COMMENTARY

The Future of Hodgkin Lymphoma -- Brentuximab and Beyond

Bruce D. Cheson, MD; Ann S. LaCasce, MD, MSc

Disclosures

December 18, 2014

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Still Room for Improvement in Hodgkin Lymphoma

Bruce D. Cheson, MD: This is Bruce Cheson, deputy chief of hematology and oncology and head of hematology at Georgetown University Hospital and Lombardi Comprehensive Cancer Center in Washington, DC. Welcome to this edition of Medscape Oncology Insights, coming to you from the 2014 annual meeting of the American Society of Hematology (ASH) in San Francisco. Joining me is my friend Ann LaCasce, assistant professor of medicine at Harvard Medical School and a senior physician at the Dana-Farber Cancer Institute in Boston, Massachusetts.

Today, we're going to talk about Hodgkin lymphoma—truly one of the success stories of modern hematology/oncology. Everybody goes around saying, "Oh, we cure more than 90% of those patients with limited disease and more than 80% with advanced disease. Let's just go home. We have achieved what we need."

But that's not it. We have room for improvement, both safety- and efficacy-wise. And there is a drug in town, brentuximab vedotin, that seems to be changing what we are doing. A great study is being done comparing a regimen that I call "A-squared-VD" (brentuximab with doxorubicin, vinblastine, and dacarbazine) vs ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine). The A-squared-VD data are being updated here.[1]

New Brentuximab Data

Dr LaCasce: Yes. Joe Connors is updating those data on Monday, and the results look phenomenal. At 3 years, 96% of the patients remain in remission, which exceeds anything we have ever seen in the patient population with advanced-stage disease. So the randomized study is going to be very interesting, and practice-changing.

Dr Cheson: The ECHELON study. But until we have those data, we are still using the drug primarily in the relapse setting, and a lot of these patients underwent transplant. In the past, they all underwent transplant after receiving some noxious substance, such as ICE (ifosfamide, carboplatin, and etoposide) or DHAP (cytosine arabinoside, cisplatin, and dexamethasone) or one of those concoctions. The data show that brentuximab may supplant that. What do you think about those data?

Dr LaCasce: There are a couple of studies. We participated in one combining brentuximab with bendamustine,[2] thinking that the drugs have very different toxicity profiles. Both are very active, with complete remission rates of about one third. When they were combined, the overall response rate was 96%, with 83% of patients achieving complete remission, which is probably the best predictor of good outcomes after autologous transplant. So we were pretty excited about that.

As a single agent, the complete remission rate is about one third—about what we would have expected. You could argue that there may be a subset of patients who get to transplant using brentuximab alone, without needing any chemotherapy. If you really want to optimize the complete remission rate, the combination is going to be more potent.

Dr Cheson: There are data from Memorial and from California suggesting that in some people, you can add chemotherapy later.

Dr LaCasce: Right, but I don't know. By giving the combination immediately, it's fairly well tolerated. We saw a lot of infusion reactions, which were mitigated by giving steroids and antihistamines as premedication. You see a quick, complete response, and then you can go directly to autologous transplant. The longer you drag it out—if the patient doesn't respond to rituximab and then needs chemotherapy—we see more toxicity and delayed transplant.

Dr Cheson: How many cycles do you have to give?

Dr LaCasce: In our study, the majority of people had complete remission after two cycles; 34 of 40 had a complete remission after two cycles, and they went directly to transplant. There was no issue with mobilizing stem cells.

Dr Cheson: And no untoward complications with the transplant?

Dr LaCasce: No. One patient had sepsis during transplant, but you could see that regardless of the salvage chemotherapy regimen.

Dr Cheson: So, we have a new way to get patients there without exposing them to terrible treatments.

Dr LaCasce: And as outpatients, which is another benefit for a lot of our patients.

Dr Cheson: But one of the other potential indications for this drug was after transplant.

Dr LaCasce: Right. We await the AETHERA results,[3] which are going to be presented tomorrow as well. This is purportedly a positive study showing that patients with high-risk disease at autologous transplant, early relapse, or primary refractory or extranodal disease will benefit from maintenance brentuximab for up to a year vs placebo.

Dr Cheson: We don't know what is going to happen if they get brentuximab first—whether they will benefit from more brentuximab after.

Dr LaCasce: Right. In our study, looking at it in the salvage setting, patients could go on to receive monotherapy for up to a total of 16 doses. But it's going to be a small number of patients and difficult to tease out the added benefit.

Is The End of Chemo in Sight?

Dr Cheson: For more than a decade, I have been trying to push nonchemotherapy regimens. This drug by itself has achieved, what, a 76% response rate in patients with transplant-failed Hodgkin lymphoma? And now there are some studies of up-front therapy being presented here. It was up-front alone, and up-front with dacarbazine.[4] Tell us about those data.

Dr LaCasce: They are looking very exciting. The dacarbazine study is in elderly patients, whom we know do poorly with ABVD in terms of toxicity, response rates, and durability. The investigators started with brentuximab alone, and in the second part of the study, they added dacarbazine. It looks like quite a tolerable regimen.

We need more follow-up on that, but it is very exciting. Hopefully, we will be able to combine brentuximab with some of these other novel agents, not chemotherapy agents, and get rid of the chemotherapy altogether, which is what you have been trying to do for a long time.

Dr Cheson: Let me ask you about this. It wasn't presented here, but it was recently published by the German Hodgkin Study Group.[5] This was their long-awaited trial of ABVD vs the various deletions.

Dr LaCasce: Omitting the various drugs, right?

Dr Cheson: Yes. They published those data, suggesting that we needed all of them. And when I reviewed those data, I was unconvinced. Do you think we really need the bleomycin?

Dr LaCasce: I don't think so. We know that if we omit the bleomycin somewhere along the line during the course of ABVD, there is no adverse impact—but it's indirect evidence.

Dr Cheson: On the basis of their data, the outcome was kind of the same whether you had it or not.

Dr LaCasce: The difference was minimal.

Dr Cheson: In my practice, if a patient walks in and coughs, I say, "Oh, no more bleo for you."

Dr LaCasce: Right. You look for the first opportunity to drop the drug, because it can be so toxic.

Dr Cheson: Yes. That is when we substituted brentuximab vedotin for the bleomycin, because obviously we can't give them together.

Dr LaCasce: Because of the pulmonary toxicity.

Dr Cheson: Right. But with brentuximab vedotin, the curve falls off. No one seems to be cured, and we need new agents. We have been struggling for new agents for a long time. Do we have anything?

The PD-1 Checkpoint Inhibitors

Dr LaCasce: We do. The PD-1 checkpoint inhibitors are looking really exciting, and in the Monday session, two drugs are being presented: nivolumab and pembrolizumab.[6,7,8] They look phenomenal, particularly nivolumab.[6,7] It has an 87% response rate in patients with highly refractory disease. And they seem quite durable. A lot of the responses were partial remissions, but they seemed to be durable and maybe getting people onto allotransplant, or not. Who knows?

Dr Cheson: They are interesting drugs. They have been used in a lot of solid tumors where patients initially may have what looks like disease progression.

Dr LaCasce: I think our assessment of response is going to have to be delayed.

Dr Cheson: Yes. This is a problem that we have seen with a number of drugs in a new biological era—with the lymphocytosis with ibrutinib and idelalisib, with the flare reaction with lenalidomide, and now here. So physicians, when these reach the market for lymphoma, are going to have to be very cautious not to say that patients have progressed and stop using a great drug.

Dr LaCasce: Right. We have to be very careful.

Dr Cheson: We have actually been in discussions with a couple of the companies trying to figure out how we might modify response criteria to accommodate new drugs.

Now, I'm going to throw you the big question. Do you think that we can use the combination of these two drugs in an up-front setting and get rid of a regimen that has the potential for cardiotoxicity, pulmonary toxicity, gut and neurotoxicity, and myelotoxicity?

Dr LaCasce: I do. This is where we are headed, and a combination of one of these checkpoint inhibitors and brentuximab would be a great up-front study.

Dr Cheson: I can only hope to get my hands on that. It would be great for patients, and for doctors. The issue now with these new regimens is identifying biomarkers as to who might benefit most from novel, noncytotoxic programs vs those who require chemotherapy. We don't have any markers in Hodgkin lymphoma.

Dr LaCasce: We have PET. But I think PET in the setting of these new agents will need to be investigated thoroughly. And now we have the NanoString® (NanoString Technologies; Seattle, Washington)—the ability to do gene expression profiling from paraffin-embedded tissues—which may help us, hopefully. And we have some of these new serum markers as well. It will be interesting to see how that plays out.

Dr Cheson: For a disease in which we are curing so many people, we now have a very exciting time ahead of us.

Thank you for joining us, Ann; it's been great having you here. 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 in San Francisco.

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