Staging and Prognostic Factors in CLL

Guest:

Michael J. Keating, MB, BS
Professor of Medicine, Department of Leukemia
M.D. Anderson Cancer Center

Andrew Schorr:

Hello once again. This is Andrew Schorr on CLL Perspectives. Thank you so much for joining us as we continue to bring you a connection between leaders in the field of CLL and research and treatment and let you hear their perspectives on some of the most current issues that can make a difference for you as you practice with your patients wherever you may be listening to us.

Joining us today is Dr. Michael Keating, who happens to be my doctor from M.D. Anderson. So, that's important to me, but for everybody he is a Professor of Medicine, and he is in the Department of Leukemia at M.D. Anderson Cancer Center in Houston. He has practiced there for 23 years, and as you probably know, Dr. Keating has received many honors and awards for his work in CLL. Dr. Keating, thanks so much for being with us.

Michael Keating:

It's good to be here, Andrew.

Andrew Schorr:

Now, Dr. Keating, you have just gotten back very recently from the iwCLL meeting, that was in London this year, and that's where you and others who have devoted their lives really to the research and treatment of CLL get together. Are there some areas that were discussed that you would like to highlight for people who are in the trenches, if you will, in community oncology practice?

Michael Keating:

Well I think that for a start we need to just let people know that the International Workshop on CLL started out as just being a workshop with about 20 people turning out to the first workshop, and because of the developments that have occurred in CLL, the meeting in London actually had 750 people who turned up for this meeting. So there's been tremendous energy in the CLL area that has developed, I think from the point of view of physicians in the community and because actually academic clinics are trenches as well. I would like to highlight a couple of things. There has been a lot of discussion over time that the genetics as defined by the FISH technology and also the mutation status and ZAP-70 and CD38 are major new prognostic factors, and there was not a lot of discussion about the mutation status, which is more expensive and more complicated to do, but there was a lot of discussion about ZAP-70, and we still don't know exactly the right way to measure it. There have been some harmonization studies that have been conducted over in Europe, but they still don't apply to the United States where many of these patients actually have their assays done in commercial labs without necessarily a lot of validation of the accuracy of the results compared to some standard, and so far it hasn't really emerged that there has been a strong association with the likelihood of patients responding to treatment or staying in remission if they do respond.

What it has told us is that they are more likely to need treatment at some point in time. So, I think it's important from the practicing clinician point of view to start saying, well if I do this when the patient first comes in, what does it mean, and if the patient demonstrates that they're progressing and need therapy, what does it tell me from that point in time, and does it lead me in the direction of one treatment versus another? And so far there has been a lot less clarity for the CD38 and the ZAP-70 from that point of view and even the mutation status. The mutation status appears to predict for patients that are less likely to develop additional changes and transform into Richters, etc., but the only two things which have emerged really have been this mutation status and the FISH abnormality, in particular the 17p deletion, which is, I think, universally accepted as being an adverse prognostic factor no matter at what time it happens to be measured.

Andrew Schorr:

So therefore, with these deletions, how do you decide who to treat sooner? Or do you?

Michael Keating:

I think that most of the patients who have these adverse parameters; unless they have the traditional characteristics leading to treatment, namely bone marrow failure with anemia and thrombocytopenia or bulky disease or significant symptoms or evidence of progression of their disease; I think it is still warranted to observe the pattern of growth of the patients. Even in the patients that we see that are 17p deleted, if they present with Rai stage 0 and have the 17p loss, they actually have a very good natural history. So, you have to put in addition to the 17p the stage and all they're telling you really is the biologic behavior and to a degree the responsiveness to particular treatments such as fludarabine and alkylating agents.

Andrew Schorr:

Then the question is, how aggressively do you treat CLL, and I'm reading off the sort of cover page of the web site from the iwCLL, and it says, "Although the initial goal was to achieve palliation in patients with CLL, the ability to achieve a high complete response rate with evidence of PCR negativity has changed the philosophy." So, where are we with that?

Michael Keating:

I think that the most significant change in thinking that's occurred has been from palliation to having the same goals as we have had in the other leukemias and lymphomas, namely it's good to get a complete remission. In every study that's been looked at, complete remission patients have long periods free of disease recurrence versus those who are in partial remission, and it's clear that if when you evaluate these patients, and if they have no evidence of residual disease on sophisticated flow cytometry or by PCR testing, these patients have much longer remissions or progression-free intervals than patients who still have residual disease. So, in actual fact, we're in a situation where we can now get many patients to have remissions of 5-10 years rather than in the past it would have been 2-3 years in duration.

Andrew Schorr:

So, then the question is, if you can have someone get a longer remission, what do you do then? What happens when that remission ends?

Michael Keating:

There's a lot less information available on that, and I think the only systematic data was what I presented at the ASCO meeting that patients that had had the FCR regimen as their induction program, if they relapsed, about half the patients could achieve a 2nd complete or partial response, but only about 13% of the patients could get a complete remission, and when we looked at the associations with that, it appeared that the regimens that combined the 2 antibodies, alemtuzumab or Campath together with rituximab were the ones that were associated with the highest likelihood of getting a complete remission. The other thing is that I think patients that only have a partial response or relapse fairly quickly after getting a remission are very good candidates for having the nonablative stem cell transplantation.

Andrew Schorr:

Let's back up for a minute related to initial treatment. So, there is a study going on to see the difference between FCR and FR. Now, you've been in the FCR camp. What's your continuing feeling about that while this research goes on?

Michael Keating:

The FCR program has the only regimen that has had a complete remission rate above 50%, and also the remission duration is significantly longer than the FR regimen that's being reported by cancer and leukemia group B. Now, whether there is comparability of treatment groups or not, the data is persuasive that the remissions are a lot longer and a lot more durable with the FCR than they had been with the FR. And the other regimen that's been floating around has been the PCR regimen from Memorial Sloan-Kettering and the Mayo Clinic, and again they have a fairly good complete and overall response rate, but the remission durations have been somewhat disappointing in that they are really no better than have been achieved with the fludarabine cyclophosphamide combinations without rituximab.

Andrew Schorr:

Now, is there any argument to use alemtuzumab or Campath earlier? You mentioned it being combined with Rituxan for people who have relapsed. Is there any use of that earlier?

Michael Keating:

Well, it's been an interesting week last week in that alemtuzumab was approved for front line use in patients with CLL. This is largely as a result of a randomized comparative trial conducted almost exclusively in Europe, in particular eastern Europe, showing that alemtuzumab had a significantly higher complete response rate and overall response rate than chlorambucil, which is the accepted standard for therapy over in Europe, and they have a longer progression-free survival and in particular in the patients that have 17p abnormalities. These are the patients who appear to have to the greatest likelihood of benefiting from alemtuzumab. So I think that alemtuzumab is now going from the point of being given when patients are refractory to all other therapies to now being available to be explored more extensively as earlier treatment, and I know that there are studies ongoing of rituximab plus alemtuzumab as front line therapy for older patients with CLL taking away the chemotherapy element, and we've been conducting a study of the FCR together with alemtuzumab, that's the CFAR regimen, and this is for patients that we see who have a beta-₂ microglobulin more than twice the upper limit of normal that are less than 70 years of age, and so far the results appear to be promising now that we're more familiar with the way that we should diagnose a cytomegalovirus reactivation and how we should manage that when it occurs.

Andrew Schorr:

Right, and let's talk about that for a minute. So that's been a concern is how do you manage this risk? Any comment you'd like to take on what you do at M.D. Anderson?

Michael Keating:

I think one of the things that has become more apparent is that when you're using alemtuzumab by itself or combined with rituximab for example, the patients will often, when they're not neutropenic, develop and episode of fever, and it's in about one patient in five or one patient in four who will develop a CMV reactivation, which appears to occur in the 4th, 5th, or 6th weeks of therapy, and it can usually be very easily managed by giving valganciclovir at 450 mg twice a day, and we usually just continue to treat the patient while adding the antiviral medication to their regimen. So, I think that it's become clear that CMV reactivation is fairly common. It is not usually associated with organ dysfunction of lungs and liver and gastrointestinal tract such as you see in the transplant environment, and it's usually well handled on an outpatient basis with the oral valganciclovir.

Andrew Schorr:

Dr. Keating, some clinicians with patients who have gotten a remission with CLL, like in lymphoma, are using so-called maintenance Rituxan. So maybe that helps us launch you in our discussion about similarities or differences with lymphoma. So first of all, the idea of maintenance Rituxan in CLL, what do you think about that?

Michael Keating:

If we're talking about evidence-based medicine, there is no evidence that rituximab does prolong remission or have any impact on survival, so from the point of view of post-remission therapy, in CLL we're way behind in the indolent lymphoma group. They are showing a number of studies in follicular lymphoma prolonging remissions and now beginning to have a positive impact on survival, but I think we have to go back and look at the initial studies of rituximab in low-grade lymphoma and be aware that in follicular lymphoma in salvage situations, more than 50% of the patients got a response whereas only about 10-15% of small lymphocytic lymphoma patients get responses. So, it is obvious that rituximab is not as potent an agent in SLL or CLL compared to the follicular lymphoma. So, I think it's imperative that we set up comparative studies to try and establish what the role is in prolonging remission duration and compare it to what has become the standard postremission therapy which is alemtuzumab.

Now, there have been proposed studies comparing one to the other or one versus no maintenance or no postremission therapy, and some studies are actually incorporating the combination of the two antibodies as one arm of the study, and these are just being put in place at the present time, so I tend not to do postremission work in patients that have achieved remission on FCR because the remissions are so long that it's going to be very difficult to define any difference in remission duration in less than 5 to 10 years' time. So, I think that we have to be careful as to how we set up these studies to get the most information out of them.

Andrew Schorr:

Now obviously community physicians see more lymphoma than they do CLL, although they may have several if not many CLL patients over many years. What's your caution to them about CLL being different from lymphoma?

Michael Keating:

I think one of the things we have to be aware of is that we've always tended to put SLL in with follicular lymphoma in the indolent diseases, and because it's such a small subfraction, there has never been any consistency in evaluating the impact of different treatments, specifically in SLL. So, I think it's important that we realize that the biology of SLL and CLL are identical, and it's just that the SLL is a leukemic CLL, and follicular lymphoma is obviously very different, so I think that now more and more studies are grouping SLL together with CLL as a group to be investigated, and I don't think we should necessarily extrapolate studies in follicular lymphoma, which has a very defined biology, directly to SLL, which has a very different biology.

Andrew Schorr:

Dr. Keating, so people often will go to you for a 2nd opinion and their regular doctor is a community hematologist/oncologist. Is there any comment you'd like to make of what you see sort of on the receiving end and when you think sometimes, gee, I wish this had been done differently or any advice you'd give just generally knowing there's great variation of course?

Michael Keating:

Well I think that there are two elements to it. One is that there have been no comparative studies that have demonstrated a survival advantage of one approach over another, and in particular there has not been a comparative study that shows that early intervention of which is the watch and wait as delivered by chlorambucil therapy versus watch and wait, has had any benefit. So I think that clinicians have been reluctant to initiate immunosuppressive and myelosuppressive and DNA damaging therapy to SLL patients and CLL patients without evidence in an improvement in survival. However, I think that there are two things that happen. One is that a number of patients with significant symptoms watched and waited until the tumor burden gets too high, and I don't mean this on the basis of one of the prognostic factors or whatever but just based on the fact that these patients have progressive increase in their tumor burden while they're being observed, and I don't think that that's a wise strategy because it increases the likelihood of emergence of resistant clones of cells. The other is that the purpose of the watch and wait is to identify the patient population that don't have the disease of CLL, that is they have nonprogressive CLL, and all of us can relate to patients that we have been following with moderately enlarged lymph nodes and a white cell count of 30,000-50,000 for a period of five-ten years without any symptoms, so I think we have to go back to being doctors and say, okay, if this patient is symptomatic, we should treat the disease, and if the patient has progression of their malignant cell population, we should try and decrease that population and based on the observations that are made, if you're going to treat, you might as well treat them to complete remission because that gives them long periods of time free of any therapeutic intervention.

Andrew Schorr:

Dr. Keating, let's just take our last few minutes just talking about agents you're working on that maybe show promise, and I'd like to just know what you think could end up having impact at the community level if the research continues to be promising.

Michael Keating:

I think that the two treatments which had the most attention at the iwCLL were flavopiridol, which has been championed really by the investigators at Ohio State University, and it's a very potent agent but somewhat challenging to administer. In particular in the earlier times, patients had to be treated in intensive care units with dialysis machines standing by for tumor lysis syndromes, and it's been a bit easier to manage now that it's been defined that the very-high white cell patient population is the group that suffers that, and the group at Ohio State has to be complimented in developing the guidelines for this. So, it's a potent drug. The thought is that it may be safer to administer and more effective when the patients have a lower tumor burden, so it may be useful for residual disease. But the family of drugs, which again got a lot of attention at the iwCLL, were the IMiDs. A number of investigators, in particular Dr. Chanan-Khan at Roswell Park had done thalidomide with or without fludarabine and got a very high response rate, and then lenalidomide, or Revlimid, has been studied by the group at Roswell and also at our place finding that not only is it a very effective oral medication, but it actually has significant activity against the 17p-deleted group of patients and also patients that have un-mutated immunophenotype in the 11q abnormalities. So this is an exciting new drug because it works through a number of different mechanisms, most of which are ill defined, but it's not a DNA damaging drug and by interfering with stromal interaction, I think that this is a very important element, and I think that this is the most exciting drug for us to push forward right now because it will be broadly applicable to patients at various stages of the disease.

I know that from our point of view we have a protocol which we will be opening in a couple of weeks in late September/early October of this year for patients over the age of 65. We also have a salvage protocol in conjunction with Rituximab being put in place and also the use of lenalidomide for treatment of residual disease. So, I think that these are the two chemotherapy drugs which are most likely to have an impact in clinical hematology-oncology in the next couple of years.

The other feature, however, that is standing out is that the nonablative stem cell transplantation really offers a true prospect of cure so that about 50% of the patients who are having the nonablative transplants; usually as a 2nd, 3rd, or 4th line therapy; will often have plateaus on the curve at around about the 50% mark, and it appears at least as effective as the full transplants, so I think that this is, again, going to be an important element for us to be able to identify the patients who we should be referring along to the transplant centers and see if we can maximize the benefit and minimize the risk on this group of patients.

Andrew Schorr:

One question just about monoclonal antibodies; so, Rituxan has become part of treatment for many CLL patients and now there is development of humanized CD20 approaches. So, where do we stand with that?

Michael Keating:

Well, they're not so much even humanized now because rituximab has been humanized as a chimeric antibody but the human antibody ofatumumab or HuMax antibody is well into clinical trial at the present time in two areas. One is in fludarabine and Campath refractory patients and patients who are fludarabine refractory with bulky lymph nodes that alemtuzumab is not very useful for, and this study is almost completed at accrual and hopefully will be available in the middle of next year. The other is that it's been brought forward together with FC in two different dose levels to see what the best dose level to administer in conjunction with chemotherapy is to front line patients, so that this is an important study for us to look at not only from the effectiveness but the safety of combining this new antibody together with chemotherapy.

Andrew Schorr:

Dr. Keating, we're going to visit with you again at ASH, which is coming up, but it seems like with what will be presented at ASH, what you heard at iwCLL, there is a lot to talk about that seems to be changing in CLL, again though with the caution of not treating people too soon but people who need treatment then driving towards a complete remission, so I know we'll need that perspective again, but at least there's a lot to talk about.

Michael Keating:

There's a tremendous lot to talk about, and I think that one of the things that we have to realize is that clinicians need to act as clinicians and not pseudoscientists and not do whatever is most popular or most en vogue with the latest fancy test. I think we've always in oncology treated patients on the grounds of what their clinical behavior is, and this strategy has stood the test of time, and I think in the next year or two, many of these issues regarding prognostic factors, early intervention, are really going to emerge and be clarified, but I would highlight that most of the information that we have in CLL therapy at the present time has not been derived on patients over the age of 65 or 70. It's primarily in younger patients, and we're in desperate need of clinical research specifically looking at all the patients so that we can make treatment both effective but safe and improving rather than diminishing the quality of life of this group of patients.

Andrew Schorr:

Well, wonderful comments. We've been visiting with Dr. Michael Keating, Professor of Medicine in the Department of Leukemia at the University of Texas M.D. Anderson Cancer Center in Houston, and we'll have more with Dr. Keating as we continue our interviews and articles on cllperspectives.com. Thank you so much for being with us as always Dr. Keating. It's always a great educational experience, and I know I learn a lot as a patient, but I know our provider audience learns a lot too. Thanks for being with us.

Michael Keating:

It's a pleasure. It's always good to talk to you Andrew.

Andrew Schorr:

Thank you, sir. This is Andrew Schorr with CLL Perspectives thanking you for joining us, signing off.