light bulbs will last somewhere close to the 1,000 hour mark (the mean of this data set), there are always going to outliers. A few bulbs will last a lot longer than 1,000 hours, and an equally small number of bulbs will die a lot sooner than 1,000 hours.  The further you get away from the mean value of 1000 hours, the smaller the chances that you will get such a light bulb, either that extremely good or extremely bad.

Now, lets talk about what all this has to do with CLL patients.

Let us say you fall into a particularly bad prognostic group and the mean overall survival for this group of unlucky folks is quoted to be 5 years.  That means in a sufficiently large group of such patients, half of the group would be gone by 5 years, half would survive past 5 years.  And here you are, 4 years into this 5 year mean overall survival mark.  That sucks!!  What to make of it?

If you are not familiar with statistics, you might take that to mean you have one year left to live.  You may decide to quit your job, sell your house, say goodbye to heartless family and friends and head out to see the Taj Mahal or the pyramids, buy that red sports car you always wanted  - whatever happens to be on the short form of your “Bucket list”.  But beware.  You may well find that you live past the one year deadline, run out of money and have to slink back home – sans job, money, family or friends.  Of course, it is equally likely that you are an outlier on the other (ugly) side of the mean value, and you kick the bucket sooner than the one year you thought you had.

Same sort of logic holds for patients with the best of all prognostic indicators, where the group’s mean overall survival is, say, 25 years.  You would not be too far off the mark to look at that statistic and thank your lucky stars.  With reasonable safety you can continue to procrastinate getting your affairs in order, writing out your will and last testament or mailing off the checks to your favorite causes (ahem).  However, it is important to remember that this good statistic of overall survival does not guarantee that you as an individual will indeed live for another 25 years.  Anything can happen.  You could get hit by a bus crossing the street. You could develop a second cancer, a nothing squamous cell carcinoma on your balding scalp that decided to get aggressive.  Lots of things can go bump in the night.

Which of these scenarios is the right answer?  Should you expect to do better than the mean value quoted for your risk group, or worry that you may not do as well as the mean?  That depends on your personality, your individual circumstances.  Are you an optimist, a glass half full type of guy who expects to win the lottery every time you buy a ticket?  Or are you the kind that worries lightning may strike you as you head out into a light spring time drizzle?

There are also more concrete circumstances having nothing to do with optimism or pessimism.  Do you have good medical insurance?  Do you have a good support system to help take care of you, give you something to live for?  Are you otherwise in good health? Do you come from a long line of family that lived well into their eighties?  Do you take care of yourself or do you believe in burning the candle both ends?

You see what I mean?  Statistical averages based on large groups of patients just give you the odds – what are the most likely outcomes, if everything else is exactly the same.  But nothing is ever exactly the same; so while it is important to know the odds stacked in your favor or against you,  it is also important to remember your own mileage may vary.  That is perhaps the single most important take away lesson from statistics.  You are an individual, and group statistics cannot exactly predict what will happen to you.  You can influence the odds, either in your favor or against yourself, by the decisions you take.  Not always, since Lady Luck is notoriously fickle.  But enough of the time that it is worth the effort.  You agree?

As promised, here is the latest information on the PCI-32765 clinical trial at the NIH.  Given the importance of this trial, I will ask Radha (our webmaster) if there is some way we can have a special tab on the homepage where our members can access the latest information, read the discussions and comments readily.

The citation for the trial on clinicaltrials.gov is up.  Click on the link to access all the detailed information regarding inclusion criteria etc.  Cross-checking with the information I posted in my previous article I did not notice any discrepancies.  But while I try to be as accurate as I can, please remember the last word is theirs, not mine.

Notice the comment right on top of the trial announcement, saying “This study is not yet open for participant recruitment“.  I hear that will change as soon as staff get back from their New Year vacations.  Please allow me to emphasize once again, I believe this trial will finish recruitment very quickly.  The actual process of getting patients in to Bethesda MD for pre-assessment etc may take some time.  So, I am afraid it is going to be a bit of hurry up and wait (what else is new in life, right?).

• Be sure to read all the details of the clinicaltrials.gov citation, as well as our review articles on PCI-32765 articles (CAL-101 too, after all it too is a member of the kinase inhibitor drugs).  You can find the articles by typing in the appropriate key word or phrase into the search box at the top right hind side of our homepage.
• If after due consideration you decide you fulfill the inclusion criteria, and further more, you are seriously interested in participating in this trial, that is when it is appropriate for you to contact them.
• Please don’t jam their phone lines or overload their email system with irrelevant questions at this time.  The time and resources you waste will cost another patient who may really need access to this technology.  We have to watch out for each other.
• Once you have  your interest in participating on their record, the next step is the hardest:  be patient.  I expect they will get an avalanche of queries from patients and it will take a little time for them to sort through all the mail. I am afraid I am partly to blame for the huge interest.  Just Google “PCI-32765 clinical trials” .  My recent article is very high on the citation list of Google, no small achievement.  And we do have an awful lot of devoted readers of this website.
• You can bet on it that I will be keeping close watch on this trial.  You can do your bit by adding your voice to the discussion section.  We can learn a whole lot more when we work together.

Site News

Kinase inhibitor trials

Mind you, I am just as enthusiastic as the rest of you in hoping these new drugs will prove to be important addition to our arsenal against CLL.  But just in case I was too subtle and you did not read between the lines of my previous couple of reviews of kinase inhibitor trials (CAL-101, PCI-32765), I have been a little frustrated by the design and conduct of these trials thus far.   I prefer clinical trials that are (1) more transparent (2) do good science while they are about it (3) let the chips fall where they may when discussing clinical trial results and especially adverse efefcts (4) last but by no means least in my opinion, be more concerned about patient safety – and not so much about rocking the boat of the drug company sponsors.

So, it is with considerable relief and enthusiasm I bring to your attention a hot-off-the-presses new clinical trial of PCI-32765.  It is so new that it has not yet been announced on www.clinicaltrials.gov .  I am not kidding when I designate this trial as this year’s timely Christmas (substitute the holiday of your preference, if you do not like Christmas) present for our patient community.

If you are even the tiniest bit interested in participating in a well designed kinase inhibitor trial, or heck, you just want to learn about a family of drugs that may be the greatest thing since the age of monoclonals, I suggest you sit up, pay attention, and read the details below.  And I suggest you log-in to follow the member discussion that follows my review as well.  We have some very smart and well informed members on this site, if I say so myself.  You can learn a lot from their comments.

If you wish to learn how these new family of drugs work, I recommend an earlier article where we discussed a cartoon version of their biochemistry.

A well designed trial

What do I like about this trial?  Let me count the ways, in brief.  But since it is next to impossible for me to be brief about anything for too long, the bullet point summary below will be followed by a longer (much longer) exposition of the details.  Who ever said patient advocates have to be succinct?  And since this review is a bit of a scoop, details ahead of the formal announcement and so forth, I want to make sure you guys have a real head start.  The more you know about the details of this study, the better you will be able to make an informed decision about participating in the trial.

What I like about this trial:

• Very sensible inclusion criteria open this trial to a large section of our patient community.
• I cannot find fault with their plans to do detailed science while they are about it. I will have more to say about what you can do to facilitate this, in the editorial section.
• The trial design is very detailed in how they plan to protect patients from adverse effects.  I like that.
• This research group has a track record of patient friendliness, world class expertise and quality of care that few institutions can better.
• Icing on the cake:  the trial is going to be conducted at the NIH (National Institute of Health), Bethesda, MD.  If you are not familiar with the NIH/NCI clinical trial programs, shame on you.  I urge you to read an earlier article – and even more important, our member comment section that follow it – to get a feel for what you can expect.  Nothing like prior satisfied customers to spread the word.
• Pharmacyclics, the drug company that owns PCI-32765, does not pay for this trial. Your tax dollars do that – a good way of spending the money, in my humble opinion.
• Worried about the status of your medical insurance? Perhaps you are unlucky enough to be winging it without adequate medical insurance? Let me give you helpful hint.  They do not (repeat, not) ask for medical insurance card when enrolling patients for this clinical trial.  Some of our members who participated in other NIH / NCI clinical trials can tell you a lot more about how the financial stuff works out.  Speak up, you guys.  You know more about this aspect of it than I do.  Your prior experience can guide the new volunteers better than I can.

Nothing in life is totally perfect

• This trial does not include all CLL patients, there will be some that will not fit the inclusion criteria. Left out in the cold are those young and feisty CLL patients younger than 65, unless they have been ‘blessed’ with 17p deletion.  Pity. (I suggest you read the section on inclusion criteria below carefully – and be sure to confirm the details with the folks at the NIH.  I do my best to be accurate, but the last word is not mine, it is theirs.)
• This is a single agent trial.  We need to learn to walk before we can run.  I have every expectation that down the road PCI-32765 and others like it will be combined with other drug regimens.  But for now, we need to know what this drug can do, on its own; what it can achieve in all three major compartments where CLL cells hide: in the blood, in the lymph nodes, and in the bone marrow.
• This trial is only offered at Bethesda, MD.  That may pose an accessibility problem for people who don’t live on the East Coast.  But as you will read later, it may be possible to have much of the blood monitoring done by your local physician and fax the results in. The study drug PCI-32765 is an oral pill, so no need to come to the NIH for lengthy drug infusions etc.
• Actual recruitment will begin after January 1, 2012.  Please don’t make a pest of yourself and tie up their phone lines with requests before then.  Use the time between now and then to get your thoughts together, discuss it with your family, make sure you are truly interested in participating in the trial; get your medical information in one place so that you can answer questions etc.  Do your due diligence!
• I will publish contact information and any other updated information regarding this trial after January 1, 2012.  Keep an eye out for it.
• The number of people they plan to recruit is unfortunately limited – but I suppose that is to be expected.  First come, first served, folks.  Word to the wise, I am pretty sure this trial will be sold out quite soon.

Clinical Trial Design

Dr. Mohammed Farooqui is the Principal Investigator of this trial.  I do not personally know Dr. Farooqui. But I do know Dr. Adrian Wiestner, who is medically responsible investigator for this trial.  Dr. Wiestner is on my very short list of good guys.  I remember giving him a very hard time when we got into an argument at an ASH conference.  I am glad he did not hold it against me, and we have since become good friends.

• This is a Phase-II trial, single agent (PCI-32765) clinical trial. Two cohorts of patients will be recruited.  First cohort is any CLL/SLL patient who is over 65, either chemo naive or previously treated, so long as they are presently in need of treatment (based on standard IWGCLL guidelines).  The logic here is to see if this drug will give decent responses in ‘senior citizens’ who may be contra-indicated for aggressive chemoimmunotherapy combinations such as FCR or bendamustine containing regimens.  This is particularly of importance in people who have already been through therapy and relapsed, the so-called “salvage” cases.  Uggh.  I hate that word.
• The second cohort is anyone with 17p deletion or dysfunction – irrespective of their age or the level of progression of their disease (yeah, they can’t be minors, they have to be older than 18.  Crying out loud, do you know any CLL patients younger than 18?  I don’t.).  Logic of inclusion of this group is to see if early intervention in this very high risk group will improve otherwise bleak overall survival statistics.
• Left out in the cold are CLL patients younger than 65, unless they have been ‘blessed’ with 17p deletion.  Pity.
• PCI-32765 will be given at a dose of 420 mg/day without interruption.  It is an oral pill, you can take it with meals or all by itself.  This dose was identified as appropriate in the earlier trial.
• After 6 months (6 cycles, each cycle is 28 days long), patients will be re-assessed using CT scan and physical examination, as well as blood tests.
• If they have done well on therapy for the fist 6 months, after a 3 month drug holiday (if necessary), drug treatment can be continued for a total of 12 months at the NIH.  It may be possible for patients to continue therapy beyond 12 months under the supervision of their primary care physician – if the drug is still working well for them and there are no intolerable side effects.
• There is a ceiling of 64 on the total number of patients to be recruited.
• None of the researchers or staff involved in this trial have any financial conflicts of interest with this drug or its manufacturer.  Pharmacyclics supplies the drug to the NIH for the purposes of this study, but does not in any way compensate any of the researchers or staff.

Inclusion Criteria Details

Please read this laundry list carefully.  Most of it is quite familiar.  You have seen these inclusion criteria before.  But as always, devil is in the details and you need to know if there is anything in here that becomes a red flag for you.  All the same, if you are not sure that you fit the bill, you should check with the PI yourself – rather than taking my word for it.

• I have already described the two cohorts they will be recruiting.  Those over 65 (treated or naive) who need treatment now, and those with 17p deletions or dysfunction – irrespective of age.
• You must have confirmed CLL.  That means ALC higher than 5K, or confirmed case of SLL where all the cancer cells are hiding out in the lymph nodes and very few of them are in the blood.  You must have immunophenotype of CD5, CD19, CD20 and CD23 – this is the confirmatory fingerprint of CLL that we have discussed many times.
• Need for treatment is defined by the usual guidelines set forth by IWGCLL
• Neutrophil counts need to be higher than 0.5K and platelet counts above 25K.
• You must not have had pretty much any CLL therapy in the past 4 weeks prior to start of this therapy.  Frankly, I think it will take longer than 4 weeks for all the paperwork to be sorted out – so you would be past the washout period in any case.
• People whose CLL has transformed to more aggressive lymphoma (“Richter’s transformation) are excluded.
• If you have AIHA or ITP that requires you to be on steroid therapy, you cannot be in this trial.
• Your liver function cannot be totally shot.  Bilirubin cannot be more than 1.5 times upper limit of normal range.  ALT / AST cannot be more than 2.5 times upper limit of normal.  (Folks with Gilbert’s syndrome are exempt – these guys have unusually high creatinine).
• As for kidney function, creatinine cannot be more than 2 times upper normal limit.  GFR (glomular filtration rate) must be at least 50 ml/min.
• No active or latent Hepatitis B infection, no HIV infection.
• You must be sane enough to sign the consent form, older than 18 years of age, chronologically speaking.  Young-at-heart does not disqualify.
• You must promise to use contraceptives, so that you don’t make babies while on the trial, even if you don’t think you will be feeling frisky enough to do so.

I think I got the lot of them. Phew.

Monitoring, Evaluation, Science

It is important for all of us to remember these are clinical trials.  We don’t have all the answers, and that is the point of doing these trials – to find the answers.  It kind of makes sense to use the opportunity to learn as much as we can, don’t you think?  What is the point of going to all the fuss and expense, not to mention risk to our patient volunteers, if we then pull our punches when it comes to doing good science?

• You will be given a full physical examination and your medical history taken during the eligibility assessment.  Various blood tests will be done for establishing liver, kidney function, hepatitis, HIV infection etc.
• A CT scan (neck to pelvis) will be done to evaluate the level of lymphadenopathy (size of swollen nodes). There will be a repeat CT scan after six months on the drug, to assess effectiveness of the drug in shrinking swollen lymph nodes.
• EKG will be done to check out your heart.
• Pregnancy test to make sure you are not.
• You must be evaluated at the NIH at certain time points in order to make sure stuff does not fall between the cracks.  But interim weekly blood tests can be done at the NIH or through your local healthcare provider, with the results faxed to the NIH.  This flexibility may be a huge relief to patients who are far away from Bethesda MD.
• You will stay on the drug for 6 months (six cycles, 28 days each), as long as you are benefiting from it and the adverse effects are not excessive.  Then following a 3 month “holiday” (if needed), you can continue on the drug for another 6 months at the NIH.  Of course, if the drug company goes belly up in the middle and stops supplying the drug, everything comes to a screeching halt. And you always have the right to quit the trial – that is your prerogative as a volunteer in any clinical trial.
• With your kind permission, they want to do a bone marrow biopsy before start of therapy.  Same for a lymph node biopsy.  And they would like to repeat these two again after 6 months on the drug.   I have a lot more to say about this in the editorial section.
• You may be asked to participate in a cool experiment where you swallow a small amount of “heavy water” (this has an isotope of hydrogen other than the garden variety isotope coming out of the tap).  By following this “tagged” water in your blood samples etc, researchers will be able to understand better how this drug works, its mechanism of action in clearing CLL cells out of their protective microenvironments.
• You will have full access to all (and I mean ALL) of your medical data gathered during the trial.  Just ask for it, if you want it.

Supportive Care

We do not know enough about the possible adverse effects of these new drugs.  That is the whole point of dong these clinical trials, so that we can find out what may be lurking in the bushes.  Do kinase inhibitors cause more than normal drop in immunoglobulins?  Is there an increased risk of pneumonia?  Is this due to infectious agents (bacterial, viral, fungal) or is the pneumonia more akin to drug induced lung inflammation?  How long can patients stay on the drug and benefit?  Enquiring minds want to know.

• We do not know how PCI-32765 interacts with other drugs that the patient may be taking for other medical issues.  It is important that the patient discuss all medication, herbal or otherwise, with the Principal Investigator (PI) ahead of start of therapy.
• Allopurinol (protection against risk of tumor lysis syndrome) will be given prior to start of therapy, at the discretion of the PI. I suppose it depends on the assessment of the patient’s overall tumor burden.
• If the patient is seen to be at increased risk of opportunistic infections, TMP/SMX  (“Bactrim”) prophylaxis will be provided;  or alternate antibiotic if the patient is allergic to sulfa drugs.
• Anti-viral protection for HSV  will not be used routinely, but will be given at the discretion of the PI.  (While we are on the subject of Herpes virus, be sure to tell the PI if you have had prior episodes of shingles and concerned about a repeat attack.)
• If the patient develops neutropenia, Neupogen or Neulasta prophylaxis will be used.
• Epoietin growth factors such as Epogen,  Procrit will NOT be used in case of anemia.  Good!  CLL Topics was way out front in warning of the risks associated with use of Epo drugs in cancer patients (“The dark side of Epo“).  Instead, this clinical trial will use good old fashioned packed red blood cell transfusions.  All required blood products will be irradiated prior to use, to further protect against infections.  And if you need to get blood transfusions while you are at home, they ask to talk to your local guy to make sure you will get irradiated blood products only.

Editorial

As promised, this has become a very long review.  I hope you will read it carefully, as well as participate in the discussion that follows.  Lots of details to get at first reading – but I thought it was important to give you as much information as I had.  Once the clinicaltrials.gov citation is up, you can verify most of these details there as well.

I have been a researcher and scientist all my adult life.  While I am not a professional oncologist or hematologist, I do know a little something about how to design an experiment such that it has a chance of yielding credible information.  My pet peeve with the design of the recent kinase inhibitor trials is the lack of adequate science in their clinical trial protocols – not to mention detailed scrutiny of potential adverse effects and what may be causing them (one in four chance of grade-3 pneumonia, anyone?)

Previous investigators of PCI-32765 said the only reason to do before and after bone marrow biopsies is to confirm MRD negative remission status, and since BMBs are not needed for staging patients, no point in doing them.  I humbly beg to differ.  Bone marrow biopsies are needed to judge whether or not this drug (and others like it) can clear the bone marrow compartment.  Telling us that we can infer this critical bit of information based on improving blood counts is specious and disingenuous at best.  Since the claim to fame of kinase inhibitors is that they interfere with CLL cell microenvironment, surely we need to confirm this happens both in the lymph nodes and the bone marrow?

One of the researchers was quoted as saying they did not do BMBs because patients don’t like them.  Well, while we are on the subject of what we do not like, we do not like having CLL either.  And we do not like being condescended to.  When was the last time you felt research protocols were being written with your liking or disliking being taken into account?  You want me to sell you a bridge in Brooklyn?

I do not expect any of you to volunteer for a clinical trial solely for the benefit of humanity.  You would not be signing on the dotted line of the consent form unless you thought this particular drug would do you some good, that it has a reasonable chance of being better than the alternatives you have available to you.

That said, there is a level of idealism in all of us.  We are not quite willing to donate our bodies to science while we are still alive, but if there is anything we can do to help our fellow CLL brother/sister, without going too far out of our way, I hope I can count on each and every one of you to step up to the plate.  If you tell me I am crazy to expect that, no one really cares about anyone else, then I might as well shut down this website.  Why bother, if each of you does not feel a similar sense of camaraderie for the rest of our little community?  We can hope for success, pulling together.  Or we can each fight this disease alone, all by our lonesome selves.  Which is it going to be?

And then there is this little thing called familial CLL.  This “good cancer” will not look even a little bit “good” if someday one of your kids or grand-kids inherits it from you.  Kinase inhibitor drugs may be in early stages for us old geezers now. But they may make all the difference to the next generation of patients – if we help make possible well conducted clinical trials looking for results based on solid science.

So.  Here is the proposition.  You get accepted into this clinical trial. You are not crazy, you are not particularly into S/M lifestyle, you do not enjoy the prospect of a bone marrow biopsy before and after completion of therapy.  Same goes for a lymph node biopsy.  But pretty please, do say “yes” to both procedures if you are asked.  One not-so-bad pinch on the rear-end for you, one giant leap of scientific understanding for our patient community.  We will be cheering your courage and bravery from the sidelines, I promise you.  We hope the researchers will thank you, but you can be sure we will.

As for the heavy water experiment, that is a slam dunk.  It has been done before (at Long Island Jewish Hospital, under the supervision of Dr. Kanti Rai, if I remember correctly) and it is zero hassle, you just drink this little vial of “heavy” water (no, you will not glow in the dark and your urine will not turn blue either). There is very little risk of toxicity of any kind.  Do say yes, if you are asked.  Just think, how cool it will sound when you describe it to your buddies – or better still, your grand-kids.

See what I mean about this triala being a Christmas present?  Not just a Christmas present for you, but one that you can give the rest of the patient community – by participating in this clinical trial and supporting the necessary science.  This new family of drugs are too important to leave all the testing to drug company sponsored clinical trials.  Here is your chance to make sure that does not happen.

“Soil & Seed”

There is a concept in cancer biology called “soil and seed“.  What do you need for plants to grow and flourish?  You need healthy and strong seeds with good vigor and pest resistance built into them.  But even the strongest seed cannot flourish in bad soil.  Both strong seeds and nutritious soil capable of supporting plant growth is needed for plants to grow and flourish.  Any gardener can tell you that!

This analogy works in cancer biology as well, it seems.  High risk cytogenetics in CLL (unmutated IgVH, 11q and / or 17p deletions, unmutated IgVH etc) are the equivalent of strong cancer seeds, able to resist the damage inflicted on them by chemotherapy.  A supportive microenvironment – such as lymph nodes, bone marrow etc – provides the rich soil.  Presto, when both of these conditions are met, we have a faster growing and more difficult to control CLL. (Spleen and liver are also considered to be part of the lymphatic system and therefore for the purposes of this discussion, when I write about swollen nodes I am including spleen and liver as possible locations of swelling as well).

As you know by now, CLL comes in a variety of flavors.  In some patients, almost all of the disease is seen in peripheral blood.  While these guys may have impressively high white blood counts and absolute lymphocyte counts to match, in fact they are the lucky ones and their disease is likely to be the easiest to treat.  This is why I caution patients about getting too fixated on white blood counts.  It is only a part of the picture, a small part of the picture as it turns out.

On the other hand, people who have large percent of their CLL cells nicely tucked away in swollen lymph nodes and bone marrow, spleen, liver etc have a bigger problem.  You see, CLL cells are insecure little buggers. They don’t like being alone, just cruising around in blood circulation all by their lonesome selves.  They do much better, live longer and have many more babies when they live in well established colonies of other CLL cells.  Also of importance are supportive cells surrounding the CLL clusters, giving the cancer cells much needed approval and survival signals.  In fact, some of the interesting papers at the recent ASH2011 report that microenvironment where CLL cells live plays a huge role in the progression of the disease.

Who are most likely to have lymph node centered disease?  Typically, people with high risk CLL (FISH deletions of 11q, 17p, 12 trisomy) are most likely to have enlarged nodes.  In these patients the lymphocyte count in the blood is nothing more than the tip of the iceberg.  As much as 90% of the CLL cells can be safely tucked away in lymph nodes, making these cancer cells hard to get at.  As we discussed above, these CLL cells in lymph nodes fit the classic definition of strong seeds in a fertile soil.  The cytogenetics makes it hard to kill them, and the cancer friendly microenvironment of the lymph node makes it easier for them to live long and prosper.

It has been a depressing fact of life that many of the drug regimens we had up to now were not very successful at treating patients with high risk CLL, especially if they also had massive lymphadenopathy (fancy word for swollen lymph nodes, or swollen glands if you are a Brit). Important drugs such as Campath are considered useless and contra-indicated  if the patient has large lymph nodes.  Single agent monoclonal antibodies (Rituxan, ofatumumab) are not of much use either.  More aggressive therapies such as FCR and bendamustine combinations may be able to get (most of) the CLL cells lurking in the lymph nodes, thereby giving high response rates.  But as we are learning, not everyone can handle FCR and similarly high impact therapies.  Elderly and frail patients, folks with other medical issues etc may find such aggressive regimens hard to tolerate.  For them, the price tag of therapy toxicity may be more than the remission is worth. People who have relapsed after prior therapies such as FCR or FR are another subset of patients who really needed better salvage therapy options.

This new understanding and emphasis on the microenvironment of CLL cells is fueling a lot of the excitement regarding kinase inhibitors such as CAL-101 and PCI-32765.  The science is complex and I will not go into it here.  Please read an earlier article titled “Dawn of a new Era” where I discuss a cartoon version of it.   In a nut shell, drugs such as PCI-32765 interfere with the cyotokines that act as the cookie crumb trails leading CLL cells home to lymph nodes, as well as the adhesion factors that allow them to stick there.  Deprived of their nurturing microenvironment and flushed out into open blood circulation, the soil part of “Seed & Soil” is defeated, making the CLL cells easier targets for therapy.

We discussed the first batch results of PCI-32765 in an earlier report.  Here is a followup, with more mature results.

The Bruton’s Tyrosine Kinase (BTK) Inhibitor PCI-32765 Induces Durable Responses in Relapsed or Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): Follow-up of a Phase Ib/II Study

December 13, 2011

Susan O’Brien, MD1, Jan A. Burger, MD, PhD2, Kristie A. Blum, MD3, Richard R. Furman, MD4, Steven E. Coutre, MD5, Jeff Sharman, MD6*, Ian W. Flinn, MD, PhD7, Barbara Grant, MD8*, Nyla A. Heerema, PhD9, Amy J. Johnson, PhD3, Tasheda Navarro10*, Eric Holmgren, PhD10*, Eric Hedrick, MD10 and John C. Byrd, MD11

1Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX

2Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX

3The Ohio State University, Columbus, OH

4Department of Medicine, Division of Hematology-Oncology, Weill Cornell Medical College, New York, NY

5Divisions of Hematology and Oncology and Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA

6US Oncology, Springfield, OR

7Sarah Cannon Research Institute, Nashville, TN

8Medicine, Vermont Cancer Center, University of Vermont, Burlington, VT

9Pathology, The Ohio State University, Columbus, OH

10Pharmacyclics, Inc, Sunnyvale, CA

11Division of Hematology, The Ohio State University, Columbus, OH

Introduction: Btk is a central mediator of B-cell receptor signaling which is essential for normal B-cell development. PCI-32765 is an orally-administered irreversible inhibitor of Btk which induces apoptosis and inhibits cellular migration and adhesion in malignant B-cells. An early analysis of the phase Ib/II study PCYC-1102 showed PCI-32765 to be highly active and tolerable in patients with CLL (Byrd, ASCO 2011). Here we report longer-term follow-up of this multicenter phase Ib/II trial.

Methods and Patients: Two cohorts of CLL patients (previously untreated ≥65 years old and relapsed/refractory [R/R] disease following at least 2 prior therapies, including fludarabine) were treated with oral PCI-32765 administered daily for 28-day cycles until progression of disease. Doses of 420mg (previously untreated and R/R) and 840mg daily (R/R) were examined. The patients with R/R disease are the subject of this report.

Results: Sixty-one R/R CLL/SLL patients were enrolled (420mg cohort n=27, 840mg cohort n=34). The median follow-up time for the 420mg cohort is 10.2 months and for the 840mg cohort is 6.5 months. The median number of prior treatment regimens for the 420mg cohort was 3 (2-10) and for the 840mg cohort was 5 (1-12). Seventy-two percent of patients had at least one poor-risk molecular feature: del(17p) 31%, del(11q) 33%, IgVH un-mutated 57%. Treatment has been well tolerated. Two patients have discontinued for adverse events (AE); 6 patients have required reduction of PCI-32765 dose (420mg cohort 2/27, 840mg cohort 4/34). Grade 1 or 2 diarrhea, fatigue, nausea, and ecchymosis have been the most frequently reported AEs. Serious AEs (SAEs) have occurred in 38% of patients; SAEs considered potentially related to PCI-32765 have occurred in 10% of patients. Grade ≥3 AEs considered potentially related to PCI-32765 occurred in 21% of patients. A characteristic pattern of response, with a transient phase of lymphocytosis typically peaking within the first 2 months of Rx, followed by resolution over time, has been observed in the majority of patients. Objective response (ORR; PR + CR) by IWCLL criteria in the 420mg cohort cohort, previously reported as 48% with 6.2 months median follow-up (Byrd, et al ASCO 2011), is now 70% with 10.2 months median follow-up. ORR in the 840mg cohort is 44% at 6.5 months median follow-up. An additional 19%, and 35% of patients in these cohorts, respectively, have a nodal PR (>50% reduction in aggregate lymph node size) with residual lymphocytosis. ORR appears to be independent of molecular risk features. Eighty-two percent of patients (50/61; 420mg cohort 22/27, 840mg cohort 28/34) remain on PCI-32765. Only 8% (5/61) of patients have had progressive disease (PD); 6-month PFS is 92% in the 420mg cohort and 90% in the 840mg cohort. Treatment cessation not related to PD or AE includes: death (n=2) or investigator discretion (n=3).

Conclusions: The potent Btk inhibitor PCI-32765 is well tolerated and is associated with high rates of 6-month PFS in R/R CLL/ SLL. Phase III trials of PCI-32765 in CLL/ SLL are planned.

Disclosures: O’Brien: Pharmacyclics, Inc: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Burger: Pharmacyclics, Inc: Research Funding. Blum: Pharmacyclics: Research Funding. Furman: Pharmacyclics, Inc: Research Funding. Coutre: Pharmacyclics, Inc: Research Funding. Sharman: Pharmacyclics, Inc: Research Funding. Flinn: Pharmacyclics, Inc: Research Funding. Grant: Pharmacyclics, Inc: Research Funding. Heerema: Pharmacyclics, Inc: Research Funding. Johnson: Pharmacyclics, Inc: Research Funding. Navarro: Pharmacyclics, Inc: Employment, Equity Ownership. Holmgren: Pharmacyclics, Inc: Consultancy. Hedrick: Pharmacyclics: Employment, Equity Ownership. Byrd: Pharmacyclics, Inc: Research Funding.

 

Judging credibility of research reports is an important part of understanding the results.  I discussed some of the issues that go into reading the tea leaves in my last article on CAL-101.  Same rules apply here as well.  High powered researchers, prestigious institutions, every single one of them with financial connections to the company (Pharmacyclics) that owns the drug. The lead author (Dr. Susan O’Brien, M. D. Anderson) who presented the data at ASH2001 is also on the Board of Directors of the company.  Does this mean we throw away the whole report as so much conflicted nonsense?  No, that would be throwing the baby out with the bathwater indeed.  It just means we keep things in perspective when we read glowing press reports about the new drug.

Here is a bit of a “teaser” for you guys.  In the next few days I will be publishing an important new development dealing with ongoing PCI-32765 clinical research.  You will not be off the mark if you think of it as a timely Christmas present for the CLL patient community.  (Yeah, Happy Holidays present for those of you who do not celebrate Christmas. Sheesh.)

Clinical Trial Design

This clinical trial had two patient cohorts.  First one included patients who were chemo-naive (untreated) but older than 65 years.  In other words, they are looking at PCI-32765 as a possible frontline drug in older patients for whom combinations such as FCR may be contra-indicated.  The second cohort consisted of relapsed / refractory patients who have been through at least two earlier therapy regimens, including fludarabine.  In other words, at the other end of the curve, looking at PCI-32765 as a potential salvage therapy for this tough to treat crowd.  This report is only about the second cohort, the folks who went into the PCI-32765 after relapse following prior two cycles of therapy.

There were 61 patients in this group, some were classified as SLL, the lymph node variant of CLL.  As you know by now, PCI-32765 is an oral drug, making its administration easy. Dosage varied between 420mg and 840mg per day.  Followup (thus far) is between 6-10 months.

Results, Risks, Rewards

Bear in mind this is a tough to treat patient cohort.  Besides being relapsed and/or refractory, 44 out of the 61 patients had one or more of the high risk features (17pr or 11q deletion, or unmutated IgVH). “Treatment was well tolerated”  - good, but I will take that with a pinch of salt, thank you very much.  Amazing how much perspective changes when you are at the pointy end of the stick.  Serious adverse effects occurred in 38% of the patients, of which the researchers judge 21% were attributable to the drug in question.  I suppose the definition of well tolerated is relative, and in this case it is being used in the context of ‘beggars cannot be choosers’.  All the same, I would have preferred more sympathetic language, don’t you think?

Ten months of daily administration of 420mg of PCI-32765 got an overall response rate of 70% of the patients.  Overall response rate is the sum of “CR” and “PR”.  (Here is an article that describes in detail what CR and PR mean). The abstract does not break out how many CRs there were, and how many PRs.  I am willing to bet dollars to donuts the vast majority of these were PR (“partial response”).  For starters, I do not really expect to see any full blown CR remissions in this relapsed / refractory crowd.  Second,   human nature being what it is, I suspect the abstract would have made much of the large number of CR responses, if that had been the case.

The higher dosage (840mg daily) group has been followed for only little over 6 months and in this group the overall response is at 44%.  Hopefully, they too will have more and more people getting some sort of a response as time on therapy increases.

Only 8% of the patients seem to have their CLL progress (get worse) while they were on the drug.  Two patients died, but the deaths are not considered to be due to PCI-32765.

Here is the most important part of the whole study.  Patients’ response to PCI-32765 does not seem to depend on whether or not they had high risk disease.  In other words, it did not seem to matter whether they had 17p, 11q deletions, unmutated IgVH etc, they were just as likely to get a response to the drug. That is indeed welcome news.  Remember, in our introduction to this article we discussed the need for new therapy options for patients with high risk disease, those unfortunate folks who had both the “good seed and nurturing soil” version of aggressive cancer.  This study supports some of the excitement about these new generation of designer kinase inhibitor drugs, in that they seem to be able to do what most other drugs cannot do:  treat high risk and relapsed / refractory patients.  As with CAL-101, the characteristic feature of kinase inhibitors, their ability to flush CLL cells out of comfortable lymph node cocoons, that seems to be the important feature of how these drugs act.

Notice the silence regarding action on the bone marrow front.  As in the previous article on CAL-101, this abstract does not mention the bone marrow microenvironment.  Does PCI-32765 do a good job of clearing it?  We do not know.  Once again, I do not think the bone marrow microenvironment is identical in all ways to the lymph node environment.   Is it reasonable to assume / infer / hope / expect that because PCI-32765 works well in flushing out CLL cells from lymph nodes, it will do the same for the bone marrow as well?  We do not know – and frankly, I think it is a bit of a stretch to make that assumption.  I realize drug companies spend good money getting these important trials done.  But how about doing good science while we are about it?  Our guys are risking their necks in volunteering for these early stage trials. How about making the best use of their sacrifice, and thanking them too, while we are on the subject?

Are these drugs truly low toxicity?  I am not too sure of that.  In my layperson opinion, the jury is still out on that.  At the same time, please allow me to remind you that we are willing to accept a certain amount of toxicity risk, if the drug in question can actually deliver in terms of deep and lasting remissions.  Until better drugs become available with even better responses and fewer adverse effects.

Will the remissions be long lasting?  Will the patients have to take PCI-32765 indefinitely, or can they quit after a good long time and still expect to stay in remission?  That question has not even begun to be answered, yet.  If I were to bet, I would expect patients would not stay in remission for very long after stopping daily use of PCI-32765.  But that is just a guess on my part.

My guess is that these early trials of kinase inhibitors as single agents will be followed by the inevitable combinations of these drugs with other agents; chemotherapy agents such as F and C come to mind.  We may expect to see more full fledged CR responses in such combinations, as well as deeper, longer lasting remissions.  Unfortunately, I think most of you can figure out by now, addition of standard chemo agents such as F, C and B(bendamustine) will increase the toxicity of the regimens too.  Sigh.

So, what is the Christmas present I promised all about?  You will just have to wait a couple of days, no more than a week,  I promise.   And if you are getting busy making your “nice” and “naughty” lists for holiday giving, I hope you will put us in the “nice” category.  Supporting our work through your donations is what keeps us going.  It is easy to do. You can do it using your credit cards (through secure PayPal).  Or you can put your check in the mail.  Hit the “Donate” button below and the page has all the information you need, including our mail address.  That’s it folks – that is the sum total of our “donations drive” for the year.

CAL-101: New Generation of Kinase Inhibitors

 When Rituxan made its debut about a decade ago, this immunotherapy drug revolutionized the treatment of CLL.  Addition of this monoclonal antibody to existing standard chemotherapy drug regimens improved response rates as well as duration of remissions in majority of patients.  The good thing about chemo-immunotherapy combinations (FCR is a famous example of such a combination) is that the addition of the immunotherapy component did not add significantly to the toxicity of the regimen, and at the same time it made significant improvements on the response side.  Better results, with no increase in toxicity – that is what I like to hear.

Now we can hope for the next breakthrough, the next phase of targeted and designer made drugs.  I am sure most of you have heard of Gleevec, the drug that changed the playing field entirely for CML patients. It gave hope and life to CML patients who had none before.  True, it fell a tad short of full and no-looking-back cure of CML.  Patients do develop resistance to it over time, and certain percentage of patients relapse even while on the drug.  But the impact it has had on CML treatment is nevertheless stunning, to say the least.  Building on success, new and better versions of Gleevec style drugs are already in the works.

Gleevec and CAL-101 belong a group of drugs called kinase inhibitors.  We discussed the science of kinase inhibitors (cartoon version, I am afraid), in an earlier article.  The science has not gotten any easier to explain and understand since I wrote that last article. I  therefore suggest you refer to it to refresh your memory of how CAL-101 works.

For now, as a quick heads-up, let us remember CAL-101 is an orally available drug.  You pop a pill, once or twice a day depending on the dose and schedule, and that is it.  No trips to the back room of the oncologist’s office for a long and tedious infusion, no nasty needle pokes while they try to find a good vein. It seems to be relatively well tolerated.  We have no idea how much it will cost, when (if) it is a fully FDA approved drug and available for the general patient.  Right now, it is only available to patients participating in registered clinical trials.  Call me a cynic, but something tells me this is not going to be a cheap drug, once it does become available.

CAL-101 seems to mess with CLL cells ability to congregate in cozy little groups in lymph nodes, spleen etc.  It has become increasingly clear that CLL cells are a lot harder to kill when they are nicely tucked away among their fellow cancer cells and other sympathetic “nurse-like cells” giving them encouraging survival signals – telling the cancer cells to live long and prosper, as it were.

Most drugs available to us are able to clear CLL cells floating around in open blood circulation pretty easily.  Blood counts are the first to recover. Sky high WBC and ALC take a nose dive downwards pretty soon after start of most therapies.  But clearing bulky lymph nodes, that is an entirely different matter and much harder to do.  Some drugs are terrible at it – for example, Campath is contra-indicated for patient with bulky nodes since it does such a poor job of clearing them.

This seems to be where kinase inhibitors such as CAL-101 have their most impact.  Kinase inhibitors such as CAL-101 seem to be able to drive the CLL cells out of their lymph node locations and out into open blood circulation, where they are then easily killed.  A consequence of this mechanism of action is that soon after start of therapy with CAL-101, there is a very satisfactory melting away of bulky nodes, and this is paralleled by increased numbers of CLL cells in the blood counts.  All those CLL cells flushed out of the lymph nodes and spleen have to go somewhere, and that is why your WBC and ALC may shoot up immediately after start of therapy.  But this should not alarm people who understand the mechanism.  Given a little time, the lonely CLL cells cruising around in the blood are easily picked off, one at a time.  Blood counts soon normalize, along with continued reduction in lymph node size.

OK, with that quick primer on how CAL-101 works, it is time to review the latest clinical trial results published at ASH 2010 conference.

Abstract 55:  CAL-101, An Isoform-Selective Inhibitor of Phosphatidylinositol 3-Kinase P110, Demonstrates Clinical Activity and Pharmacodynamic Effects In Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia

Richard R. Furman, MD1, John C. Byrd, MD2, Jennifer R Brown, MD, PhD3, Steven E. Coutre, MD4, Don M Benson, Jr., MD5, Nina D. Wagner-Johnston6, Ian W. Flinn, MD, PhD7, Brad S. Kahl, MD8, Stephen E. Spurgeon, MD9, Brian Lannutti, PhD10, Neil A. Giese, Ph.D.*,10, Heather K Webb, Ph.D.*,11, Roger G Ulrich, Ph.D.10, Sissy Peterman*,12, Leanne M. Holes*,10 and Albert S Yu, MD*,10

1 Weill Medical College of Cornell University, New York, NY, USA,

2 The Ohio State University, Columbus, OH, USA,

3 Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA,

4 Stanford University School of Medicine, Stanford, CA,

5 The Ohio State University Medical Center, Columbus, OH, USA,

6 Washington University, Saint Louis, MO, USA,

7 Oncology, Sarah Cannon Research Institute, Nashville, TN, USA,

8 University of Wisconsin, Madison, WI, USA,

9 Division of Hematology and Medical Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, OR, USA,

10 Calistoga Pharmaceuticals, Seattle, WA, USA,

11 Drug Safety, Calistoga Pharmaceuticals, Seattle, WA, USA,

12 Clinical, Calistoga Pharmaceuticals, Seattle, WA, USA

Introduction: The class I phosphatidylinositol 3-kinases (PI3Ks) regulate cellular functions relevant to oncogenesis. Expression of the PI3K p110 isoform (PI3K) is restricted to cells of hematopoietic origin where it plays a key role in B cell proliferation and survival. In chronic lymphocytic leukemia (CLL) the PI3K pathway is constitutively activated and dependent on PI3K. CAL-101 is an isoform-selective inhibitor of PI3K (EC50 of 62 nM in a whole-blood assay with >200-fold selectivity relative to other PI3K isoforms) that inhibits PI3K signaling and induces apoptosis of CLL cells in vitro.

Methods and Patients: This Phase 1 study evaluated the safety, pharmacokinetics, pharmacodynamics and clinical activity of CAL-101 in patients with relapsed or refractory hematologic malignancies. Sequential cohorts of patients were enrolled at progressively higher dose levels with cohort expansion based on toxicity profile and plasma exposure. CAL-101 was administered orally one or 2 times per day (QD or BID) continuously for 28-day cycles for up to 12 cycles (with the potential for more prolonged therapy on an extension protocol thereafter). Clinical response was evaluated according to standard criteria.

Results: At data cutoff, the study had enrolled 37 patients with CLL. Patients included: males/females n=31 (84%)/6 (16%) with median age of 65 [range 37–82] years, refractory/relapsed disease n=24 (65%)/13 (35%), bulky disease n= 29 (81%), and adverse cytogenetics of del(17p), del(11q) or both n=22 (63%). The median number of prior therapies was 5 [range 2–14]. The number (%) of patients with specific prior therapies included: rituximab n=37 (100%), purine analog n=37 (100%), alkylating agent n= 31 (84%), and alemtuzumab n=12 (32%). CAL-101 dose levels were 50 mg BID (n=1), 100 mg BID (n=4), 150 mg BID (n=11), 200 mg BID (n=10), 350 mg BID (n=7) and 300 mg QD (n=4). The median number of treatment cycles was 9 [range 1–13], with 21 (57%) patients continuing on treatment (11 on study and 10 on the extension protocol after 12 cycles). Symptomatic adverse events were infrequent, usually low-grade, and not clearly CAL-101-related. Grade 3 pneumonias occurred in 9 (24%) patients. Grade 3 hematological laboratory abnormalities included neutropenia n=9 (24%), thrombocytopenia n=4 (11%) and anemia n=3 (8%) that were not usually considered CAL-101-related. A pharmacokinetic analysis of dose-proportionality showed minimal increases in plasma Cmax and AUC at CAL-101 doses >150 mg BID; these data, taken together with the tumor regression results, have proved helpful in supporting Phase 2–3 dose selection. Flow cytometry of CLL cells from patients showed that CAL-101 reduced constitutive expression of phospho-AKT to background levels when measured after 1 week of treatment (p<0.0001), demonstrating pharmacodynamic inhibition of activated PI3K signaling. Plasma concentrations of chemokines CCL3, CCL4, and CXCL13 were elevated at baseline and decreased significantly within 1 cycle of CAL-101 administration (p<0.001 for all comparisons). CAL-101 reduced lymphadenopathy in all 32 (100%) patients with at least 1 post-treatment tumor assessment; 29/32 (91%) achieved a lymph node response (50% reduction in target nodal lesions). An initial increase in peripheral absolute lymphocyte counts of >50% from baseline was observed in 21/35 (60%) patients; increases were maximal during the first 2 cycles and decreased thereafter; the pattern suggested drug-mediated lymphocyte redistribution. Considering nodal and peripheral blood changes together, partial responses were observed in 11/33 (33%) of patients. The median duration of response had not been reached; 7 patients had response durations of 6 months. Of 20 patients with CLL-related thrombocytopenia (baseline platelet counts <100,000/µ L), 15 (75%) had either an improvement to >100,000/µ L or a >50% increase from baseline.

Conclusions: CAL-101, an oral PI3K isoform-selective inhibitor, shows acceptable toxicity, positive pharmacodynamic effects, and favorable clinical activity in heavily pretreated patients with CLL, including patients with refractory disease, bulky lymphadenopathy, and poor-prognosis cytogenetics. The high level of lymph node regression and prolonged duration of symptomatic tumor control strongly support evaluation of CAL-101 alone and in combination with other chemo/immunotherapy approaches to CLL management.

Disclosures: Byrd: Calistoga Pharmaceuticals: Consultancy, Equity Ownership. Brown: Calistoga: Consultancy. Kahl: Calistoga Pharmaceuticals: Consultancy, Research Funding. Lannutti: Calistoga Pharmaceutical Inc.: Employment. Giese: Calistoga Pharmaceuticals: Equity Ownership. Webb: Calistoga Pharmaceuticals: Employment. Ulrich: Calistoga Pharmaceuticals: Employment, Equity Ownership. Peterman: Calistoga Pharmaceuticals: Employment. Holes: Calistoga Pharmaceuticals: Employment. Yu: Calistoga Pharmaceuticals: Employment, Equity Ownership.

Clinical Trial Design, Adverse Effects

This clinical trial recruited 32 previously treated CLL patients.  I think it is fair to say, they are a pretty tough crowd to treat.  The median age was not all that high (65 years), and it reminds me once again that there is a real disconnect between the average age of clinical trial participants and the average age of CLL patients in general.  Pity.  It makes it harder to apply the lessons learned in clinical trials to real live patient populations. Almost all of the patients were either refractory or relapsed.  (Remember, ‘refractory’ is worse than merely ‘relapsed’).  29 of the 32 patients had bulky disease.  22 of the patients had 17p and / or 11q deletions, the high risk FISH abnormalities we are all aware of by now, I hope.

Drug dosage varied greatly, from as little as 50mg tablets twice daily all the way to 350 mg / twice daily.  It looks like the researchers are zeroing in on 150 mg/twice daily as the optimum dose.

I am worried to see the continued observation of pretty serious grade-3 pneumonia in a quarter of the patients.

Since I take patient confidentiality seriously, I am not at liberty to disclose the full details – but I think it is OK to disclose that I have heard from more than a couple of the patients in this trial who came down with pneumonia.  Pretty scary stuff.  Since the patients take CAL-101 at home, in a couple of the cases that I am aware of the early stages of the pneumonia were not readily noted and treated correctly by local healthcare providers.  Confusing matters further, apparently the lungs of the patient sound just fine when physicians listen to them.   More often than not, patient is sent home with a prescription for antibiotics, on the assumption the horrid cough is due to bacterial infection of some sort.  Not the case at all, it seems.  The driving force behind the pneumonia seems to be some sort of drug related lung inflammation.  The only thing that seemed to work in the couple of cases I heard from is massive doses of steroids, sooner the better, to reduce the inflammatory process underway.

As I said above, this perspective is purely anecdotal and I am basing it on just a few cases that I heard from.  Nevertheless, it is worrisome.  I wish the authors of this paper had gone a bit further and gave their opinion as to why fully a quarter of the patients developed high grade pneumonia, rather than just stating the fact of this observation.  If you are a participant in CAL-101 trials, this one or others in the future, please be aware that pneumonia is perhaps the single biggest concern as far as adverse effects go.  If you develop a bad cough while on the drug, please do not dismiss it lightly.  Make sure you get to your clinical trial researcher, not just make-do with local talent that has no clue what is causing the cough. Pneumonia caused by drug related inflammation is very different from the general garden variety pneumonia and needs to be treated differently.

Other adverse effects were grade 3 neutropenia (9 patients), thrombocytopenia (4 patients), anemia (3 patients) – out of the 32 patient cohort.

Results

So, what did this group of high risk, relapsed / refractory patients get for their efforts? As advertised, CAL-101 did indeed shrink lymph nodes in all 32 of the patient volunteers.  29 of them had as much as 50% reduction in their target lymph node.  As expected, there was a big spike in WBC in the first couple of weeks, observed in 60% of the patients.  But this spike gradually resolved itself and the blood counts normalized nicely thereafter.  Overall, 33% of the patients had what is termed “PR” – partial response.  Please refer to our earlier article “(Almost) Everything you need to know about CLL” for a clear understanding of what a “PR” response means.

This is how the researchers themselves evaluate the potential importance of CAL-101:

“CAL-101 shows acceptable toxicity.  The high level of lymph node regression and prolonged duration of symptomatic tumor control strongly support evaluation of CAL-101 alone and in combination with other chemo/immunotherapy approaches to CLL management.”

Symptomatic tumor control?  And quarter of the patients experiencing grade-3 pneumonia is “acceptable toxicity“?

Boy, that is a far cry from a CURE.  But let us be reasonable, let us be optimistic.  These are early days.  In combination with other drugs – wait for it – Rituxan and / or bendamustine – CAL101 may prove to be a much needed drug to better treat high risk patients with bulky lymph nodes.  And its impact as a single agent may be much better in lower risk patients who have not been as heavily pre-treated as this lot. It is also important to remember that the single stellar feature of CAL-101, its ability to shrink swollen nodes, is very much a desired feature.  And that too in poor prognostic patients with unfavorable FISH cytogenetics.  At this point in time we are sorely lacking in drugs that can do it as well as CAL-101 can, and that is not something to sneeze at.   But anyone who thought this drug is going to be the slam-dunk CURE we are all hoping for, or walked into the trial expecting to see very few  adverse effects – after all, how much harm can a couple of tiny little pills do? – these folks were no doubt disappointed.

This abstract did not thank the patient volunteers who made this study possible – hopefully this oversight was corrected at the actual oral presentation of the research at ASH 2011 conference.  In any case, please join me in a heartfelt round of applause for these brave volunteers.

Editorial: Reading the Tea Leaves

Reading research abstracts, understanding the clinical details and almost as important,  understanding the details buried between the lines and not quite spelled out – this has to be an art form.  I have read thousands of these abstracts and articles in my career as a layperson observer of the CLL scene for the last ten years.  I think I have gotten pretty good at it, even if I say so myself.

Credibility is paramount.  Results are worth only as much as the credibility of the study that reports them.  What makes some papers more credible than others?  For starters, the name recognition of the researchers involved, as well as the reputation of their respective organizations.  I have highlighted the well known names of some of the authors on this abstract, as well as their institutions.  Clearly, this is an important paper with some high powered CLL experts on the author list.

Another aspect of credibility is the disclosure statement at the bottom of the abstract.  10 out of the sixteen authors on this paper had significant financial dealings with Calistoga Pharmaceutical, the company that owns CAL-101.  That does not mean automatically that the credibility of the paper is destroyed, lost in a haze of conflict of interest.  We cannot afford to be such purists in this day and age, where much of the research funding comes from drug companies.  Three of the authors on this paper actually work for Calistoga.  Does this invalidate the results?  I do not think so.  It is important not to throw the baby out with the bath-water, as we follow the money trail.  All I am doing is pointing out to you some of the details I pay attention to, as I read and review these articles.

Somethings were left unsaid in this report.  No discussion of why they had high grade pneumonia in fully a quarter of the patients.  Notice, they did not say this is possibly unrelated to the drug.  I would also have liked to see some comment on what they thought was happening in the bone marrow.  Yes, CAL101 cleared lymph nodes, swollen spleen.  But what about that most crucial and one-of-a-kind organ of hematological health, the bone marrow?  We are gently nudged to assume, infer, hope – you name it – that because platelet counts improved, this means that the bone marrow cleared out as well.  Perhaps this is indeed the case.  Me, I would have liked to seen more direct proof that indeed this was the case.  I am not sure the FDA is going to buy the argument either, without bone marrow biopsies to prove it is indeed the case.  As I said, read between the lines to get the full flavor of the report.

Disclosure:

Since I discussed the financial disclosures of the authors, it is only fair that I undergo the same scrutiny.  For the record and in the interests of full disclosure, I receive no consultancy fees, no research funding, no favors or “gifts”  from any drug company.  Neither I nor my family have any equity ownership in Calistoga.  I have never worked for a drug company and most likely never will.  To cut to the chase, I get no money – not a single dime – from anyone other than you, my readers, by means of your donations.