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.
23 comments on "How to Treat Elderly CLL Patients"
With the loss of Dr. Hamblin, your guidance has become even more critically important. Knowing you remain ‘on watch’ for us is so important, emotionally and medically. Thank you! May you always be aware of how you are valued by those in your debt.
Although I am an almost 77 patient with “SLL” and a Chl fan, I don’t remember seeing Chl + prednisone as a favored combination – as it is listed above.
Is more information on Chl + prednisone available?
mrblot:
Back in the 1990’s or thereabouts, prednisone was often used in conjunction with chlorambucil. When fludarabine came along, that too was sometimes combined with prednisone. Back then, prednisone was a popular chemotherapy agent and they added it to just about every other drug. Then it fell out of favor as we discovered some of its not so lovely side-effects. More recently, researchers have begun to appreciate its ability to flush CLL cells out of the protective environment of the lymph nodes, as well as its ability to control autoimmune diseases like AIHA and ITP. If you wait long enough, things seem to come back into fashion.
I will have to dig through my files to find actual clinical trial information. It would have been so easy to ask Terry Hamblin to point me in the right direction! He had an archival memory that I could only envy. I will miss him, his wisdom, his generosity and his sense of humor. It is hard to believe he is really gone.
I’m 81, diagnosed in Dec. 2005, unmutated. Good general health (no health problems other than CLL plus arthritis.
First treatment in spring of 2010 for AIHA using RCD (Rituxan, Cytoxan, Dexamethason). Result: complete remission wihout any toxicity.
Since 2010, my abs lymphocyte count has been increasing, (ALC doubled in te last 3 months. My oncologist believes I will need a second treatment before the year is up. He plans to use RCD again.
Question: RCD was a very successful first treatment for me, both for the AIHA and for CLL in general. Dr Rai personally recommended this treatment. Nevertheless, it has hardly been mentioned as an alernative either for elderly patients or the younger set. Why is that?
Good info as always. My husband was diagnosed 9/2011 at 69.5. Before reading this, I’m afraid even I was guilty of viewing him as an “elderly” patient, even though I was adamant that if he becomes symptomatic he will receive the best treatment, not just patted on the head. This has made me realize that he is not physically elderly, even though over 65. Other than carrying extra weight, he doesn’t have a single other health issue, works hard in his big garden & yard, actively golfs several times a month, and is walking several miles a week with me in preparation for a trip. So much for the calendar age. Great article to hit the reset button.
THE WORDS OF qb ARE MY WORDS.
With the terrible loss of Dr.Hamblin your guidance has become more critically important.
For me, is very important the factor that you add: patient’s own wishes and attitude towards cancer treatment. I think some physicians dont”look” to our unalienable rights.
Great article again.Thank you.
UncleWolf:
RCD is an excellent therapy option in situations like yours, where CLL is combined with AIHA. It is generally not used as such in CLL patients who do not also have autoimmune disease.
Chaya,
I am 78 and as you know, a tough old broad. I had RF first time chemo in 2002. 2009, I refused the fludara because of the terrible effects on my bone marrow and other complications.
After much research, I chose B/R. It was not a walk in the park but not as rough as R/F. I am in remission 21 months.
Right now, I am not in a good mood as I am scheduled to have a trigger finger injected and have to get to an orthopedic surgeon re: a pinched nerve in my leg.
What a mess and snow is predicted in a couple days.
Take care and many Blessings.
Rita
Slightly off topic…….if you are a UK patient or have a loving interest in a UK patient who may be elderly. In the UK medics are not supposed to used the words ‘old’ or ‘elderly’ so the situation may get confusing; the phrase ‘co-morbidities’ is used, ably explained by Chaya in her article.
However, in the UK, because of our NHS, there may not enough time to make sure that the patient understands the treatment that is being proposed. If you have co-morbidities, or a loved one does, please take some time if you can to understand the effects that a treatment may have. Treatment can be very rough on a patient. There is a whole spectrum between palliative and agressive treatments, even in the UK. Know your aim and what you are prepared to experience to acheive it.
Like several others, I am very sorry that TH has gone. He will be missed, his wisdom, knowledge and kindness. He had no fear though.
To sian, as someone who resides in the UK; as for not naming as elderly or old, the words might not be popular, but the attitude most certainly is very actively employed. One gets the impression that being of pensionable age also means that ones brain is viewed as having been pensioned off. Hmmmm.
Am lucky to have developed a good understanding with “my” haematologist, poor chap, after extensive correspondence and several meetings, no treatment as yet (and may it long continue that way).
Thank you Chaya; will contact re full article. Look after yourself and stay well
I’ve been meaning to donate – I can’t even put a dollar value on the usefulness of your site and its goldmine of info when I was newly diagnosed and searching for knowledge.
Now I read about a 12-year-old who’s doing the research on behalf of her dad. I never cease to read it, and I hope you never cease to know, how sincere we all are when we say thank you for your work on behalf of patients and in honor of P.C.
The donation is on its way. God bless that 12-year-old.
As I look at some of the therapy options listed in the Israeli paradigm, the thought struck me that there are some country differences here. There are subtle but clear differences between USA and Europe, even bigger ones when it comes to less developed countries. We tend to like new and sexy drugs a lot more here, I see the Israeli choices are a bit more conservative, looking for long track record rather than sexiness. Not a bad approach when it comes to cancer therapies.
I confess that I would really like to become one of the 50% of the patients who is over 75! Very sorry to hear about Dr. Hamblin.
Keep up the good work Chaya!
I am to have a consult with surgeon on Friday, Jan 20 regarding a 53 X 42 mm axillary node my oncologist has said needs to be biopsied or dissected to rule out a transformation to lymphoma. This is the first I have had to have anything done other than to take antibiotics and anitviral meds on occasion in the last 10 years and I am now 71.
Is it a whole other ballgame as far as treatment if I do have “Richters”? The Dr. has
said, if it is a transformation, treatment will be more immediate–but I am afraid I blanked out in the brain area after that, so did not ask for specifics regarding protocol. I will see oncologist one week after biopsy/dissection
I have been losing about a pound every 8 weeks and have had CT scan with dye to detect any abnormally large (abnormal within the “normal” of CLL that is stable). The scan also shows a 21 X 18 mm splenic lesion and a 12 X 8 mm periaortic node as well as other “mildly enlarged” nodes.
I will go back into your articles Archive to see what I can find about Richter’s and
treatment. I know you can’t answer everyone
As usual you are very helpful, thoughtful and lucid. I’m 69 treated twice. Once w/ FCR and once w/ PCR (I switched to a Dr. who was a better listener). My new doctor seemed to have some concerns about F long term and in terms of the two treatments I really did not notice a difference. I got 3 year remissions both times. I’m probably looking at treatment again in the next year of so. I take green tea supplements and now vitamin D (as suggestion of my internist). I still work and stay active. Thanks for all you do and you humanistic approach to medicine
Appreciate the info Chaya…
I realize you didn’t include everything in the article but I do wonder if Rituxan + Fresh Frozen Plasma was discussed. I also have been meaning to ask about any info on low dose Revlimid. I did notice that you reviewed a phase I trial with Revlimid and the ‘elderly'(also recall that you had a friend who had convinced their Dr to try low dose Rituxan). My epidemiologist sister was asked about such an approach in CLL by a friend who had read about it being used in Multiple Myloma. Apparently it’s all the rage with ‘fountain of youth-ers…but wondered if you had heard any followup on lower dosing than what ultimately caused the toxicity that was seen. Thanks.
My grand daughter is just 30 and was diagnosed at age 20 with CLL. A rarity, I guess. She has been in remission after chemo and meds for about 5 yrs now. Interestingly, her paternal grandfather was Jewish. Her maternal grandmother (me) had full-blown mono at age 17. Could these mean anything?? Also…this morning she got up violently sick and vomiting, all day long. It did subside but she is still sick today….any cluse?? Thanks…Fifilala
This is a general question to everyone. I’m new to the CLL community. Apparently I’d been watching and waiting for quite a while without knowing it. Once discovered, I have a 10x10cm bulky node by the stomach and what I call chromosomal chaos. Deletion of 14q; trisomy 9 and 12; 11;13 translocation. Plus some other things. My question is, when I am declared to be in remission, how is that determined? Do the trisomys go away, do the translocations relocate and I get back a normal spread of chromosomes?
Thank you all, and thank you Chaya for this forum.
Bill
A6SEA
I am sorry to tell you that when you are in remission, none of these chromosomal abnormalities go away completely and forever. A remission does not mean a cure. If you are fortunate and the remission is deep, it means the vast majority of CLL cells have been killed. Most, but not all. With the exception of a stem cell transplant, all of the the therapy regimens we presently have are not capable of a full cure of this disease. Relapse is inevitable, it is a question of when and not if. But the “when” is important. It could be a nice long remission, which would be nice, and the next best thing to a cure.
When relapse happens, this indicates a grow back of the CLL, seeded by the left over cancer cells after therapy. Most likely they will have the full set of chromosomal abnormalities their ‘parent cells’ had, with a chance that they may even have acquired one or more new ones – a case of clonal evolution.
Please refer to an earlier article titled “(Almost) everything you needed to know about CLL”. It has a lot of the details you need to understand.
A6SEA
Thank you, Chaya.
Thanks for addressing us older CLL folks! We are suppose to go to Houston and begin a Clinical Trial. Date is set, but I am not sure about doing this trial. Going to see what our local Hemo/Onoc has to say about our test results on 3/7…and go from there. The cost of doing a CL X’s 2 must be mindboggling..and we are only on SS with Medicare as only ins. Pretty sure out of pocket costs would be horrid!
Would rather be at home, do treatments locally if necessary.
I know trials are wonderful,and admire those who do them, but at this moment, going to wait awhile longer..
Again, thanks for all you do for the CLL world !
Thanks for providing me with the information on treatment for elderly patients. Although your summary does not provide information on best treatment, it does make me wonder. Iam 76 and was diagnosed 41/2 years age. First treatment with Lukeran and Prednisone in August 2009 and second in March 2011. Now talking about Bendamustine and Rituxan. Your article implies the B+R might be too severe and present a high risk of bone amrrow damage. Where can I get more details?
Thanks
JJK
JJK:
I cannot define the “best treatment”, one that would fit all patients and all situations. This too falls in the category of looking for simple answers to very complex situation.
As for the possible toxicity of bendamustine, we have reviewed this drug several times on this website as well as on http://www.clltopics.org . Look up these reviews by using the search box at the top right hand corner of the website. Use the keywords ‘bendamustine’ / brand name ‘Treanda’. That will help you get started in learning more about this drug. My reviews always have embedded in them the abstracts of the professional articles on which I based my analysis. I suggest you read the original articles themselves, if you want to get hold of the clinical and scientific details.
Devil is indeed in the details, and the last thing I want to do is hand out “easy answers” that can end up doing more harm than good.
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