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.


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.