Weighing the Risks and Benefits of Nivolumab in Patients With Hodgkin Lymphoma Undergoing AlloHCT

For patients with Hodgkin lymphoma (HL), allogeneic hematopoietic cell transplantation (alloHCT) can induce long-term disease control; however, relapse is common and rates of 3-year progression-free survival (PFS) range from 20 to 60 percent – suggesting a need for new treatment agents.

In May 2016, the U.S. Food and Drug Administration (FDA) approved nivolumab (a programmed death receptor-1 [PD-1] blocking antibody) for the treatment of patients with relapsed classical HL. The drug carries a warning, though, about complications in patients who have undergone alloHCT, based on reports of transplant-related deaths and hyper-acute and severe-acute graft-versus-host disease (GVHD) following nivolumab treatment. The FDA also required that the drug’s manufacturers conduct a postmarketing study to assess the safety of nivolumab in these patients.

Charles Herbaux, MD, from the Department of Hematology at the Hospital Center Regional University De Lille in France, and co-authors published results from a retrospective study of patients with HL (median age = 33 years; range = 20-48 years) who were treated with both alloHCT and nivolumab, finding a high overall response rate (95%; 95% CI 74-100) and an “acceptable” rate of GVHD (30%; 95% CI 9.9-50.1).

Dr. Herbaux and colleagues collected patient data from the French Medical Drug Agency’s Authorization for Temporary Use program to identify participants who had undergone alloHCT between March and September 2015. Most patients were male (n=11; 55%) and had an Eastern Cooperative Oncology Group performance status score of ≤1 (n=15; 75%).

Patients had received a median of seven prior therapies (range = 4-13 therapies). Most (n=13; 65%) had a history of GVHD: 10 had acute GVHD and three had chronic GVHD. Two patients had an improved response 100 days post-transplant, converting from partial response (PR) to complete response (CR).

Six patients (95% CI 9.9-50.1) experienced nivolumab-induced GVHD after a single infusion, which prompted discontinuation of the drug. Each of these cases occurred at least one week after infusion, and all patients who experienced GVHD had a history of acute GVHD, “which might reflect greater alloreactivity,” co-author Franck Morschhauser, MD, PhD, told ASH Clinical News. “Intriguingly, nivolumab did not induce chronic GVHD in any patients,” he noted.

Other reasons for treatment discontinuation included second alloHCT (n=1), lack of response (n=1), hematologic toxicity (n=1), cerebellar ataxia (n=1), and disease progression (n=3).

The time from alloHCT to nivolumab treatment was significantly shorter in patients who presented with nivolumab-induced GVHD than in those who did not: median of 8.5 days (range = 2-19 days) versus 28.5 days (range = 7-111 days; p=0.0082). Two patients who developed GVHD died and three were still in response at the time of the report.

“This substantial clinical activity occurred in a heavily pretreated patient [population] whose median time to disease progression after alloHCT was short,” Dr. Morschhauser added. “Disease progression required initiation of another treatment before nivolumab in 65 percent of patients.”

Serious hematologic adverse events included grade 4 neutropenia (n=1) and grade 3 thrombocytopenia (n=1). Two other patients (who did not develop GVHD) died. “Toxicity of nivolumab post-alloHCT was manageable with careful monitoring and close clinical assessment,” the authors wrote.

However, the authors advised that, given the risk of GVHD in this patient population, “physicians [should] carefully weigh the benefits against the risks in patients with prior history of acute GVHD, [and] follow-up visits after administration of nivolumab should be carried out by physicians with expertise in alloHCT and management of GVHD.”

At publication, seven patients (35%) remained on nivolumab.

After treatment, 42 percent of patients achieved CR (95% CI 21-67; n=8), whereas 52 percent of patients achieved PR (95% CI 29-76; n=10). Five patients experienced relapse, which occurred after a median of 132 days (range = 98-245 days).

After a median follow-up of 370 days (range = 24-486 days), PFS and overall survival (OS) had not been reached. At 12 months, the probability of OS was 78.7 percent (95% CI 52.4-91.5) and the probability of PFS was 58.2 percent (95% CI 33.1-76.7).

“We believe nivolumab to be a suitable option to treat relapsed HL after alloHCT, with a potentially better risk−benefit ratio compared [with] other therapeutic options, such as brentuximab vedotin and donor lymphocyte infusion,” Dr. Morschhauser told ASH Clinical News. “In all cases, we recommend a systematic clinical and biologic evaluation one week after nivolumab initiation.”

The study, a case series, is limited by its retrospective design and small patient population.


Reference

Herbaux C, Gauthier J, Brice P, et al. Efficacy and tolerability of nivolumab after allogeneic transplantation for relapsed Hodgkin’s lymphoma. Blood. 2017 March 21. [Epub ahead

 

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