What is the aim of CLL therapy?

SunflowerYou would think this is an easy question to answer, wouldn’t you?  Actually, there are as many answers to this question as there are interest groups.

I am sure many of you have heard the parable of the elephant and the five blind men – each reported a very different perspective of the elephant, depending on whether they groped the trunk, leg, tail, ears or body of the elephant.  CLL patients and therapy options options open to them are a bit like that.  Local oncologists and nursing staff see it in terms of logistics, infusion times, scheduling etc.  Researchers conducting clinical trials focus on response statistics: overall response and percentage of “CR” response – bragging rights for their pet therapy regimen.  No doubt insurance companies look at the costs of the various therapy options as the most important criteria.  Your GP and local emergency room physicians may focus on the impact of therapy choices on frequent infections and secondary complications.

How do you perceive the elephant, if you are a relapsed or refractory patient, perhaps an elderly patient with a few more miles on the chassis than you would like to acknowledge, a few patches of rust here and there, strange noises when you take your body out for a spin and the tires not quite up to par anymore?  Once we get past the wish for eternal life and perfect youth / health (so not going to happen!) reality is actually quite simple for most of us. We would like to live as long as possible, as comfortably as possible; and so long as those two desires are addressed,  we don’t particularly care one way or the other about the labels attached to our CLL remission.

And this is the crux of the problem. Very few CLL clinical trial protocols focus on patients’ quality of life. It is only recently that CLL experts have started looking at treating relapsed / refractory and elderly patients from the perspective of survival and quality of life; treating the patient and not their disease.  Making the alphabet soup of drug combinations longer and more toxic may not always serve the best interests of the individual patient.  We used CFAR as an example of therapy overkill in the last article.  Don’t just take my word for it that CFAR is therapeutic overkill.  Here is a direct quote from the M. D. Anderson authors on their evaluation of CFAR:

In view of the high infectious toxicity and lack of survival advantage following CFAR in patients with relapsed or refractory CLL, we believe that further investigation of this regimen in this setting is not warranted.

Phew.  Glad we are agreed on that one doc!  I would hate to see any more trials of this combo recruiting elderly / refractory patients.

CFAR is just one example. There are many others.  FCR + mitoxantrone is another combination that piles on the toxicity with not much by way of improving survival odds or quality of life.  FC + Campath and FC+ Revlimid are couple more examples of combinations that proved to have too much toxicity for most patients.

Focusing on the specific needs of refractory, elderly patients

I spent quite some time trolling the published literature to find the single best article that explores the needs of the elderly, relapsed / refractory CLL patient.  What I found instead is a wide range of perspectives.  In other words, this review is going to be a complicated one, with different pieces of the puzzle extracted from different articles.  Failing to pay attention to the special needs of elderly patients can be an expensive mistake.

Overview articles

Recently I reviewed one of Dr. Smolej’s articles dealing with FCR- Lite.  Below is another one, where Dr. Smolej discusses therapy options for elderly patients who may also have other health issues in addition to CLL.  You can read the full text by clicking on the link.  It is well written, very well worth reading.  Dr. Smolej has also indicated that he is willing to respond to questions you address to him in the comments section of this review.  Here is your chance to get some expert advice.

Acta Medica (Hradec Kralove). 2010;53(4):213-20.

How I treat elderly or comorbid patients with chronic lymphocytic leukemia.

Smolej L.

Department of Medicine, Charles University in Prague, Faculty of Medicine and University Hospital Hradec Králové, Czech Republic. smolej@seznam.cz

Treatment of chronic lymphocytic leukemia (CLL) has recently undergone several major changes. Most importantly, large randomized trials (CLL-8 in first line and REACH in relapse) clearly demonstrated superiority of chemoimmunotherapy consisting of fludarabine, cyclophosphamide and rituximab (FCR) over fludarabine and cyclophosphamide (FC) alone, thus establishing FCR regimen as the new gold standard in younger and physically fit patients. However, management of elderly and/or comorbid patients is still a challenging task because they cannot be treated with agressive approaches due to high risk of unacceptable toxicity. To date, no randomized trials in this patient population have improved therapeutic results over chlorambucil; therefore, this agent remains the backbone of treatment against which the new protocols should be tested. When deciding about the intensity of treatment, performance status, biological age and number as well as severity of comorbidities should be taken into account. Emerging treatment concepts for elderly/comorbid patients include combination of chlorambucil with monoclonal antibodies (rituximab, ofatumumab, GA-101), fludarabine-based regimens in reduced doses or protocols based on bendamustine and lenalidomide. Combination of high-dose steroids with rituximab represent a promising option in relapsed/refractory CLL; however, infectious toxicity remains a serious issue. Finally, ofatumumab monotherapy appears to be a safe and effective therapy for heavily pretreated patients with CLL. This article reviews the current and future possibilities in the treatment of elderly and comorbid patients with CLL.

PMID: 21400979

There seems to be more of a trend to look for age appropriate therapy options in Europe than in this country. Perhaps that has something to do with the “youthfulness” of USA as a country compared to older European cultures.  We tend to like brand new stuff, the latest miracle-of-the-month, just because it is so sexy.  Or maybe it has to do with the nature of our healthcare system.

Dr. Smolej  compares the typical age of participants in some recent and pivotal clinical trials (range 58 – 64 years) against the typical age of CLL patients at the time of diagnosis (65 -72 years). In the real world, patients older than 65 make up the bulk of the patient population, to the tune of 50-75%.  It is a fact of life that organ function deteriorates as we age.  Of particular importance: kidney and liver function, cardiac and pulmonary health, decay in function of the thymus, leading to poorer T-cell function and corresponding increase in risk of of infections, cancers.  Clinical trial results based on much younger patients do a poor job of predicting how older and more at-risk patients are likely to respond to aggressive therapy regimens. Even with “kinder and gentler” approaches, selecting a more realistic patient cohort such as the one recruited in the Czech FCR-lite study highlight potential for higher than expected toxicity and adverse effects.

Here is another overview article that looks at the topic of how to treat elder CLL patients. The German CLL group is well known for their well conducted and detailed clinical trials.  This 2009 paper looks at the specific needs of the elderly CLL patient.

Leuk Lymphoma. 2009 Feb;50(2):171-8.

Treatment of elderly patients with chronic lymphocytic leukemia.

Eichhorst B, Goede V, Hallek M.

Department I of Internal Medicine, Center of Integrated Oncology Köln Bonn, University of Cologne, Cologne, Germany. barbara.eichhorst@uk-koeln.de

Chronic lymphocytic leukemia (CLL) is dramatically increased in patients above the age of 65 years up to an incidence rate of 22-30/100 000. Although elderly patients represent the largest group of CLL patients they are clearly underrepresented in clinical trials. One important prognostic factor in the elderly is the burden of comorbidity. Survival is significantly impaired in CLL patients with multiple comorbidities (>or=2) or with severe comorbidity (Charlson score >or=2). Therefore, not only age but also the incidence and burden of comorbidity should influence the choice of treatment strategy for every patient individually. A reliable tool for measuring comorbidity is the Cumulative Illness Rating Scale. The German CLL Study Group (GCLLSG) has used this tool within their clinical trials to distinguish between physically fit and non-fit patients. Although chlorambucil is still the standard treatment of choice in non-fit patients, dose-reduced purine analogue-based combination therapies with or without immunotherapy are currently investigated within clinical trials. Because full-dosed combination treatment might cause increased toxicity rates in relapse situation, dose-reduced combination therapies should be considered in this situation. An adequate supportive treatment is necessary for the prevention of toxicities as well as for the improvement of health-related quality of life. In summary, the treatment decision in elderly CLL patients is carefully to be made in each patient individually considering not only the stage and risk factors of the disease but also the patients’ physical condition and social environment.

PMID: 19197731

Therapy decisions taking into account the patient’s social environment? What an outlandish idea!  (Not!). No man is an island and our social environment is a huge issue in what we can or cannot “afford” by way of cancer therapy.  Amazingly, this is the first time I have seen this issue given any importance.  The authors develop a three tier grading of patients and therapy choices likely to best serve them:

  1. Medically fit patients with no or just mild comorbidity and a normal life expectancy:  these patients should be treated intensively with chemoimmunotherapy (FCR is a good example) , irrespective of their chronological age (principle of action: ‘GO GO’).
  2. Medically less-fit patients with multiple or severe co-morbidities and an unknown life expectancy: treatment should be carefully adapted to the co-morbidity burden and a higher risk of both toxicity and disease progression must be kept in mind (principle of action: ‘SLOW GO’).
  3. Medically frail patients with fatal comorbidities and a very short life expectancy.  These patients will not benefit from any CLL treatment and therefore should not receive any chemotherapeutic drugs (principle of action: ‘NO GO’).

Obviously, the boundaries between these three different groups are a little blurred. Where in the spectrum do you fall? Send me a personal email if you want help locating full text versions of either of these two well written overview articles.

The rest of my analysis of therapy options that may be a good fit for elderly /relapsed / refractory patients comes from these two articles as well as a variety of other sources.  In the interests of keeping the length of the article within reasonable limits, I will not cite abstracts in each and every case.  But where ever possible, I will provide links to earlier reviews I did on the subjects – and you can find the necessary citations there, chapter and verse.

Single agent monoclonals

Single agent Rituxan is a popular choice with patients.  There is no doubt this monoclonal antibody has changed the CLL waterfront in a big way, especially when it is combined with more standard chemotherapy agents (examples are FCR, FR, PCR etc.).  Every new drug (or old drug) seems to work better with a little “mouse juice” (Rituxan has some mouse protein in it, hence this slang term for it)  thrown in for good measure.  But as a single agent it does not do a very good job of doing the heavy lifting.  If you have already been around the therapy circuit more than a couple of times, if you have developed any kind of drug resistance, if you have some of the high risk categories of CLL (11q or 17p deletions by FISH, for example), single agent Rituxan is not likely to give you deep or long lasting remissions.  It may be a good idea to do a careful cost versus benefit analysis if you are in any of these groups of patients.

Who is likely to benefit from single agent Rituxan therapy? Some one with very good prognostic indicators, lucky enough to have very chemosensitive disease that is willing to keel over and die at the first whisper of therapy, any therapy (my buddy Malcolm is one such patient.  He survived for more than a decade on nothing but Rituxan!); people who are terrified of the word “chemotherapy” and who would otherwise dither right up to the end without getting any therapy at all; people with excellent crystal balls who are looking to just pass a little time until the real CURE comes down the turnpike – and in the meantime they want to keep themselves chemo-virgins; elderly patients who really cannot tolerate the toxicity of any more aggressive therapy than single agent Rituxan; folks who are getting close to their natural life span anyway, therefore  just looking to ride out the clock and get a few more miles under their belts, not really looking to hit a home run.

Notice a common theme here. The idea is not to get deep and long lasting remissions with single agent Rituxan.  Don’t even worry about whether or not you are going to get MRD negative CRs – it is not likely you are going to get that far with the usual 4 weekly infusions of Rituxan.  The point of single agent Rituxan therapy is to keep the toxicity low, while shaving a little off the top off of the tumor load. Not a bad strategy, but you need to know what you are buying.  That way you won’t be disappointed.

Ofatumumab (brand name Arzerra, known earlier as Humax-CD20) is similar to Rituxan in the sense that it too is a anti-CD20 monoclonal antibody.  But as the company pointed out in their FDA application, ofatumumab seems to work better than Rituxan – especially in fludarabine and Campath refractory (or ineligible) patients.  How much better than Rituxan?  Now you are looking at the fine print.  If you have been exposed already to some amount of chemo, single agent ofatumumab may be a better choice than single agent Rituxan.  But not a whole lot better, in general you are still looking at not-so-deep and not-so-long lasting remissions.  Ofatumumab also has the advantage of being a fully humanized monoclonal antibody, no mouse protein here.  People who develop allergic reactions to Rituxan can still get anti-CD20 monoclonal therapy because of the FDA approval of ofatumumab.  That was indeed a huge big deal for my husband, back in 2006.  He was one of those people who developed hypersensitivity to Rituxan.

Anybody up for single agent Campath as front-line therapy?  Mind you, this is the only monoclonal that has received FDA approval for front-line use as a single agent in CLL patients.  No serious restrictions of any kind on its use.  How the heck did the company manage that?  If you ask me (and if you ask Dr. Terry Hamblin, I think), this almost miraculous approval was obtained by comparing Campath against a significantly under-dosed chlorambucil regimen.  What I would call a head fake or a straw-man comparison.  Campath is a powerful drug.  It has the huge advantage of being able to handle patients with the dreaded 17p deletions.  But on the other side of the coin, it is also immensely immune suppressive.  The CD52 marker that Campath targets is found in many cell lines, including T-cells, NK-cells, macrophages, neutrophils and of course, B-cells.  Campath therapy does such an excellent job of killing off T-cells that these very important defenders of our bodies find it hard to recover even as long as a year after completion of Campath therapy.  Death due to opportunistic infections and the like have come down after we learned to include prophylactic medications as part of Campath therapy.  Don’t go near this drug without discussing Bactrim (pneumonia prophylaxis) and acyclovir (or other anti-herpes drug to prevent CMV, shingles etc) with your doctors. Elderly patients with poor bone marrow reserves and already at increased risk of pneumonia and/or other viral infections may find Campath therapy hard to tolerate.  Who is likely to benefit from single agent Campath therapy?  Possibly younger and healthier patients who nevertheless need Campath in the mix because they have 17p defects to deal with.

Mayo clinic tried an interesting clinical trial, combination of Rituxan with reduced dose Campath in chemo naive and fit patients who had high risk CLL (11q or 17p deletions).  As expected, Campath helped get these patients better overall responses and higher percentage of CRs, even some MRD negative responses.  But unfortunately, as the patients were followed for longer time after completion of therapy, all of the MRD negative responders eventually relapsed – reflecting the aggressive nature of their disease in the first place.

“Not quite chemo” options

Revlimid (lenalidomide) has gained a lot of attention in the last few years, as witnessed by a large number of articles I published on the subject on this website.  Revlimid is not considered a chemotherapy drug – not quite.  It falls into the category of immune system modulators – it is an “imid” – and it works by getting the patient’s own immune system all up in arms.  We have reviewed clinical trials where Revlimid is being used as a way of prolonging the period of Watch and Wait (chemoprevention after the fact, as it were).  Revlimid has been suggested as an adjunct to improve our response to regular vaccination shots, such as the pneumonia shot our patients need so badly.  Revlimid has been paired with Rituxan in clinical trials.

As always, there are adverse effects to watch for in Revlimid therapy.  A significant portion of patients may experience “tumor flare” reaction, where their lymph nodes swell up, they feel like they have come down with the mother of all flus.  Some folks get body rashes that need heavy doses of Benadryl to resolve.  And more recently, we have learned that Revlimid may increase the chances of blood clot formation.  Never a dull day, as they say.  But the drug has its advantages. It does not pose serious bone marrow toxicity.  Even folks with 17p deletion can respond to this drug.  It is an orally available drug and can be taken as simple pill each night.  As time goes by, we are learning more about Revlimid maintenance therapy – especially in older patients. Here is the latest on Revlimid, as of July 1, 2011.  It seems M. D. Anderson does do some clinical trials with less than aggressive therapy regimens for older patients.  Who knew.

Lenalidomide as initial therapy of elderly patients with chronic lymphocytic leukemia

Xavier C Badoux1, Michael J Keating1, Sijin Wen2, Bang-Ning Lee3, Mariela Sivina1, James Reuben3, William G Wierda1, Susan M O’Brien1, Stefan Faderl1, Steven M Kornblau1, Jan A Burger1, and Alessandra Ferrajoli1,*

University of Texas M. D. Anderson Cancer Center, Houston, TX, United States;

The best initial therapy for elderly patients with chronic lymphocytic leukemia (CLL) has not yet been defined. We investigated the activity of lenalidomide as initial therapy for elderly patients with CLL. Sixty patients with CLL age 65 years and older received treatment with lenalidomide orally 5 mg daily for 56 days, then titrated up to 25 mg per day as tolerated. Treatment was continued until disease progression. At a median follow-up of 29 months, 53 patients (88%) are alive and 32 patients (53%) remain on therapy. Estimated 2-year progression-free survival is 60%. The overall response rate to lenalidomide therapy is 65% including 10% complete response, 5% complete response with residual cytopenia, 7% nodular partial response, and 43% partial response. Neutropenia is the most common grade 3-4 treatment-related toxicity observed in 34% of treatment cycles. Major infections or neutropenic fever occurred in 12% of patients. When compared with baseline levels we noted an increase in serum Immunoglobulin levels across all classes and a reduction in CCL3 and CCL4 plasma levels were noted in responding patients. Lenalidomide therapy was well tolerated and induced durable remissions in this population of elderly, symptomatic patients with CLL. This study was registered in www.ClinicalTrials.gov (ID# NCT00535873).

Unlike Rituxan and the other monoclonals, Revlimid is a simple and small molecule.  It is a new version of an older drug – thalidomide – that you may have heard of.  I for one cannot understand why Revlimid is being marketed at such exorbitant prices.  A generic version is available from India.  I believe it is called “Lenalid“.  One of our more enterprising members got hold of it from the Indian company and from everything that I have heard, it is identical to the Revlimid sold here.  But seriously guys, I am not telling you to start taking the Indian version of Revlimid to save a few bucks.  I cannot vouch for its purity or authenticity and I cannot afford that kind of litigation and lawsuits!  I am just passing on information that I thought you might find interesting.  Please don’t do crazy stuff, OK?

Rituxan with high dose steroids: R + HDMP is another not-quite-chemo option.  This was not a favorite of mine, I had (still have, to a lesser extent) real concerns about heavy handed use of steroid drugs.  Prednisone and methyl prednisolone (or dexamethasone and a bunch of similar drugs) all fall into the category of glucocorticoidal steroid drugs.  They are all very powerful drugs that influence a variety of primary systems in your body.  Long term use rots your bones, reduces your immune function and may play havoc with your sugar control.  But there is a difference between heavy dose / short term use of steroids and lower dose / long term use of the same drugs.  HDMP falls into the former category, extremely heavy doses over a relatively short time.  I am told this is likely to cause less long term problems.  But diabetic patients should discuss their situation carefully with their physicians before embarking on any steroid based regimen. You (or your caregiver) should also be prepared for some “mental” changes while you are on the high dose steroids.

How well does R + HDMP work? For starters, the most important thing about this regimen is that it does a very good job of de-bulking very large lymph nodes, something that few other drugs seem able to do as effectively.  It is also thought to work to some degree on people with 11q and 17p deletions.  The downsides?  Infections.  Steroidal drugs such as prednisone reduce immune function significantly. In CLL patients who are already at risk of infections, this is a real bummer.

Below are two abstract.  The first one is from the researchers at UCSD, the place where R+HDMP combination was first tried.  The second one is from well respected British researchers.  I think you will find the differences between the two perspectives more than a little interesting.  As they say, beauty is in the eyes of the beholder.  No infections noted in the UCSD trial; and in contrast, the British study cautions about increased risk of infections.  Two groups of wise men groping the elephant blind folded, coming up with different answers to the question.

Leukemia. 2008 Nov;22(11):2048-53. Epub 2008 Aug 28.

Rituximab in combination with high-dose methylprednisolone for the treatment of fludarabine refractory high-risk chronic lymphocytic leukemia.

Castro JE, Sandoval-Sus JD, Bole J, Rassenti L, Kipps TJ.

Moores UCSD Cancer Center, La Jolla, CA 92093-0820, USA.

We examined the clinical response of fludarabine-refractory CLL patients treated with high-dose methylprednisolone (HDMP) and rituximab. Fourteen patients were treated with three cycles of rituximab (375 mg/m(2) weekly for 4 weeks) in combination with HDMP (1 gm/m(2) daily for 5 days). All patients were refractory to fludarabine and 86% had high-risk disease by the modified Rai classification. In all, 79% of the patients had CLL cells that expressed ZAP-70 and three patients had poor prognostic cytogenetics. The overall response rate was 93% and the complete remission rate was 36%. The median time-to-progression was 15 months and the median time-to-next treatment was 22 months. Median survival has not been reached after a median follow up of 40 months. Four patients have died of progressive disease. Patients tolerated the treatment well and serious adverse events were rare. This allowed patients to receive all planned treatments on schedule with no dose modifications. All but one patient responded to treatment and the overall survival and time-to-progression were superior to those of other published salvage regimens.

PMID: 18754025

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

Haematologica. 2008 Mar;93(3):475-6.

High dose methylprednisolone and rituximab is an effective therapy in advanced refractory chronic lymphocytic leukemia resistant to fludarabine therapy.

Dungarwalla M, Evans SO, Riley U, Catovsky D, Dearden CE, Matutes E.

The Royal Marsden Hospital, Sutton, Surrey, United Kingdom.

The combination of high dose methylprednisolone and rituximab induces superior overall (93%) and complete (14%) response rates compared to high dose methylprednisolone alone (overall 43%, complete remission 0%) in heavily pre-treated chronic lymphocytic leukemia patients with advanced disease. Despite its efficacy the combination is not easily manageable because of the high rate of opportunistic infections.

PMID: 18310545

Chemotherapy options

Until recently, that is all we had to treat CLL: standard issue chemotherapy agents.  I will restrict this discussion to either single agent chemotherapy options or at most combinations with no more than 2 drugs in it.  Longer strings of chemotherapy drugs may be more toxicity than elderly refractory / relapsed patients can tolerate – as we have seen in the cases of CFAR, FCR-M etc.

How about single agent fludarabine?  It  is reasonably cheap, it is off patent, there is even an oral version of it (available in Europe).  Local oncologists often prescribe this drug as the frontline therapy for newly diagnosed patients.  I know, because that is what my husband’s local guy recommended immediately after preliminary diagnosis. (He did not last very long, we fired him within weeks, and rightly so).  I do not think highly of this drug as single agent for elderly or refractory patients.  This group of patients are likely to have damaged immune systems and depleted bone marrow reserves.  Fludarabine is justly infamous for serious level of T-cell destruction, leaving patients vulnerable to all sorts of viral infections. Even when administered with great attention to prophylactic medications to prevent infections, in my humble opinion it is just not worth the risk.  And an older and even cheaper drug, also a pill, does a better job of taking the edge off of the CLL, without necessarily wiping out what remains of the patient’s immune protection as thoroughly as fludarabine does.  The name of the drug?  Chlorambucil.  Also known as Leukeran.  The very first chemotherapy drug used to treat CLL, generations of CLL patients grew familiar with this little brown pill.

Blood. 2009 Oct 15;114(16):3382-91. Epub 2009 Jul 15.

First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia.

Eichhorst BF, Busch R, Stilgenbauer S, Stauch M, Bergmann MA, Ritgen M, Kranzhöfer N, Rohrberg R, Söling U, Burkhard O, Westermann A, Goede V, Schweighofer CD, Fischer K, Fink AM, Wendtner CM, Brittinger G, Döhner H, Emmerich B, Hallek M; German CLL Study Group (GCLLSG).

Department I of Internal Medicine, Centre of Integrated Oncology Köln Bonn, University of Cologne, Cologne, Germany. barbara.eichhorst@uk-koeln.de

Although chronic lymphocytic leukemia (CLL) is a disease of elderly patients, subjects older than 65 years are heavily underrepresented in clinical trials. The German CLL study group (GCLLSG) initiated a multicenter phase III trial for CLL patients older than 65 years comparing first-line therapy with fludarabine with chlorambucil. A total of 193 patients with a median age of 70 years were randomized to receive fludarabine (25 mg/m(2) for 5 days intravenously, every 28 days, for 6 courses) or chlorambucil (0.4 mg/kg body weight [BW] with an increase to 0.8 mg/kg, every 15 days, for 12 months). Fludarabine resulted in a significantly higher overall and complete remission rate (72% vs 51%, P = .003; 7% vs 0%, P = .011). Time to treatment failure was significantly shorter in the chlorambucil arm (11 vs 18 months; P = .004), but no difference in progression-free survival time was observed (19 months with fludarabine, 18 months with chlorambucil; P = .7). Moreover, fludarabine did not increase the overall survival time (46 months in the fludarabine vs 64 months in the chlorambucil arm; P = .15). Taken together, the results suggest that in elderly CLL patients the first-line therapy with fludarabine alone does not result in a major clinical benefit compared with chlorambucil. This trial is registered with www.isrctn.org under identifier ISRCTN 36294212.

PMID: 19605849

Never mind the labels attached to the remissions, in the two criteria that matter to us (namely, remission duration and overall survival), there was no difference between fludarabine or the much older chlorambucil! I do not know about you, but if I am getting the same deal with either drug, I would much rather take chlorambucil with its “kinder & gentler” adverse effect profile.

Chlorambucil is an alkylating agent.  Two other alkylating agents you may have heard of are cyclophosphamide and bendamustine.  Cyclophosphamide is well known, the third leg in the present day gold standard of FCR.  Bendamustine (Treanda) has been around just as long.  In fact it was discovered right around the time of the second world war, in what used to be Eastern Germany.  But its present day roll-out with the new sexy name of “Treanda” has generated a lot of buzz.

Treanda has obtained FDA approval for frontline therapy and as a single agent in treating CLL.  How the heck did they manage that in record quick time?  Same way that Campath did, by using what I consider to be inappropriate comparison with under-dosed chlorambucil control group.  Here is a link to an earlier article where I discussed my problems with Treanda approval process.  Just in case, here is the link to Terry Hamblin’s recent post on his blog, dealing with the same subject.

So, how well does Treanda work in refractory / relapsed patients? A 2011 article in the British Journal of Hematology described it in detail and here is the link to my review of it.  It is also good to remember bendamustine is  another alkylating agent – like chlorambucil, like cyclophosphamide.  It has some of the same adverse effect profile, including the risk of secondary myeloid cancers.  All in all, if I were an elderly patient with relapsed / refractory CLL and  my choices were one of the three alkylating agents (chlorambucil or cyclophosphamide or the latest bendamustine), I would look hard at chlorambucil as the lesser of the three evils.

Before we close the section on straight chemo drugs, let us consider the combination of fludarabine + cyclophosphamide. If your profile fits the type of patients we are discussing here (namely you are no spring chicken and you have relapsed / refractory disease) and your local oncologist recommends F+C as the therapy of choice for you, I think you should seriously consider getting a second opinion. Or even fire the guy and get yourself a new doctor.  The reason for my bluntness is quite simple.  The jury has come back, there is no good reason left for treating patients with F+C, not when they can be treated with FCR instead and get far better responses.  That was the whole point of the excellently conducted German trial.  Here is the link to my review of it.

Don’g get me wrong:  full strength FCR may not be a good choice either for elderly and refractory patients.  This is one of the most significant contra-indications for use of FCR therapy, as we discussed at our last workshop (“Everything you wanted to know about FCR“).  If you have set your heart on FCR, using a regimen that reduces the dosage of the two chemotherapy drugs (F and C) and either keeps the level of R the same or increases it somewhat may be your best bet.  We are talking about FCR-Lite, either the version tried at UPMC or the more pragmatic version of the Czech study.

Kinase inhibitors

No listing of possible therapy options can be complete without discussing kinase inhibitors such as CAL-101 and PCI-32765, as well as a host of new ones in the pipeline.  These are the new “smart” drugs that are attempting to do for our guys what Gleevec (imatinib) has done for CML patients.  We have reviewed the status of both of these drugs and I refer you to those articles for more details.  There are good reasons for optimism, that these drugs or their later versions will prove effective in giving our guys longer remissions with fewer side effects.  To date, both of these drugs seem to work best in patients with enlarged lymph nodes. There are still some questions about efficacy, whether they can do an adequate job in bone marrow clearance – not a trivial issue, given the bone marrow is probably the single most important and unique organ in your body as far as healthy blood supply is concerned.   Still, what little we know at this point (very early stage results are the only ones we have so far), is encouraging and the adverse effect profile is quite limited.  So, if you are the type that does not mind taking bit of a chance with a relatively new type of drug, and your CLL seems to be mostly restricted to bulky lymph nodes, you may want to sign up for one of the many clinical trials out there.  Just be sure to read the fine print.  Some of these trials use kinase inhibitors (CAL-101, PCI-72365) along with some other drugs; such as bendamustine, fludarabine etc.  Make sure you are comfortable with all aspects of the trial before you sign on the dotted line.  That is the meaning of informed consent, anything less than that means you are buying a pig in the poke.

Editorial

Patients worry a lot about making the right therapy choice.  Will it be too toxic?  Will it have enough oomph?  Will my insurance cover it?  Will the remission I get from it help or hurt me in the long run? What are my guarantees that things will work out just right?

Allow me to let you into a little secret that you may not have focused on.  In the long run, if we wait a sufficiently long time, all of us are dead. That is probably the only guarantee I can give you, and that does not even depend on whether or not you have CLL!  There is some amount of risk in everything we do.  And that includes crossing the street or making therapy choices.  There are no perfectly right therapy choices.  Just reasonably good choices and outright silly ones – depending on your individual situation.  The best you can do, the best any of us can do, is to make choices that seem right for you, given the  less than complete information we have available to us.

We need to face thorny issues of quality of life and reasonableness of expectations right upfront.  It is not just researchers that sometimes forget they are treating living, breathing patients who are nevertheless mortal.   Often enough patients are just as guilty of wanting the impossible.  Our culture does not allow honest discussion of death – most of the time – and in our doomed quest for eternal youth and forever life, we throw away precious years and better quality of life.  We buy into therapy options that are unrealistic, close our eyes and sign on the dotted lines for clinical trials that may be inappropriate in our personal situations and do little more than transform us into under-appreciated statistical data points in someone’s journal article.

Here is a stark example.  Stem cell transplant recruitment guidelines and age restrictions have eased since the development of mini-allo (non-myeloablative) approaches.  Does that mean every 70+ year old CLL patient is a valid transplant candidate, even if there are one or more serious co-morbidity issues? Not unless he wants to spend how ever many months / years of life he has left under miserable circumstances. He would be trashing quality of life for himself and his family, even perhaps reducing  the life span he would otherwise have had.  On the other side of the coin, a young and fit patient with unfortunately high risk CLL is well advised to consider mini-allo stem cell transplant sooner rather than latter.  He has too much risk of reduced life expectancy riding on the decision.  One shoe does not fit all CLL patients.  So, after reading this long and boring article, what is your shoe size?

In this article I have attempted to give you quickie information on many of the therapy options open to older and refractory / relapsed CLL patients.  None of them is a full fledged CURE for CLL.  But many of them offer the possibility of reasonable responses and better quality of life, compared to overly aggressive regimens and therapeutic overkill.  There is a time to fight, and there is a time to rest.  Wisdom is knowing the difference between the two.

On the subject of wisdom, here is guidance from a far older and wiser source than me.

To everything there is a season, and

a time to every purpose under heaven:

A time to be born, and

a time to die;