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Oncology Times:
doi: 10.1097/01.COT.0000444035.18056.e0
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Hodgkin Lymphoma: Brentuximab Active in Relapsed Disease, but Use as Maintenance Debated

Carlson, Robert H.

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NEW YORK—In the pivotal trial of brentuximab vedotin in patients with Hodgkin lymphoma recurring after autologous transplant, first reported at the 2011 ASCO Annual Meeting (Chen et al, Abstract 8031), the overall response rate was 75 percent and the complete response rate was 34 percent.

That's the good news. The question then becomes what to do next: continue brentuximab or go to allogeneic transplant?

Two speakers here at the Lymphoma & Myeloma International Congress had their own suggestions, which they defended in a debate: “Recurrent Hodgkin Lymphoma After Auto-Transplant in CR on Brentuximab Vedotin: Allogeneic Transplant or Maintenance Therapy?”

The case for allogeneic stem cell transplant was argued by Koen van Besien, MD, PhD, Director of the Transplant Program at Weill Cornell Medical College and Attending Physician at New York-Presbyterian Hospital.

On the other hand, maintenance with brentuximab was favored by Anas Younes, MD, Chief of the Lymphoma Service at Memorial Sloan-Kettering Cancer Center. (In Congress Chair Morton Coleman's introductory remarks, he credited Younes with playing a significant role in the development of that agent.)

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Koen van Besien: Allogeneic Transplant Highly Effective

Van Besien said he favored allogeneic transplant because it is highly effective and is well tolerated if implemented before multiple treatment failures and with adequate prophylaxis against graft-versus-host disease (GvHD). “What we can expect from brentuximab vedotin is limited durability and toxicity,” he said, illustrating this by reviewing four typical cases from his and other institutions. All four patients received the ABVD regimen followed by salvage treatment with the DICE (dexamethasone, ifosfamide, cisplatin, etoposide) or ICE regimen.

After relapse, patients were subsequently treated with brentuximab. Only one of the four patients achieved a complete response after nine cycles, two of the other three had progressive disease after partial response, and in the fourth patient disease progressed immediately after brentuximab treatment.

“Do you really want to follow up with an agent with a relapse rate of 50 percent at least? I don't think so,” van Besien said.

If brentuximab had mild, manageable toxicities one might consider continuing it, he said. But in Phase II studies it has been associated with debilitating paclitaxel-like grade 3/4 peripheral neuropathy in eight to 10 percent of cases, and an incidence of thrombocytopenia of eight to 14 percent (Wagner-Johnston et al: Leukemia & Lymphoma 2012;53:2283-2286).

KOEN VAN BESIEN, MD
KOEN VAN BESIEN, MD
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Several cases of multifocal leukoencephalopathy have also been reported, as well as pulmonary toxicity when brentuximab was given in combination with bleomycin.

Another option for Hodgkin lymphoma patients after relapse on brentuximab is a second autologous transplant, but this is not an easy option, van Besien said, because of the potential for delayed engraftment, opportunistic infections, and organ involvement.

In a series of 40 patients with Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL), 73 percent of patients had died at six years, 62 percent secondary to relapsed lymphoma. The authors of that study concluded that a second autologous transplant should be considered for patients with relapsed HL or NHL if they did not have the option of an allogeneic transplant.

His choice in this setting, he said, is allogeneic transplant, citing a British study as proof of principle (Peggs et al: J CO 2011;29:971-978). Among 24 HL patients who underwent donor lymphocyte infusion for relapsed disease, the overall response rate was 79 percent, which included 14 complete responses, 11 of which had no prior salvage. The relapse rate at nine years was 33 percent.

ANAS YOUNES, MD
ANAS YOUNES, MD
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Van Besien concluded by saying that responses to brentuximab vedotin are rarely durable in HL, while allogeneic transplant is an excellent treatment option and overcomes disease resistance, and with supportive care and GvHD prophylaxis, the incidence of that problem is limited. “And, we have donors for practically everybody in this day and age,” he said.

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Anas Younes: Maintenance Therapy with Bendamustine

“We have a problem with patients with HL who relapse after autologous transplant—they do not do well,” Younes began. Median survival was recently estimated to be only about 1.9 years, which is the same as it was in 1990. “These are patients typically under age 30, and we want to prolong their survival but also let them have a good quality of life.”

With targeted agents such as brentuximab vedotin, response rates today are higher than ever seen before, he said. “This is the most active single agent we have tried in the past two or three decades in this setting”

To show the activity, Younes cited a pivotal Phase II trial of brentuximab he led in 102 patients with relapsed/refractory HL after autologous stem cell transplant (Younes et al: JCO 2012;30:2183-2189). Those results led to accelerated approval by the Food and Drug Administration of the drug for patients with CD30-positive HL who had disease relapse after autologous stem cell transplant.

Seventy-five percent of patients in that trial had an objective response, with complete responses in 34 percent. Median duration of response for those in CR was 20.5 months. Toxicities were manageable, with the most common treatment-related adverse events peripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea.

If patients relapse while on brentuximab vedotin, they can be retreated with that drug and still achieve high response rates, Younes said. “This is remarkable—you can use the same drug a second time around and achieve again a very good response rate and a very good CR. It's a second chance that you missed on the first chance.”

He cited a review he wrote published last month in Hematology/Oncology Clinics of North America (2014;1:27-32) that noted partial response rates of 41 percent after treatment as well as after retreatment with the drug. In addition, complete responses have been seen in approximately 20 percent of patients after retreatment with brentuximab, compared with approximately 35 percent after first treatment, which is much higher than that achieved with any other single agent in that setting, Younes said.

Brentuximab also compares favorably in that setting against the multiagent GVD regimen of gemcitabine, vinorelbine, and liposomal doxorubicin. And, retreatment with brentuximab vedotin was also shown in one small study to be effective against systemic anaplastic large cell lymphoma (sALCL) (Bartlett et al, 2012 ASCO Annual Meeting, Abstract 8027).

“The idea is that there is no rush to go for another transplant if you give the patient the benefit of the doubt with regard to progressing again,” he said. “You can go back again and use the same drug for a second chance, and then go to the transplant.”

Younes said he does send some of his patients in this setting to allogeneic transplant, but he does not consider it the standard of care.

His algorithm for patients with less than a complete remission or a relapse after autologous transplant is treatment with brentuximab. Those achieving a CR in his practice continue on observation, he said. “I don't rush them to transplant because if they relapse I can use brentuximab vedotin again, with allogeneic transplant always an option.”

Those with less than a CR after brentuximab vedotin are considered for allogeneic transplant, or considered for evaluation for B2MG mutations.

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Pre- and Post-Debate Survey

Those in the audience of approximately 1,000 with handheld devices capable of accessing the Internet could vote before and after the debate on the question at hand: “Recurrent HL after Auto-transplant in CR on Brentuximab Vedotin: Allogeneic Transplant or Maintenance Therapy?”

Younes apparently swayed some of the audience, as many “not sure” voters switched to brentuximab, with the percentage of those voting for transplant dropping slightly.

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