COMMENTARY

Double-Hit Lymphomas Explained, With Surprising EPOCH-R Data

Bruce D. Cheson, MD; Andrew D. Zelenetz, MD, PhD

Disclosures

December 16, 2014

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Double-Hit Lymphomas Defined

Bruce D. Cheson, MD: Hello. I'm 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, from the 2014 annual meeting of the American Society of Hematology (ASH) in San Francisco.

Joining me today is Andy Zelenetz, vice chair of medicine, medical informatics, and attending physician on the lymphoma service at Memorial Sloan Kettering Cancer Center, and professor of medicine at Weill Cornell Medical College in New York.

We have heard many interesting abstracts at the ASH meeting this year, and I think the audience would benefit from an in-depth discussion on the topic of large cell lymphoma. For years, we thought that large cell lymphoma was a single entity, and then we questioned why some cases responded better than others—they look pretty much the same under the microscope. Then we identified germinal center B-cell–like (GCB) and activated B-cell–like (ABC) lymphomas. Now, there is a lot of buzz around double-hit lymphomas, and this is a subject that a lot of people don't fully understand.

Andrew D. Zelenetz, MD, PhD: The double-hit lymphomas are a confusing area. You have to start with what you're talking about. The original description was lymphomas that had a MYC translocation and a B-cell lymphoma-2 (BCL-2) translocation or, in some rare instances, a BCL-6 translocation. And then there were the so-called triple-hit lymphomas—which don't behave very differently from the double-hits—that had translocation of all three genes. But that is expression of the target gene by translocation.

One of the features of the true double-hits is that, by definition, they are all germinal center B-cell lymphomas. You virtually never see a BCL-2 translocation in an activated B cell. When you get BCL-2 expression in activated B-cell lymphomas, which is very common, it's always part of the normal program of the activated B cell, and that's what introduced this concept of the immunohistochemical double hit. The immunohistochemical double hit is large cell lymphomas that express MYC and BCL-2 as detected by immunohistochemistry, and there are cutoffs—30% MYC, 40% BCL-2. The true double hits represent about 6% of large cell lymphomas. The immunohistochemical double hits represent about one third of large cell lymphomas. And they cross the barrier between activated B-cell and germinal center lymphoma. They are about half and half.

The true double hits have a very poor prognosis. The question is, what, if anything, is the best treatment approach for the true double hits? The immunohistochemical double hits are somewhat more complicated because they are crossing a barrier between two different diseases—activated B-cell large cell lymphoma, and germinal center large cell lymphoma—and that's going to complicate any analysis of what this immunohistochemical double hit is.

Surprising Results for Dose-Adjusted R-EPOCH

Dr Cheson: That leads me to a studythat was presented at the ASH meeting. Kieron Dunleavy from the National Cancer Institute presented a study[1] of dose-adjusted R-EPOCH (rituximab, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone) in poor-prognosis, double-hit—kind-of, sort-of—lymphomas.

Dr Zelenetz: This was a study of patients with an aggressive large B-cell lymphoma. They could be characterized under the microscope as diffuse large B-cell lymphoma. Some were characterized as aggressive lymphomas, B-cell unclassifiable lymphomas, but they were aggressive large cell lymphomas. An entry requirement was a MYC translocation.

But many of the patients had expression of BCL-2 by translocation. Fourteen of the patients who were tested also had BCL-2 translocations, and those were true double-hit lymphomas. And a proportion of patients had BCL-2 expression by immunohistochemistry. Overall, the group did extremely well. With dose-adjusted EPOCH-R, patients had a disease-free survival of about 80%, and the curves look remarkably flat. There was an early drop-off, but they dropped off quickly and then the curves looked very flat.

They did some subset analysis, with some interesting findings. Among the 14 patients of true double hits—and this is a small number, I admit—dose-adjusted EPOCH had the surprising event-free survival of 87%. Why is that surprising? Because these were patients who are notoriously difficult to treat. Last year we put together a multicenter study to suggest that patients who received transplant did a little bit better. But it wasn't an overwhelmingly strong signal. The fact that 87% of patients have been rendered disease-free with dose-adjusted EPOCH in the true double hits was really surprising.

In the immunohistochemical double hits, the results were not nearly as good. The progression-free survival wasn't bad; it was 60%, not 80%.

Dr Cheson: In the R-CHOP [rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone] range.

Dr Zelenetz: It's in the range that we see for R-CHOP. Those immunohistochemical double hits are frequently activated B-cell tumors. In the CALGB [Cancer and Leukemia Group B] confirmatory study of dose-adjusted EPOCH-R,[2] we confirmed the high response rates and good results. But we also found that in the germinal center B-cell lymphomas, the outcomes were outstanding—so outstanding, in fact, that at the time of the publication, there hadn't been a failure. The curve was at 100%, whereas the results in the nongerminal center diffuse large B-cell lymphomas actually were pretty similar to the results one would expect with R-CHOP.

That is what we are seeing recapitulated here: that dose-adjusted EPOCH is particularly good—for reasons that we don't fully understand—in these germinal center B-cell lymphomas. We are going to learn a lot more about this and why this is the case from CALBG 50303—now ALLIANCE 50303—which is the prospective, randomized trial that you helped put together, between dose-adjusted EPOCH-R and R-CHOP. Importantly, in that study we have the built-in prospective molecular profiling, so we are going to try to understand what it is about germinal center B-cell lymphomas that make them particularly responsive to dose-adjusted EPOCH-R.

Adding Brentuximab in Relapsed Hodgkin's

Dr Cheson: Great discussion. Let's move on to another form of lymphoma, Hodgkin lymphoma, which has been the success story of modern oncology—at least hematologic oncology. But patients do relapse. We have brentuximab, which is a great drug but could be better. We see high response rates that could be more durable and could be higher. At this meeting there has been some tweaking of brentuximab, such as by adding other drugs—for example, bendamustine.

Dr Zelenetz: Ann LaCasce presents a very interesting study[3] of a combination of brentuximab vedotin at the standard dose, 1.8 mg/kg, given every 4 weeks rather than every 3 weeks, with bendamustine. Bendamustine has already been shown to be active in relapsed/refractory Hodgkin lymphoma.

The problem that we found is that we see very high response rates with very short response durations. A couple of things are different in this study. One, these are slightly better patients. They are not all post-transplant. In fact, they are all pre-transplant, so they are at first relapse. They are combining bendamustine with this very active drug, brentuximab vedotin. The overall response rate is outstanding—in excess of 90%—but the really surprising thing is that the complete response rate to this regimen was 82%. There's a lot of data from our group and others suggest that having a PET-negative complete response before high-dose therapy and autologous stem cell rescue is absolutely essential to a good outcome in Hodgkin lymphoma. A simple regimen combining very tolerable drugs results in a high complete response rate, and the vast majority of those complete responses were seen after two cycles of bendamustine and brentuximab vedotin. That means that patients were exposed to relatively limited treatment in the second line before they were able to move on. Patients who were PET negative after two cycles could move directly to the high-dose therapy and autologous stem cell rescue. Some patients did need four and six cycles, but most patients actually achieved this very high-quality complete remission after only two cycles. That is very exciting and certainly less toxic than ICE (ifosfamide-carboplatin-etoposide) or DHAP (dexamethasone, high-dose cytarabine, cisplatin), and so it is an exciting way to get to transplant in the relapse setting.

The Next Frontier: Checkpoint Inhibitors

Dr Cheson: Speaking of exciting and less toxic approaches to Hodgkin lymphoma: checkpoint inhibitors. There were a couple of abstracts at this meeting about drugs that target PD-1, and their results were rather impressive.[4,5]

Dr Zelenetz: Yes. A couple of checkpoint inhibitors are being developed that specifically target PD-1: nivolumab and pembrolizumab. They are different monoclonal antibodies developed independently, but they both do the same thing. They interfere with the interaction between the T cell and its target. PD-1 puts a brake on the immune system. We want T cells to be reactive, and so the second signal—the B7 and CD28 signal—revs things up.

PD-1 comes in and dampens down that response, but the problem in cancer is that many times it's already dampened down, so you never get the positive signal at all. The idea is to interrupt that checkpoint—that brake—by adding the anti-PD-1. Both of these drugs have shown substantial activity in Hodgkin lymphoma. With nivolumab, the overall response rate is 87%. Pembrolizumab is a little bit lower. It is 53% overall, but if you look at the waterfall plots, there are many cases that were just shy of a partial response. Both of these drugs are quite active in the relapsed/refractory setting.

With pembrolizumab, the patient had to be exposed to brentuximab, so these were failed patients. They had had up-front treatment, transplant, brentuximab, and then pembrolizumab, and still had response rates in excess of 50%.

Dr Cheson: Interesting combinations will follow. These drugs are not just active in Hodgkin lymphoma, and there were some interesting data on non-Hodgkin lymphoma.

Dr Zelenetz: Yes. Alex Lesokhin[6] presented some of the information on nivolumab in non-Hodgkin lymphomas. This is also a part of the same phase 1 dose-escalation study. There were some interesting hints of activity, with about 40% overall response rates in large cell lymphoma, follicular lymphoma, and T-cell lymphomas. Again, that can be substantially improved with interesting combinations. I've already heard about interesting combinations being planned at this meeting, so, more to come on that.

Dr Cheson: There are so many drugs; the combinations and permutations are—

Dr Zelenetz: Endless.

Dr Cheson: Endless, to say the least. Thank you, Andy, for joining us here. It's really been great having you. And thank you to the audience for joining us for this edition of Medscape Oncology Insights. This is Bruce Cheson, signing off from ASH 2014.

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