Immunotherapy for older patients with classic Hodgkin lymphoma

In The Lancet Haematology, a team led by Bruce Cheson reports on using a combination of two recently developed immunological drugs, the antibody-drug conjugate brentuximab vedotin and the checkpoint inhibitor nivolumab, to treat classic Hodgkin lymphoma in a special population: patients who are too frail to be treated safely with standard cytotoxic chemotherapy. 1 Cheson BD Bartlett NL LaPlant B et al. Brentuximab vedotin plus nivolumab as first-line therapy in older or chemotherapy-ineligible patients with Hodgkin lymphoma (ACCRU): a multicentre, single-arm, phase 2 trial. Lancet Haematol. 2020; (published online Oct 1.)https://doi.org/10.1016/S2352-3026(20)30275-1 Summary Full Text Full Text PDF PubMed Scopus (30) Google Scholar They chose this combination for sound reasons. Patients with classic Hodgkin lymphoma who, because of age or organ dysfunction, cannot be safely treated with a standard regimen, such as doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), have worse outcomes than those seen in fitter patients, and they have a major unmet need for more effective, safer treatment. 2 Howlader N Noone AM Krapcho M et al. SEER Cancer Statistics Review, 1975-2017. National Cancer Institute, Bethesda, MD2020 Google Scholar Brentuximab vedotin is directed against CD30, which is ubiquitously expressed in the malignant cells of classic Hodgkin lymphoma, and the drug is highly efficacious for both relapsed 3 Younes A Gopal AK Smith SE et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma. J Clin Oncol. 2012; 30: 2183-2189 Crossref PubMed Scopus (1176) Google Scholar and previously untreated classic Hodgkin lymphoma. 4 Connors JM Jurczak W Straus DJ et al. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin's lymphoma. N Engl J Med. 2018; 378: 331-344 Crossref PubMed Scopus (419) Google Scholar Nivolumab targets and neutralises programmed death-1 protein, thus undoing the classic Hodgkin lymphoma-associated blockage of a patient's ability to mount an immune attack on classic Hodgkin lymphoma cells. It is also highly effective against relapsed 5 Ramchandren R Fanale MA Rueda A et al. Nivolumab for newly diagnosed advanced-stage classical Hodgkin lymphoma (cHL): results from the phase 2 Checkmate 205 Study. Blood. 2017; 130 (abstr).: 651 Google Scholar and newly diagnosed classic Hodgkin lymphoma. 6 Ramchandren R Domingo-Domènech E Rueda A et al. Nivolumab for newly diagnosed advanced-stage classic Hodgkin lymphoma: safety and efficacy in the phase II CheckMate 205 Study. J Clin Oncol. 2019; 37: 1997-2007 Crossref PubMed Scopus (129) Google Scholar Both drugs have modest, non-overlapping toxicity, and can be tolerated in fully effective doses even by frail patients. 3 Younes A Gopal AK Smith SE et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma. J Clin Oncol. 2012; 30: 2183-2189 Crossref PubMed Scopus (1176) Google Scholar , 4 Connors JM Jurczak W Straus DJ et al. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin's lymphoma. N Engl J Med. 2018; 378: 331-344 Crossref PubMed Scopus (419) Google Scholar , 5 Ramchandren R Fanale MA Rueda A et al. Nivolumab for newly diagnosed advanced-stage classical Hodgkin lymphoma (cHL): results from the phase 2 Checkmate 205 Study. Blood. 2017; 130 (abstr).: 651 Google Scholar , 6 Ramchandren R Domingo-Domènech E Rueda A et al. Nivolumab for newly diagnosed advanced-stage classic Hodgkin lymphoma: safety and efficacy in the phase II CheckMate 205 Study. J Clin Oncol. 2019; 37: 1997-2007 Crossref PubMed Scopus (129) Google Scholar Hoping that the combination would be even more effective than either drug alone, the investigators set a very high bar for success: an overall response rate of 80%. Disappointingly, at the planned interim analysis, when 25 patients could be evaluated for response, the combination fell short of that, producing an overall response rate of 64% (95% CI 43–82), and the trial was closed. Because accrual had continued while the first 25 evaluable patients completed treatment and were assessed, 46 patients were ultimately treated, of whom 28 (61%) responded. The promising combination failed to be effective enough to justify further evaluation. Brentuximab vedotin plus nivolumab as first-line therapy in older or chemotherapy-ineligible patients with Hodgkin lymphoma (ACCRU): a multicentre, single-arm, phase 2 trialAlthough the trial did not meet the prespecified activity criteria, brentuximab vedotin plus nivolumab is active in older patients with previously untreated Hodgkin lymphoma with comorbidities. The regimen was also well tolerated in the majority of patients in this older population. Future trials should be based on optimising the dose and schedule, perhaps combined with other targeted agents that might permit chemotherapy-free strategies in older patients with Hodgkin lymphoma. Full-Text PDF