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

Disclosures

December 27, 2011

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Introduction

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.

It's my pleasure to welcome you to this edition of Medscape Oncology Insights, which will serve as the wrap-up of the 53rd Annual Meeting of the American Society of Hematology (ASH) from San Diego.

Joining me for this informal discussion is my friend Dr. John Leonard, Professor of Medicine at the Weil Cornell Medical College in New York. Thanks for joining us, John.

John P. Leonard, MD: My pleasure. It's nice to be here.

Follicular Lymphoma

Dr. Cheson: John, it has been an interesting year at ASH. I am not sure how many breakthroughs there were, but we put the spear in a couple of myths, such as maintenance therapy in follicular lymphoma. I know we have had lots of studies, because it is one of the most controversial subjects out there, and the PRIMA study[1] got everybody going gangbusters again, which was chemotherapy with rituximab, with or without maintenance.

At this meeting we heard about the RESORT trial.[2]

Dr. Leonard: This is a very important study and the implications of the study potentially go beyond the population in the actual trial. Just to remind the audience, this was a group of patients with untreated low-tumor-burden follicular lymphoma, who basically received 4 doses of rituximab, and they were then randomly assigned to maintenance rituximab vs re-treatment at the time of progression.

Dr. Cheson: Indefinite maintenance.

Dr. Leonard: That's right. That's an important point, unlike some of the other studies, which are limited in terms of how long patients received maintenance. The bottom line goal of the study was to determine the duration of rituximab benefit for the patients with the 2 approaches.

The take-home message is that progression-free survival and essentially the mileage that the patient got from rituximab were quite similar in the 2 approaches. Patients who did not get the maintenance relapsed a bit sooner, as you would expect.

Dr. Cheson: Sure.

Rituximab on Demand

Dr. Leonard: However, when they progressed, they went on to receive rituximab. Basically, these patients ended up getting the same amount of mileage out of the rituximab. This was associated with fewer doses of rituximab being administered to the patient. This tells us that it is fine to manage patients with follicular lymphoma with more or less rituximab, in a "rituximab on-demand," as opposed to a "rituximab automatically" maintenance strategy.

From the standpoint of the upfront follicular lymphoma setting, a fair number of patients in my practice and yours would opt for 4 doses of rituximab. They need some treatment for whatever reason, but they are not so sick that they need chemotherapy.

To me, the take-home message is give them the 4 doses, see what you get out of it, and then you can always re-treat them down the line rather than committing them to a maintenance strategy.

Dr. Cheson: Right.

Dr. Leonard: At some point, the cost of that approach makes one question the use of maintenance. As you alluded to, when extrapolating that to other maintenance settings (for instance, the PRIMA study), one might argue that although there is a benefit to maintenance vs observation, what the PRIMA study did not look at after R-chemotherapy was the scenario of maintenance vs rituximab on-demand.

One might argue that for many of those patients, rituximab on-demand as in the RESORT trial would have done just as well.

Dr. Cheson: My argument, taken from the PRIMA study, shows me a survival benefit. To this point, there is no survival benefit. Show me that it doesn't compromise responsiveness to subsequent therapies. We know from the CORAL study in large cell lymphoma that 1 of the 2 factors that most negatively affected outcome was prior rituximab therapy in patients with large cell lymphoma who were receiving autologous stem cell transplant. Show me that patients with follicular lymphoma, which is characterized by relapse after relapse, aren't negatively affected by all that rituximab.

Dr. Leonard: If you have 2 groups of patients who are more or less in the same place, and the first group got there with 10-15 doses of rituximab, and the other got there with many fewer doses, you might argue that patients who had fewer doses at the end of the day might be better off in the future. It's quite possible that we could even see an advantage to re-treatment in the longer term, because those patients will not have been exposed to rituximab enough. Obviously, that is speculative, but it will be interesting to see that play out even further.

A GA101 Love Fest

Dr. Cheson: We have been talking about rituximab, but there are perhaps 10 other anti-CD20s in development. We have heard a lot about ofatumumab in the past. It was a little disappointing that only about 11% of patients who were refractory to rituximab responded to ofatumumab, but at this meeting, there was kind of a "GA101 love fest."

Three abstracts in a row at a session were about GA101 (obinutuzumab). Tell us a little bit about GA101. What is it, and what were the results of those studies?

Dr. Leonard: GA101 is an antibody that is engineered. It's a different type of antibody, and the main purported difference is that it has greater induction of apoptosis, greater signaling. That is the principal difference from rituximab.

The question is in the laboratory this seems to be interesting and potentially meaningful, but does it really matter in patients? The common theme, to which you have alluded to with almost all of the novel anti-CD20 agents, is that all of the clinical trials have given them at higher doses than standard rituximab and often for longer periods of time. If these agents appear to be better (which is one question) one wouldn't necessarily know whether it is a dose effect or schedule effect, or whether it is actually a better antibody.

Salles[3] presented some data looking at GA101 in recurrent follicular lymphoma. In patients with relapsed follicular lymphoma, Laurie Sehn[4] presented some data from a randomized phase 2 study of rituximab vs a GA101 regimen with a little bit higher dose and schedule. The bottom line of that study was there were some trends, depending on how you slice and dice the data, and by some analyses, the primary endpoint of response rate was a little bit better with the GA101.

However, when you look at progression-free survival, the curves that were presented were pretty much super-imposable. They made the point that it's an early timepoint, but in fact, most of the patients were already beyond the median time to progression. So, I don't think that those curves are going to change a great deal.

There was also a little bit more toxicity with GA101 with respect to infusion reactions. This is a "glass half-full/half-empty" finding, depending on your perspective. From my perspective, in lymphoma, as of today, I have not seen compelling evidence in patients that any of the novel anti-CD20s are meaningfully better than rituximab.

How will that play out over time? If you do enough studies, you may find that one of them becomes positive, but it gives me pause. We have both shared, among others, the enthusiasm that these new anti-CD20s were going to be a real advance. It's becoming less and less likely that at the end of the day that is going to happen.

Dr. Cheson: Returning to your initial point, the Gilles Salles study[3] actually looked at 2 different doses of GA101 and showed that the higher dose was much more effective, but had many more toxicities. There may be a dose effect.

Dr. Leonard: Right.

Mantle Cell Lymphoma

Dr. Cheson: One disease with which your institution has a lot of expertise and about which you have published a lot of interesting papers is mantle cell lymphoma. A gaggle of unusual mantle cell papers were presented at this meeting.

Dr. Leonard: One was an update. As you know, cooperative groups are strictly guided by the statistician, who says when you can present the data. It seems that in some of the other larger trials done elsewhere in the world or some of the early phase drug trials, that just in time for a meeting, it's time for an update. It makes you wonder a little bit, particularly when, in a phase 2 trial -- you report good results, people get excited, you are going to get better patients, so you are going to get better results. It feeds on itself.

Mantle cell lymphoma gave us 2 examples of that. One was from the European mantle cell working group[5] that presented a study in older patients with mantle cell lymphoma, in which they randomly assigned patients to either rituximab-cyclophosphamide-hydroxydaunomycin-oncovin-prednisone (R-CHOP) or fludarabine-cyclophosphamide-rituximab (FCR) and then a secondary randomization to interferon or maintenance rituximab.

The gist of the analyses (when you look at the curves in the study, you see different subsets of patients) is that R-CHOP was better than FCR upfront in this mantle cell population. Furthermore, maintenance rituximab was better than interferon in this patient population.

Dr. Cheson: That is the problem with the study.

Dr. Leonard: Yes. At the end of the day, the study is important in that it suggests a benefit to maintenance rituximab. It doesn't prove it. In contrast to our earlier discussion, the role of maintenance in mantle cell may be a little bit more convincing based on these randomized data. But, there are, as you point out, caveats.

Dr. Cheson: It was in an elderly patient population, and who knows whether the interferon wasn't detrimental to their health.

Dr. Leonard: That's a fair point. I think the R-CHOP vs FCR argument is kind of obsolete. I don't think I have ever treated a patient with mantle cell with FCR. There was also a British study[6] that looked at FC (fludarabine and cyclophosphamide) vs FCR. Not surprisingly, FCR was better.

At this point in time, the key issue is the benefit of bendamustine-based regimens vs R-CHOP, and data from the STILL trial show that bendamustine has significant activity compared with R-CHOP and is better tolerated. The cooperative groups are looking at that regimen. We will be seeing more studies of maintenance rituximab in mantle cell. It's reasonable to consider.

At the other end of the spectrum is the new drug, the BTK (Bruton's tyrosine kinase) inhibitor PCI-32765, and we saw data[7] how it is important in B-cell signaling, and the proliferation of malignant B cells that are resistant to chemotherapy.

Targeting that pathway makes sense. We have seen activity with this oral, well-tolerated drug in subsets of large cell lymphoma, in chronic lymphocytic leukemia, and in mantle cell, where there was a response rate in the 65%-70% range, which is remarkable.

In my own experience, anecdotally, I have seen some very impressive responses. The issue, like anything with mantle cell, is the durability. It's a little surprising that they present these data with relatively short follow-up, but it is an exciting drug that warrants further evaluation.

Peripheral T-Cell Lymphoma

Dr. Cheson: Let's look at another collection of lymphomas that have been particularly problematic -- the peripheral T-cell lymphomas. There were 2 abstracts of particular interest.[8,9] One looked at the survival of patients after they relapsed,[8] whether they were transplantable (they didn't do so badly) or were not transplant candidates (their outcomes were particularly dreadful).

There was an exciting new drug that Jonathan Friedberg[9] presented -- an Aurora-A kinase inhibitor.

Dr. Leonard: The Aurora-A kinase is involved in mitosis. Some elements of the mitotic process are important targets in cancer. This was a broad trial, looking at aggressive lymphomas, with a few different histologies, including large cell. Four of 7 peripheral T-cell lymphoma patients who were treated responded, and so, that has received a lot of attention.

Dr. Cheson: They had some complete remissions.

Dr. Leonard: We are pursuing, through the cooperative groups, some broader phase 2 studies with this agent, and potentially even some randomized trials are being prepared and set up.

It's an interesting drug. I have no experience with it. It does appear that some toxicity is associated with it, particularly cytopenias and some gastrointestinal toxicity. We certainly need new agents for T-cell lymphoma. We do have to keep in mind, it's 4 out of 7 patients. When we are at 40 out of 70, we will feel a little more confident about it.

Hodgkin's Lymphoma

Dr. Cheson: The last study I want to mention is one that was actually published in The New England Journal of Medicine[10] the week of ASH, and that was the Canadian-North American Intergroup Trial led by Ralph Meyer, which looked at a randomization in patients with relatively early-stage Hodgkin's lymphoma.

They looked at adriamycin-bleomycin-vinblastine-dacarbazine (ABVD) therapy vs shorter ABVD, followed by subtotal nodal radiation, admittedly an outmoded form of radiation. This was a long-term follow-up study. They published their initial data in 2005 in the Journal of Clinical Oncology,[11] and suggested that maybe there was a progression-free survival advantage for radiation of 93% vs 87%, but it was relatively short follow-up. Overall survival didn't appear to be different, and they weren't pushing radiation. So now, its 11.8 years, and what do we find? No surprise, the group that got radiation, in fact, had an inferior survival, significantly worse because of cardiac toxicity, secondary malignancies, and pulmonary toxicity.

This set of results provides great support for the ongoing clinical trials in the cooperative groups looking at trying to minimize the amount of radiation that one needs, particularly in bulky patients, but also in limited-stage patients. Hopefully this will encourage physicians to put patients on these studies so we can find out if we can actually minimize toxicity. We can cure so many, the goal now should be to limit therapy and limit toxicity.

Conclusion

We are about running out of time here, so I would like to thank John, and I'd like to thank our audience for joining us for this Medscape Oncology Wrap-up from ASH 2011 in San Diego. Thank you for your attention, and I hope to be speaking with you in the near future.

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