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Management of Chronic Lymphocytic Leukemia
Guest:
Kanti Rai, M.D.
INTRODUCTION
Andrew Schorr:
Hello. This is Andrew Schorr, and welcome again to another edition of CLL Perspectives. I am a CLL patient, and over many years I have gotten to meet some of the world renown doctors who are leaders in the field, and one I have always grown to love is Dr. Kanti Rai. Dr. Rai is an internationally recognized clinician and investigator in chronic lymphocytic leukemia, and he's at Long Island Jewish in Long Island in New York, and he's certainly been recently president of the American Society of Hematology and well known for his devotion in CLL.
Dr. Rai, thank you so much for being with us today.
Kanti Rai:
It's always a pleasure to talk to with you Andrew.
HOW FAR HAVE WE COME IN CLL TREATMENT?
Andrew Schorr:
My pleasure, of course. Dr. Rai, you have a long history with this illness, and certainly people come to you for second opinions. They come from around the country and sometimes around the world, and you've also seen progress that's been made. Now, your Rai staging systems continues to be used of course, but now we have other ways of also trying to stage the illness and looking at new prognostic factors. We've come a long way. Where are we now, and how far have we come?
Kanti Rai:
I think that we have come a considerable distance from the time I proposed the staging system in 1975. My sincere opinion is that we are treating CLL patients better, more in a planned manner rather than haphazardly that we used to do 25-30 years ago, and our patients enjoy a good quality of life for a longer period. I wish I could say that our patients with CLL are living longer. They are certainly living longer, but they are not living a whole lot longer, or at least not as long as we all would like our patients to live. So, on the longevity side we have not made important, strong, serious improvement, but in terms of available armamentarium for treating CLL, we are much better poised than we ever were.
WHAT DO WE KNOW ABOUT PROGNOSTIC FACTORS?
Andrew Schorr:
We talked about your staging system, but now we're looking at prognostic factors. Where are we with that? I know you're involved in research in that. We look at mutational status, CD38; we hear ZAP-70. What are some of the things on the table, and what is their significance now in community practice?
Kanti Rai:
That's a very good question, Andrew, because there are two aspects of these new developments, which are very important to point out, particularly to our colleagues who are not actively involved in CLL research but who see and treat CLL patients.
Now, from their perspective, I think that they know, and it is not wrong to think that they understand, that those people who have mutated Ig variable region heavy chain genes have a significantly longer life expectancy than those who are unmutated. Similarly, it is now well known that just as the unmutated patients have shorter survival time. Similarly those who are ZAP-70 positive have a shorter survival time than the ZAP-70 negative, and CD38-positive patients have a shorter survival time than CD38-negative. Similarly by FISH, or fluorescent in situ hybridization, method of finding chromosomal abnormalities, there are certain chromosomal abnormalities that give us an indication of a person having a longer survivorship. Those are the people who have 13q deletion as the single or the only abnormality and no other abnormality. Those are the people who have a significantly better outlook whereas people with the 17p deletion, 11q deletion, 6q deletion are the ones who have worse prognosis, and those who are trisomy 12 or 12+ are somewhat in between. They are not as good as 13q deletion and not nearly as bad as 17p deletion.
Then there is a group of patients who have complex 13q deletions. Complex means besides 13q they also have other abnormalities such as 6 or 11 abnormalities. There the power of a good prognosis of 13 as the solo abnormality is markedly reduced, so one cannot tell one way or the other.
The problems with these markers are; there are two problems that I would like to caution our clinical practicing colleagues.
Number one is we don't know, we have no idea, what to do when these prognostic markers do not seem concordant with each other. In other words, with a mutated patient and what to do if he's ZAP-70 positive because ZAP-70 points to a bad prognosis and mutation points to a good prognosis. Similarly, if you did all three; 38, ZAP, and mutation; and they point to different direction, we still don't know.
The current data from the recently done studies by CLL Research Consortium, which is likely to be published soon, has been presented at national meetings suggest that it is the ZAP testing that trumps all other tests. In other words, if a person is ZAP-negative and happens to be unmutated, well you can disregard the mutation status because the ZAP negativity pointing to good prognosis seems to be overpowering other bad prognosis markers, but that is not completely proven, whereas other people, for example in Germany, find that it is the mutation status that trumps the ZAP and the CD38.
Well, I don't know what to do about this, and what I do, and I would urge other practicing colleagues to do, is that in times of discordance between these markers you look at the patient herself or patient himself. If the patient is doing well, has not had any symptoms over the few years preceding while the doctor has been watching them, then you disregard the bad prognosis indicator be it unmutated or be it ZAP-positive. You say it is meaningless. I have to go by what I see, and what I see is a person who is doing well, has been doing well, and there are no indications on clinical grounds to suggest that he or she is likely to get into deep trouble very soon. That is a message which is very important to pass on to the colleagues because we get very upset, patients get upset, the doctors get upset, and we don't know how to interpret this. I'm not suggesting that I know how to interpret this. I only know that I, by my own experience, that it is the patient's clinical status which should trump everything else.
Andrew Schorr:
So, that leaves us where we've been really then. That's sort of the art of medicine, and so while we have these prognostic factors being discussed, it doesn’t' sound like there's any big action to take, even though everybody is talking about it.
Kanti Rai:
I agree with that. I will emphasize what you were saying in your earlier remarks at this question, and that is a doctor should continue to act as a doctor and not be an automaton. That is, a doctor's clinical skills should not be left at home when you are in the clinic because it is in that level that you need your clinical skills. Nowhere have we ever suggested that these tests will replace the doctor's experience and ability to think and look at the situation critically.
PROTECTING THE IMMUNE SYSTEMS WITH TYPES AND TIMING OF TREATMENT
Andrew Schorr:
Dr. Rai, let me ask you about another aspect of this though. Often there's the pressure to do something, and many of the treatments that have been available for CLL certainly affect a patient's immune system; not just short-term but long-term, yet there's the hope of new and better treatments coming along. So, what's the plan then for what we should do now, what should be done now, that doesn't damage the plan for the future and giving the best chance for a patient to have a longer life as new agents become available?
Kanti Rai:
That's a tough question because it goes to the fundamental of the art and science of doctoring. We as doctors should start with an understanding that even though we wish that we had a cure against this disease, the fact remains that we do not have a cure.
My colleague and friend and clinician scientist, Michael Keating, M.D., has come up with the FCR combination. It's a combination that should certainly achieve a complete remission by clinical criteria, by molecular criteria, and by flow cytometry criteria in a very large majority of CLL patients who have been given this treatment as front line, but even Dr. Keating says that we have not found a cure in FCR and that in FCR complete-remission-patients the curves are not remaining flat at 80 or 90 or 70%, but with the passage of time, they continue to decline. In other words the patient's slide back into relapse or reactivity or re-evidence of disease.
So, as long as we have not found a cure, my sense is that I would like to treat a patient with less aggressive treatment, which gives me a chance of achieving remission, but I still have powerhouses such as FCR and other combinations up our sleeve in reserve for the second-line treatment, and your point that with most of our treatments we further reduce the immune potential of our patients has to be remembered in that nothing that we do is entirely benign. It renders our patients vulnerable increased risks of infections, sometimes major infections, opportunistic infections, and therefore we ought to make a decision of intervention only when we are clear in our mind that the risks and benefits of going in and intervening with the treatment are in favor of the individual, and withholding treatment and continuing to wait and watch or wait and worry or observation or the risks and benefits are against the patient by continuing the observation phase.
So those are the questions that a doctor ought to ask before saying to the patient that I think you should start treatment now, and there are no ifs and buts.
HOW DR. RAI TYPICALLY STARTS TREATMENT
Andrew Schorr:
You mentioned that you try to save an FCR as a bigger gun later, then how do you typically start?
Kanti Rai:
I start with the FR. That is a combination that we have used in cancer and leukemia group-B studies in which fludarabine and Rituxan were either used simultaneously or sequentially after six months of fludarabine and then introduce Rituxan. My own bias is simultaneous use of the two agents, and the results with FR are quite impressive and yield significant numbers of complete remissions, and they are all durable remissions. When several years later those patients need some more treatment, we either can go again with FR and have a chance of similarly good results or could go with FCR, and I think that it is fine
There are other colleagues who want to replace F for P, fludarabine by pentostatin. I have no qualms about this. I do not have a brief either for or against pentostatin or fludarabine. My sense is that because we have used fludarabine in tens of thousands of CLL patients and because the overall experience with pentostatin in front line is in numbers of about 200 or 300, I go by what the biggest experience is. Some people claim that pentostatin is less toxic or less immunosuppressive than fludarabine. I'm willing to accept that, but do a head-to-head comparative trial first and show us that it is less immunosuppressive or less myelosuppressive. So until then, people can use PR/PCR in lieu of FR/FCR. It doesn't make too much difference. In my mind the two drugs are equally effective.
COMMENTS ON INVESTIGATIONAL USE OF RITUXAN AND CAMPATH TOGETHER
Andrew Schorr:
Dr. Rai, in relapsed patients then there has been some thought in some quarters to using Rituxan and Campath together, at least investigationally. Do you have some feeling about that?
Kanti Rai:
Investigationally, if the case is made scientifically with the proper support of published literature and other pilot studies, I would certainly accept this, and I think our CLL patient populations will accept it because rituximab and alemtuzumab, or Campath, both are monoclonal antibodies, so theoretically we do not adversely effect the normal hematopoietic elements of the bone marrow, which is an advantage, and we should capitalize on that. So I feel that a combination of Rituxan and alemtuzumab is an excellent idea, and we should develop protocols.
WHAT OTHER AREAS OF RESEARCH SHOW PROMISE FOR THE FUTURE?
Andrew Schorr:
Okay, looking further then, because obviously we do want to extend life with good quality of life along the way, is there an area of research that you say to stay tuned for and that shows promise in your mind?
Kanti Rai:
Stay tuned for a clinical trial strategy for risk-adapted method. In other words, we are to do randomized clinical trials, for example, in early stage CLL patients who are free of symptoms but who have adverse prognosis, such as who are unmutated. We have to randomly assign half of those patients to observation because that is the standard one versus therapy, chemotherapy, chemoimmunotherapy such as FR or FCR.
Unless we do a trial such as that, five years from now we will never know if early intervention in unmutated patients who are free of symptoms will be of help or will hurt the patient. So those are the kinds of trials I hope that we will all undertake to help the patients in the future.
Andrew Schorr:
This has been fascinating Dr. Rai. We will talk again at ASH to see what comes out there, and I know everybody who is listening wants to thank you for your devotion to investigation and treatment of CLL over so many years. Thank you for being with us, sir, on CLL Perspectives.
Kanti Rai:
You're most welcome, and it was a pleasure. Thank you.
Andrew Schorr:
It's always a pleasure. Dr. Kanti Rai from Long Island Jewish, and I'm Andrew Schorr. Be with us again next time for CLL Perspectives with other experts in CLL. Thank you for joining us.
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