Pembrolizumab: a key for some, but not all, HL

In this issue of Blood, Armand et al describe the long-term outcomes of a phase 2 study of the immune checkpoint inhibitor pembrolizumab in patients with relapsed/refractory classic Hodgkin lymphoma (HL).¹ 

Although most patients with HL are cured with multiagent chemotherapy, a substantial minority remain in need of other therapies. Fortunately, the discovery and subsequent therapeutic exploitation of the programmed cell death 1 pathway has led to agents such as pembrolizumab becoming available for patients with a variety of cancers, including HL. In the initial report, with a median follow-up of 10.1 months, the objective response rate (ORR) was 69.7% (complete response [CR], 22.7%).² Response rates were similar regardless of prior autologous stem cell transplant (ASCT) and/or brentuximab vedotin exposure, and were consistent among the one-third of patients with primary refractory disease.³ Many patients with HL are young adults (the median age of KEYNOTE-087 participants was 35 years at enrollment) and often deal with relapsed lymphoma in the face of other major life events, such as marriage, parenthood, or establishing careers. For such patients, when their lymphoma does not respond to chemotherapy, understanding long-term outcomes from pembrolizumab provides important context for decision-making.

Now with a median observation period exceeding 5 years, the median duration of response (DOR) remained steady at 16.6 months, and the 5-year progression-free survival (PFS) and overall survival rates were 14.2% and 70.7%, respectively. Unsurprisingly, the 58 patients who achieved CR to pembrolizumab had the most favorable outcomes, with median DOR not reached. A key question for patients with HL achieving CR following pembrolizumab in this setting is whether to proceed to stem cell transplant. This question is challenging to study prospectively, and observations from studies such as this can be informative (with the caveat that the study was neither designed nor appropriately powered to provide definitive answers). Of the 58 patients who achieved CR, 10 ultimately underwent allogeneic stem cell transplant (5 proceeding directly to transplant, and the others requiring further therapy for relapsed disease), and the median DOR and PFS were 13.6 and 36.9 months, respectively. Among the 48 patients who did not proceed to transplant, the median DOR was not reached, and the median PFS was 56.5 months. Although allocation to transplant was nonrandomized, the favorable outcomes observed among the patients who did not undergo allogeneic stem cell transplant are encouraging and suggest that observation of patients achieving CR may be reasonable.

The data set also provides useful data regarding pembrolizumab retreatment. Per protocol, patients who achieved CR and received ≥6 months of therapy and ≥2 doses after CR were allowed to discontinue treatment before 2 years, with those who experienced subsequent disease progression able to receive retreatment for up to an additional 17 cycles. Among 20 such patients, the ORR (73.7%) and CR (36.8%) rates following retreatment were similar to those observed with initial treatment in the overall population, and the median PFS was 17.2 months, with no new safety signals observed.

Important unanswered questions remain, such as the role of ASCT following checkpoint inhibitor therapy. Observational series suggest a potential chemosensitization effect from checkpoint inhibitors, with a US academic collaborative group reporting favorable outcomes for patients undergoing ASCT after checkpoint inhibitor use.⁴ The 18-month PFS was 86%, and prior response to checkpoint inhibitor appeared to be a better predictor of outcome than positron emission tomography status before transplant. The role of allogeneic stem cell transplant after checkpoint inhibitors (and vice versa) also remains an open question. In a pooled analysis of allogeneic stem cell transplant after checkpoint inhibitor, rates of grade 3 to 4 acute graft-versus-host disease were increased, but chronic graft-versus-host disease and nonrelapse mortality rates were similar.⁵ However, the use of posttransplant cyclophosphamide may mitigate some of the immune activation from checkpoint inhibitors and improve their safety in this setting.⁶ Conversely, the use of checkpoint inhibitors after allogeneic stem cell transplant, although effective, does appear to result in aggressive graft-versus-host disease, with resistance to immunosuppression and deaths reported, meaning they should be used with caution.⁷ The toxicity of checkpoint inhibitor use after allogeneic stem cell transplant brings into sharp focus the importance of identifying patients likely to achieve durable responses to pembrolizumab without allogeneic stem cell transplant. It is also reassuring to know that if transplant is deferred, retreating patients who previously achieved CR is feasible and is a viable bridging strategy to transplant. Checkpoint inhibitors have substantially improved the outcomes of patients with HL, but the optimal treatment setting, sequencing, and combinations require further investigation.

Conflict-of-interest disclosure: C.Y.C. reports consulting/advisory/honoraria for Roche, Janssen, Gilead, AstraZeneca, Lilly, TG Therapeutics, BeiGene, Novartis, Menarini, Daizai, AbbVie, Genmab, and BMS; and research funding from BMS, Roche, AbbVie, MSD, and Lilly.