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.