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Recent News in Chronic Lymphocytic Leukemia: Highlights From the 49th Annual Meeting of the American Society of Hematology

Faculty
Kanti R. Rai, MD
Chief, Department of Hematology-Oncology
Long Island Jewish Medical Center
New Hyde Park, NY

This activity is not sanctioned by, nor a part of, the 49th Annual Meeting of the American Society of Hematology.

Expert Interview: A Conversation with Dr. Kanti Rai on new data with clinical trials in chronic lymphocytic leukemia recently presented at the 2007 Annual Meeting of the American Society of Hematology.

1. Fludarabine-based regimens have become standard therapy for chronic lymphocytic leukemia (CLL) and the addition of biologic agents has improved outcomes. In March, you published the initial results of a phase III trial assessing the addition of oblimersen to fludarabine/cyclophosphamide (FC), which showed an advantage in terms of complete remission (CR) for patients with relapsed/refractory CLL. What new information on this study is now available?

Dr. Rai: The publication reported that the CR and nodular partial remission (nPR) rates were indeed significantly greater when oblimersen was added to FC.

Additionally, the duration of these responses obtained with the oblimersen/FC combination was significantly longer. What is new and different in our presentation at ASH in December 2007 compared to the publication is that we are now reporting follow-up of these patients at 54 months, or 4.5 years, which suggests that these durable CRs and nPRs achieved with oblimersen/FC are associated with prolonged survival. The data reveal that the chance of achieving a CR and surviving at 1, 2, 3, and 4 years is statistically significantly greater on the oblimersen/FC arm compared to FC-alone arm. So, all those landmark data are significantly better for the oblimersen-containing arm.

At 54 months of follow-up, 12 of the 20 patients achieving a CR/nPR with oblimersen/FC remained alive compared to only 3 of the 8 patients achieving a CR/nPR with FC (60% vs. 38%). Whereas all 3 of the surviving CR/nPR patients on the FC arm have relapsed and required additional treatment, 5 (25%) of the 20 patients receiving oblimersen/FC remain in CR. An additional 4 of those patients have relapsed but required no additional therapy, and the remaining 3 have relapsed and required additional therapy. The median survival of the patients achieving CR/nPR in the oblimersen arm had not yet been reached and is estimated to exceed 55 months, whereas the median survival duration had been reached in the FC arm and was 45 months. There were no new toxicities observed with the addition of oblimersen.

2. Were there any patient characteristics in the study population that should be considered in interpreting the survival results? Were there any patient populations that benefited more than others?

Dr. Rai: The study was prospectively stratified for fludarabine-sensitive versus fludarabine-refractory patients at entry. Those patients who retained sensitivity to fludarabine had a 4-fold greater CR/nPR rate in the oblimersen-containing arm compared to the FC arm (25% vs. 6%). Additionally, even though the numbers of patients in this subset was small—about 40% of the total population—a statistically significant survival benefit was observed. So, it appears that the best results are obtained in the patients who retain sensitivity to chemotherapy. This finding suggests that the drug will have its greatest effects in less heavily pretreated patients and should be tested in up-front settings.

3. Oblimersen received a denial letter from the US Food and Drug Administration (FDA). Can you comment on the primary reasons for denial and how these new data address the concerns raised by the review committee?

Dr. Rai: My personal belief is that oblimersen’s benefits clearly outweigh the risks, but I am not actively involved in dealing with the FDA on this matter, although I was present at the time when Dr. O’Brien and Dr. Keating made a presentation a year ago in September at the Oncologic Drugs Advisory Committee (ODAC) meeting. I understand that now a further appeal is pending, and as far as I can tell, the FDA agreed that the CRs were significantly greater with oblimersen but, in the end, did not accept the primary endpoint, which the sponsoring company had used and had claimed that prior to initiation of accrual that the FDA had approved. At the ODAC meeting, the FDA denied that that was a clearly agreed-upon endpoint. They felt that in addition to CR/nPR they would have liked to see clearly demonstrated evidence of more benefit to the patients, and that is where our dispute is. I have no axe to grind in terms of financial or any other matters. I just look at it from my patients’ points of view and my own observation that we have gotten other drugs approved by the FDA with much less benefit evidence than oblimersen has shown, and now the FDA claims that more evidence of benefit is needed. I think that the quality of life of these patients was demonstrably improved after exposure to oblimersen. We have demonstrated that the toxicities suffered by the patients were not significantly different in the 2 treatment arms. I think that if fair-minded people looked at the same data, they ought to approve this agent; for patients in this category, there is an unmet medical need, and the doctors and patients need additional elements in the armamentarium.

4. What other phase III trials in CLL (front line or relapsed/refractory), reported this week at ASH do you think will impact clinical practice decisions in the near future?

Dr. Rai: There were several rather interesting reports in the ASH meeting this week, mainly in the frontline setting. One study that comes to mind is the combination of rituximab plus FCM (R-FCM).

Now, as you know, FCM has already been reported in prior meetings—the Spanish group from Barcelona had reported that FCM is a very effective chemotherapy in CLL. Now they have added rituximab both at the time of initial treatment in the frontline setting and continuing with rituximab in the maintenance phase. There was a small sample size—I believe there were 47 evaluable patients—and practically 80% of those patients had advanced Binet stage B and C disease, and about two-thirds of them had high levels of ZAP-70, which is a marker of poor prognosis.  The overall remission rate (ORR) was 94%; of these, 74% were CRs, and out of those CRs, approximately 35% were minimal residual disease–negative CRs.

A similar combination was also reported by colleagues at The University of Texas M. D. Anderson Cancer Center with R-FMC. Previously, they had reported that FMC was effective in frontline CLL patients. Now, they added rituximab and pegfilgrastim in patients aged < 70 years who had less tumor burden and β2-microglobulin < 4, and they found objective clinical responses as well as absence of residual tumor cells by CD5/CD19 dual-color testing. So, 28 patients (97%) achieved a response, with a 41% CR rate and a 17% nPR rate. They showed that there were infectious toxicities (45%). The conclusion was that there was a high CR rate in symptomatic frontline treatment. 

Also from M. D. Anderson was a report of another frontline combination: cyclophosphamide/fludarabine/alemtuzumab/rituximab (CFAR). This CFAR combination seemed active and deserving of further study.

Results of an international phase III study, which tested bendamustine against chlorambucil in frontline Binet stage B and C patients with CLL were also presented at ASH 2007. Bendamustine is a purine analogue/alkylator hybrid drug. It was given intravenously at 100 mg/m² on days 1 and 2 every month for 3 cycles. Chlorambucil was given orally 0.8 mg/kg on days 1 and 15 every month for 3 cycles.

At this analysis, 139 patients were evaluable for bendamustine and 125 for chlorambucil. Bendamustine was found to be significantly superior in terms of ORR and CR rate. Progression-free survival and duration of remission status were also superior with bendamustine. However, there were no differences in overall survival.

5. In your practice, what do you typically recommend for patients whose disease doesn’t respond to or progresses on a fludarabine-based regimen? Are there any cytogenetic or molecular prognostic markers that can help clinicians predict who might respond to therapy?

Dr. Rai: That’s a very important and probably as yet unresolved question, because these prognostic markers, in my view, are important guides for hematologists and oncologists when they’re dealing with the patient who is still previously untreated. A previously treated patient who is relapsing is a completely different group, because in that group, I don’t think that the presence or absence of ZAP-70 or mutated immunoglobulin genes are as powerfully helpful markers as they are in patients who have not yet been exposed to cytotoxic agents. In a person who is frail and susceptible to infections because of prior treatment toxicity or lingering toxicities, one might have to make a decision that the therapeutic endpoint has to be somewhat restricted to maintain the quality of life and reduce the tumor burden, whereas in a patient who has an excellent performance status and has good neutrophil level and good marrow function, we ought to go much more aggressively to try to eliminate the disease. You might also have to consider a nonmyeloablative conditioning–based allogeneic transplant if the patient’s age permits. In other words, in the relapsed setting, it is the clinical judgment of the doctor that becomes more important than cytogenetics, CD38 and ZAP-70, and mutation status.

6. What other combinations with fludarabine do you currently use in patients with relapsed/refractory disease? Do you always use chemotherapy with a biologic agent, or are there some patients for whom a biologic agent alone or chemotherapy alone might be effective?

Dr. Rai: Well, my personal approach is that first of all, I would like my patients to enter a prospectively conducted clinical trial. My primary allegiance is to Cancer and Leukemia Group B (CALGB), and we have slew of risk-adapted combination treatments for every risk category in CALGB. Second, my allegiance is to the CLL Research Consortium (CRC), which is headed by Dr. Kipps at the University of California, San Diego and in which Michael Keating, John Byrd, and Dana-Farber and the Mayo Clinic and myself from Long Island Jewish Medical Center, we all are active participants. If the patient refuses to enter any of these trials and wants me to make a judgment as to what is best, my treatment recommendation in the front line is fludarabine/rituximab (FR), which we in CALGB demonstrated a few years ago to be a very good, effective treatment. We do not use FC plus rituximab (FCR) in the front line (as Dr. Keating feels is the right thing to do for all frontline patients), because I feel that FCR has certain limiting myelotoxicity, but I find FCR much more attractive and effective and useful in the second-line setting. There are colleagues who want to replace fludarabine with pentostatin, and I have no problem with that. After I have used FCR in a second-line protocol, then I have a number of other drugs in trials. I would like to enroll patients to studies in which lenalidomide is being offered. The CRC is developing a protocol of lenalidomide/rituximab, and that is something I would encourage. Beyond that, we have a number of other phase I and phase II agents currently in trials.

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