Bruce D. Cheson, MD; Gilles Salles, MD, PhD


June 18, 2012

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Bruce D. Cheson, MD: Hello. I am Bruce Cheson, Deputy Chief of Hematology/Oncology and Head of Hematology at Georgetown University Hospital and the Lombardi Comprehensive Cancer Center in Washington, DC. Welcome to this edition of Medscape Oncology Insights. Today we will look at noteworthy studies in lymphoma that were presented at the 2012 annual meeting of the American Society of Clinical Oncology (ASCO®). Joining me is my friend, Dr. Gilles Salles, Professor of Medicine in the Department of Hematology at the University Hospital in Lyon, France. Welcome, Gilles. It’s good to see you again, as always.

A number of interesting and provocative abstracts were presented in lymphoma at this meeting. One group of presentations attempted to tell us the best initial treatment for follicular lymphoma. Which of the presentations impressed you?

First-line Regimens for Follicular Lymphoma: 6 of One?

Gilles Salles, MD, PhD: In the field of first-line treatment for follicular lymphoma, we saw 3 interesting abstracts during this meeting. Two were randomized studies that addressed different chemotherapy regimens combined with rituximab in the first-line treatment of the patient with follicular lymphoma in need of therapy. One was a randomized study performed by the Italian group, Fondazione Italiana Linfomi, which compared R-CVP [rituximab, cyclophosphamide, vincristine, prednisone], R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone], and a combination called RFM [rituximab, fludarabine, mitoxantrone].[1]This was a large study with 500 patients. The results were initially presented in Lugano but were updated during this meeting. The key message is that the response rates are not different between the 3 regimens, and that the progression-free survival (PFS) curve looked better for RFM and R-CHOP as compared with R-CVP. When we look at the toxicity, an increased rate of toxicities is encountered with RFM, resulting in a higher rate of death. The survival curve of the RFM regimen is inferior to that of the 2 others, which look similar. So, the study provides minimal information. We probably already knew from all the data that R-CHOP enables better control of the disease for some period, and that there is no overall survival difference between R-CHOP and R-CVP. The key message here is that a fludarabine-containing regimen in first-line treatment of follicular lymphoma is too toxic and should be avoided.

Should R-Bendamustine Replace R-CHOP?

Dr. Salles: The second study that was presented during the plenary session by Dr. Rummell[2] from the lymphoma study group in Germany is an update of the comparison of rituximab bendamustine [R-bendamustine] vs R-CHOP in first-line treatment of follicular lymphoma, indicating a benefit in terms both of response rate and PFS with R-bendamustine.

Dr. Cheson: Actually, it wasn't response rate; it was complete remission rate. The response rates were the same.

Dr. Salles: Yes, that is correct -- complete remission rate. However, there are a couple of questions about the poor results of the R-CHOP arm. The complete response rate is unusually low. The PFS is unusually low. Patients with follicular lymphoma are a subset of the whole study. The data are still important. R-bendamustine is clearly less toxic than R-CHOP in this study, but whether these data are sufficient to decide that R-bendamustine will replace R-CHOP, I am not convinced. What is your opinion about that?

Dr. Cheson: In the United States, the penetrance of R-bendamustine has taken over as the predominant regimen on the basis of data that have been presented repeatedly in abstract form without being published. So, I am starting to feel a little reserved about it. If I hadn't seen such excellent results in my own clinic, I would be more concerned, but I agree with you. Until we have the opportunity to see a paper and review the data on PFS -- for example, how did they measure progression? Was it standardized? What about toxicity? In the presentation, I was concerned because we saw a lot of fatigue with this regimen. There wasn’t much in the way of fatigue in the study. I agree with you that it has already changed practice considerably. Whether we should be changing [to bendamustine] at this point, I'm not sure.

Dr. Salles: To my knowledge, there is no overall survival difference between the regimens, so I do believe that we still have the choice in terms of long-term outcomes of the patient.

Dr. Cheson: Right, and it may come down to toxicity.

Dr. Salles: Yes, and probably in patients in whom we would like to avoid cardiac toxicity (eg, those older than 65), R-bendamustine may be a preferable regimen.

Dr. Cheson: I still tend to use R-CHOP in the patients about whom I am concerned something else is going on -- those who present with bulky disease and high lactate dehydrogenase (LDH) levels and night sweats, etc. For those patients, I believe that R-CHOP might be appropriate therapy.

Another Take on First-line Treatment of Follicular Lymphoma

Dr. Salles: This brings us to the third presentation, the first-line treatment of follicular lymphoma, which was the presentation by Dr. Oliver Press,[3] of the US intergroup trial, assessing R-CHOP vs CHOP followed by tositumomab iodine-labeled antibody. The results that were presented at the American Society of Hematology meeting showed that there was an equivalent result between the 2 arms of the study (R-CHOP and CHOP-radioimmunotherapy) in terms of PFS and overall survival. During his presentation, Dr. Press attempted to identify whether any subgroups of patients might benefit more from one regimen vs the other. He ran several analyses (which I didn't find completely conclusive), eventually suggesting that for patients who had better outcomes because of a low beta-2 microglobulin (B2M) level, CHOP followed by radioimmunotherapy might be better, whereas for patients who had adverse prognostic features such as high LDH and high B2M levels, R-CHOP might eventually be better. We still have to be careful with that. This relates to the earlier presentation, that in follicular lymphoma we are missing key parameters to identify which patients will benefit from a given strategy -- R-bendamustine, R-CHOP, or CHOP followed by radioimmunotherapy.

Dr. Cheson: I don't find a test such as B2M very satisfying as a marker. I look at that and think, is this multiple comparisons? There are many other, more biologically oriented markers that you are studying and that I hope will lead us to more scientifically directed ways to treat our patients.

Dr. Salles: Definitely.

A Promising Approach in Recurrent Follicular Lymphoma

Dr. Cheson: With this disease, however, patients almost always relapse. We need new therapies in the relapse setting, particularly if we are moving R-bendamustine up front. What are you going to do when the patient relapses? There are some novel approaches, and John Leonard showed some interesting data at this meeting.

Dr. Salles: Yes. Dr. Leonard showed results of a studythat was performed by the CALGB [Cancer and Leukemia Group B] group,[4]which was a randomized comparison between lenalidomide as a single agent vs a combination of lenalidomide plus rituximab. The first point is that there is a strong rationale for this combination on the basis of experimental data, indicating that when lenalidomide is added to a system where the immune cells kill lymphoma cells, it increases the killing effect. This has been shown by a couple of groups, and that is the rationale for performing such a study.

The second rationale was the early results presented by Dr. Nathan Fowler and the group from MD Anderson[5] indicating that in first-line treatment, the patient achieved extremely high response and complete response rates. It was very good that the CALGB conducted this randomized study comparing lenalidomide with lenalidomide and rituximab. They attempted to have a third group, which was rituximab only, but this probably didn't appeal to the physicians and was dropped. The take-home messages are that, with lenalidomide, the response rate (which was approximately 50%) and the complete response rate (12%) are markedly increased in this combination, with 75% overall response rate and about 35% complete response rate. This represents a substantial increase in overall response rate in patients with relapsing follicular lymphoma who were previously treated, more than doubling the complete response rate in these patients.

This was an encouraging result. Hematologic toxicity was very acceptable. There were a few thromboses, which is probably the thing we have to worry and be careful about most.

Dr. Cheson: That was more in the lenalidomide-alone arm, which was surprising.

Dr. Salles: That was surprising. Again, there is probably no explanation, but I found this result quite stimulating. They have probably confirmed the interest in this combination, a chemotherapy-free approach in follicular lymphoma. There is an international study in progress right now called RELEVANCE, which compares R-chemotherapy CHOP bendamustine vs this so-called "R-squared" regimen. Let's see in a few years where we will go.

Dr. Cheson: In CALGB (now called Alliance) we are building on R-squared and adding new kinase inhibitors to that regimen to really move forward.

ABVD vs BEACOPP for Advanced Hodgkin Lymphoma

We can't ignore Hodgkin lymphoma because there are some interesting abstracts there, therapeutically as well as biomarker-wise. What did you think about the comparison of ABVD [doxorubicin, bleomycin, vinblastine, dacarbazine] and BEACOPP [bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone]?

Dr. Salles: The comparison of ABVD and BEACOPP was a joint venture between the EORTC [European Organization for Research and Treatment of Cancer] and several other groups,[6] but it was a large study where we aimed to compare 8 cycles of ABVD vs 4 escalated cycles of BEACOPP followed by 4 standard cycles of BEACOPP in patients with advanced Hodgkin lymphoma -- stage III/IV -- with adverse prognostic features with the international index. The results are in line with previous results in this field. Response rates are similar in this study. They were different in a few other studies. The event-free survival, which was a primary endpoint, was identical between the 2 arms, but if we go into more detail, a few more patients withdrew in the BEACOPP arm because of toxicity. The rate of death was identical; death from toxicity was identical between the 2 study arms for this patient population with advanced disease, but there were a few more progressions of Hodgkin disease in the ABVD arm. So, the primary endpoints were identical. The PFS curve was slightly better in the BEACOPP arm, and survival curves were identical.

There are 2 messages here. First, ABVD is able to control about 70% of the patients and provide a 70% PFS, but the overall survival of both study arms is excellent (in the range of 90%) for this advanced-stage patient. That is a very important message for all clinicians and patients. Whether we should choose one or the other, Dr. Carde made a very elegant and diplomatic conclusion, saying that both are standard. Clearly, BEACOPP is more toxic, and we may want to avoid this kind of treatment in young women to prevent sterility. ABVD definitely is the standard of care, but maybe for a few patients who have more adverse prognostic features or present with really aggressive disease, starting with BEACOPP may be a better approach.

The Continued Hunt for Biomarkers in Hodgkin Lymphoma

Dr. Cheson: The biomarker paper[7] was interesting also. Could you tell us about that one?

Dr. Salles: That was a stimulating abstract. Sometimes we have to have new ideas. Hodgkin lymphoma is a place where we have many clinical indices that, despite recent advances by the group in Vancouver and a few others in the field of the biology of this disease, we are really missing biomarkers. Hodgkin disease is behind non-Hodgkin lymphoma in this field. There have been descriptions of immune cells in the architecture of the node. Colleagues from different groups in the United States assembled samples from the clinical trial that was run by the intergroup in the United States with the Canadian group, and they assessed plasma DNA for Epstein-Barr virus (EBV) at the onset of the disease. They found a relationship between the DNA plasma levels of EBV and the presence of EBV in the tumor as assessed with in-situ hybridization for viral nucleic acid (EBER). There was a correlation between higher levels of plasma EBV DNA and worse outcomes. It's a preliminary report. They also showed that patients whose plasma EBV DNA reappears after initiation of therapy tended to do worse. If this is confirmed by other studies, this may be an interesting tool to help classify patients, help decide on more aggressive therapy (such as BEACOPP, for instance, for those patients), or eventually adapt therapy with something that you are a fan of -- metabolic imaging such as PET scan.

Dr. Cheson: That was a very good summary of the meeting. I am impressed that you remembered all those numbers. Thank you. And thanks to the audience for sticking with us and joining us in Medscape Oncology Insights. This is Bruce Cheson and my good friend, Gilles Salles, signing off from ASCO® 2012 in Chicago. We will see you again next year. Thank you.


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