NonHodgkin Lymphoma: New Drug Combinations

Bruce D. Cheson, MD; John P. Leonard, MD


December 15, 2010

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Bruce D. Cheson, MD: Hello. I'm Bruce Cheson, head of hematology at Georgetown University Hospital and director of hematology research for the Lombardi Comprehensive Cancer Center in Washington, DC. This is Medscape Oncology Insights on nonHodgkin lymphoma. Today we are going to review several notable studies presented at American Society of Hematology (ASH) 2010.

I'm delighted to have with me today Dr. John Leonard, professor of medicine and director of clinical research at the Weill Cornell Medical College and Cancer Center in New York. Thanks for joining us, John.

John Leonard, MD: Thank you.

Large Cell Lymphoma

Dr. Cheson: As you well know, CHOP (cyclophosphamide, hydroxydaunorubicin, oncovin [vincristine] prednisone) has been the standard chemotherapy for large cell lymphoma for 40 years until R- (rituximab) CHOP came along. A number of attempts have been made to improve on this (every 14 days, every 21 days, tagging 1 drug on and then another drug on) and nothing has really happened.

New regimen. At this meeting, the GELA group has an abstract[1] suggesting a new regimen that might be better than R-CHOP -- R-ACVBP (rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone). What's your take on this abstract?

Dr. Leonard: Any time you have a several-hundred patient randomized trial showing a progression-free and overall survival benefit, obviously you need to pay close attention to it. What this is essentially doing is taking the younger, better-risk patients, giving them a more intensive treatment which is basically, it's hard to encapsulate exactly what it is, to some degree it is an every 14-day accelerated, intensified CHOP followed by consolidation with a methotrexate, ifosfamide, and other agent-containing regimen.

What was reported, not surprisingly, was increasing toxicity with close to half the patients needing transfusions of some sort, and with more febrile neutropenia, and more toxicity. But the tradeoff was a progression-free and overall survival benefit in the range of about 10%. So fundamentally, you have to pay attention to that whenever you see overall survival benefit. On the other hand, it appears to be a substantially more toxic regimen. What happens to these patients later? What are the long-term toxicities or secondary malignancies? What happens if their lymphoma relapses? Can they receive effective second-line therapy in an auto transplant? All of these issues are going to figure into the equation.

In some ways, this seems to be a little bit like the BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, oncovin, procarbazine, prednisone) situation that we are dealing with in Hodgkin lymphoma where we have a more effective regimen, but a more toxic one. The fact of the matter is that it probably benefits a small subset of patients. Which subset that is and how we can define it remain to be seen.

It is something about which we need more details and more follow-up. I would ideally like to have a patient profile within that good-risk group of patients that you could direct toward that more intensive therapy. It is going to be challenging to now say for everyone who is young and low-risk we are going to use a more intensive treatment. But again, time will tell.

Challenges to R- CHOP

Dr. Cheson: Are there other big studies ongoing that are comparing regimens to R-CHOP?

Dr. Leonard: Well, it is interesting because they are also presented, as you know, at this meeting. A couple of attempts were made by the Southwest Oncology Group to add on to R-CHOP; whether it is with radioimmunotherapy or with bevacizumab. In those phase 2 studies, unfortunately, not a lot of progress appears to have been made; although, to some degree that may be in the eye of the beholder. It is hard to know if those regimens are going to be significantly better and worth pursuing. There is a little bit of debate in that area.

To me, the most important large cell lymphoma study going on is the Cancer and Leukemia Group B (CLGB)-led study that is looking at dose adjusted R-EPOCH (rituximab-doxorubicin, etoposide, vincristine, cyclophosphamide, and prednisone) vs R-CHOP. This is being looked at across the board primarily in advanced-stage patients. It is not something that is being separated out by age, so many patients are eligible for it. It looks at PET scanning prospectively, which is an important, unanswered, complicated issue as you know.

The molecular profiling aspects are biologically probably the most important findings in lymphoma that now need to be taken to the next step in directing therapy and that is what we aim to do in this study. Here we are using, as you know, a dose-adjusted, infusional regimen that adds etoposide. It is really a very important study. Clearly, in my mind, R-EPOCH is not as toxic as the ACVBP. So, if we were to see the same effect with a less toxic regimen that would be a nice alternative.

So, there is a lot happening in large cell lymphoma. As of today, however, I'm not sure that people should change their practice except for trying to prioritize clinical trials in that subgroup as well as others, and I think people may say "this is a large cell lymphoma. I have to treat the patient right away, and you are going to do well, so you don't need a clinical trial." But that is really the wrong tack. The biggest unmet need in lymphoma is improving outcomes in large cell lymphoma despite the fact that it is curable. So, we need to encourage these trials in moving forward.

Dr. Cheson: I think the biggest unmet need is not just large cell lymphoma in general; it is the patients with the high-risk IPI (International Prognostic Index) scores because the R-ACVBP was done in low-risk patients. If you look at the R-EPOCH data both from the National Cancer Institute (NCI) and from the CLGB, the low-risk patients just do wonderfully.

Dr. Leonard: That is right.

Dr. Cheson: But the high-risk patients just do not do as well.

Follicular Lymphoma

As you well know, since you have been intimately involved in this, there are an enormous number of characters on the playing field in follicular lymphoma and a lot of partnering is going on out there, "R plus" stuff. There were a number of interesting abstracts at this meeting. Could you review some of those for the audience?

Dr. Leonard: Sure. We have a number of drugs, as you have alluded to, that have single-agent response rates from 10% to, in a few cases, 40% -- not necessarily robust numbers. However, there are a lot of active drugs that are reasonably well-tolerated in follicular lymphoma, such as a whole host of monoclonal antibodies. We have the novel anti-CD20s that you could argue are better in the laboratory than they are in patients; at least definitively. We have small molecule agents like PI3-kinase inhibitors and others that I am sure we will get to later.

What we have been seeing is some of the, not quite older, but older novel drugs. Antibodies against other targets and bortezomib are the 2 for which we have the most data at this meeting. The idea is that if we partner active drugs with rituximab, we enhance efficacy without significantly worsening toxicity. So, that paradigm of partnering with rituximab has been one that for some time has been attractive.

Drug Doublets in Relapse

It is one scenario in upfront, but another scenario in relapse. We have 2 randomized studies comparing rituximab vs rituximab plus drug X (whatever drug X is) in relapse non-rituximab-refractory (relapse follicular lymphoma). The first of these studies used galiximab and anti-CD80 antibody and had a 10%-15% single-agent response rate. Myron Czuczman led that trial and that agent is being added to rituximab. There was also a phase 3 trial converted to a phase 2 trial, randomized, with about 300 patients with recurrent follicular lymphoma, where the response rates were slightly better with the galiximab-containing arm.[2] Progression-free survival was perhaps slightly better on the order of a few months (9 months vs 12 months).

Interestingly, there were fewer deaths in the combination arm, but it is hard to argue that this is a dramatic difference. That really is not compelling that this "doublet," so to speak, at least that particular doublet, is going to move forward. On the other hand, we also have another study -- bortezomib -- which, as you and the audience know, is active in myeloma, in mantle cell lymphoma and other types of indolent lymphoma, and it is being combined with chemotherapy. It is also being looked at with chemotherapy in large cell lymphoma, one of the biggest studies ever done in relapse follicular lymphoma. A randomized trial of more than 670 patients with relapsing non-rituximab refractory follicular lymphoma were randomly assigned to rituximab alone vs bortezomib/rituximab.[3]

This was a statistically positive study with an improvement by about 10% in the overall response rate, and an improvement by a couple of months in progression-free survival; but in that context more toxicity, because bortezomib, although it is an active and useful drug in some situations, does have neuropathy and fatigue and gastrointestinal adverse effects. So we have here a very large randomized study showing a very modest therapeutic affect as far as efficacy.

Dr. Cheson: But it didn't even meet its primary endpoint.

Dr. Leonard: Well, I'm not sure of that. But at the end of the day, I think it is hard, regardless of the regulatory aspects and the statistical aspects, I'm not sure that it is so obvious to patients and clinicians that that doublet is going to pay off for patients' long-term therapy, to get into routine use, whether or not it is approved.

Drug Doublets Up Front

I think to some degree, for those of us working in this area, it is a little bit disappointing. It suggests that perhaps we need to look at these drugs in the upfront setting as we have been doing in CLGB; or perhaps the best strategy to look at new drugs is to only take forward the best drugs. Is a 25% drug in follicular lymphoma even worth pursuing? I think we are getting to the point where that may not be the case unless we think that there is a patient subset who can benefit from it.

The other area where we are moving forward in recurrent follicular lymphoma and where the drug development paradigm is going is centered around bendamustine. Partnering a drug with bendamustine, the B vs B plus X , or trying to focus on bendamustine-resistant patients. Again, various groups are looking at whether that will be a more successful strategy.

Dr. Cheson: But as you said, a day in the relapse setting may not always be translatable upfront. In fact, they may be better. There was a study from the CLGB upfront doublets at these meetings.

Dr. Leonard: Yes. In upfront follicular lymphoma we have 2 competing paradigms. One is the kitchen sink kind of phenomena where we are basically saying we are going to give chemotherapy, rituximab, plus rituximab maintenance, plus something else, whether that is radioimmunotherapy or whether that is another drug on top of that, with the hope that that short-term toxicity is going to be paying off in the long term with respect to better outcomes. That is one school of thought.

The other, which is in some ways (although this is debatable) more patient- friendly, is to say can we get rid of chemotherapy or delay chemotherapy, substitute a better tolerated drug, and get the same mileage out of the upfront regimen using a less toxic treatment. Obviously, there are advantages to that if it does not compromise things in the long-term. I think there are relative merits to this. So, as you know and have led through CLGB, we have been exploring the combination doublet approach where we have said rituximab is an effective drug as initial treatment, but we would like to make it better in a more tolerable way.

So, we have been looking at combinations of antibodies and Barbara Grant is presenting epratuzumab, an anti-CD22 antibody.[4] This combination in our study is well-tolerated and has about an 85% response rate. The key is going to be the long-term durability of this, about which we need more follow-up. I think it is striking in this approach that three fourths of the patients in this study were intermediate and high-risk FLIPIs (Follicular Lymphoma International Prognostic Index). So, it really demonstrates the patient and physician desire for this approach -- people are interested in this and we have to find a way to make it work. As you know, we are now doing lenalidomide plus rituximab and have some other studies in that vein.

Despite the challenges of showing that it is better than the kitchen sink approach, I think our patients are telling us and physicians are telling us with their interest in this approach even in higher-risk patients that we really should pursue this line of investigation.

New Drugs to Watch

Dr. Cheson: We are on our last few minutes. Are there any drugs that really stood out at this meeting as being potentially exciting?

Dr. Leonard: Well, I think there are a few. One would be the antibody conjugates. We have the klaritromisin CD22 conjugate, which is basically a targeted way to give chemotherapy using an antibody. That drug has data being presented both alone and in combination, with rituximab response rates over 50%. In fact, Andre Goy[5] presented data in rituximab refractory follicular lymphoma patients who had about a 50% response rate. So, I think that meets the threshold of interest. Whether that moves forward remains to be seen.

The SGN-35 compound is very exciting in Hodgkin. It is an anti-CD30 conjugate and that agent really has very high activity in Hodgkin and in anaplastic large cell. It is even possible it could be explored in other nonHodgkin lymphomas because there may be some patients with large cell lymphoma who have some elements of CD30 expression that could be worse.

Dr. Cheson: It has an 86% response rate on anaplastic large cell.

Dr. Leonard: In Hodgkin, roughly three fourths of patients are responding, so I think that is a very interesting drug.

I think the kinase inhibitors, which we have seen in CML and in solid tumors really are making their way in lymphoma; whether that will be PI 3-kinase inhibitor CAL-101, or the BTK inhibitor from Pharmacyclics. Those 2 in particular are very exciting drugs, perhaps because of the way they work. They do not rely on the immune system. They work through different pathways. That may be the way that we can overcome some of this rituximab resistance and actually have more rational synergistic combinations.

Dr. Cheson: Well, thank you. We could be talking for hours about the new drugs, particularly when we start talking about how to put them together which will be challenging but exciting. But we are out of time. I thank John for joining me here today to talk about the new and exciting observations presented at ASH, but some disappointing observations such as not pushing the large cell envelope further than we have. We have left room for improvement. We have all kinds of new toys to play with out there. The question is how to get patients on clinical trials so that we can best study these, understanding the science behind them, so we can develop rational combinations. Next year we will see even more interesting studies and more progress made in a variety of lymphomas.

I would like to thank our audience for their attention. This is Medscape Oncology Update on NonHodgkin Lymphoma from ASH 2010. I'm Bruce Cheson, with John Leonard and we hope that you have enjoyed this and have learned something from it.

Thank you and have a good day.


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