Outcomes of patients with the third or higher relapsed classical Hodgkin lymphoma: results from the German Hodgkin Study Group
Authors: P.J. Bröckelmann, H. Müller, E. Kücüksarioglan, P. Kaskel, V. Metterlein, H. Giezek, A. Balakumaran, M.K. Raut, A. Engert, B. von Tresckow
Journal: Annals of Oncology (2019)

As current therapeutic attempts for patients with multiply relapsed or refractory classical Hodgkin lymphoma (rrHL) are mostly palliative, further treatment strategies are needed [1.von Tresckow B. Moskowitz CH. Treatment of relapsed and refractory Hodgkin lymphoma.Semin Hematol. 2016; 53: 180-185Crossref PubMed Scopus (32) Google Scholar]. However, disease status, treatment sequence and survival of patients with the third or higher relapse are insufficiently studied. Clinical trials evaluating anti-programmed cell death receptor 1 (PD1) antibodies or brentuximab vedotin (BV) in rrHL did not include a control group because of the lack of an accepted standard in later line therapy and the rarity of the disease [2.Chen R. Zinzani P.L. Fanale M.A. et al.Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic Hodgkin lymphoma.J Clin Oncol. 2017; 35: 2125-2132Crossref PubMed Scopus (677) Google Scholar, 3.Younes A. Santoro A. Shipp M. et al.Nivolumab for classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial.Lancet Oncol. 2016; 17: 1283-1294Abstract Full Text Full Text PDF PubMed Scopus (694) Google Scholar]. Here, we report long-term clinical outcomes of patients with multiply rrHL enrolled in German Hodgkin Study Group (GHSG) clinical trials. Data from patients with at least three consecutive tumor-related events, either progressive/refractory or relapsed disease, were retrospectively analyzed in the GHSG database by descriptive statistics. Overall survival (OS) as primary end point and progression-free survival (PFS) as key secondary end point were estimated. All trials were approved by the respective ethics committees. Among 12 584 patients in GHSG first-line trials and 449 patients in trials for relapsed disease, 69 patients had third relapse of cHL. A total of 49% of the third relapses developed ≤12 months from the end of the third-line treatment and the majority of patients (41/61) presented with stage III/IV at the third relapse (Figure 1A). Patients (72.5%) were pretreated with high-dose chemotherapy and 82.6% with radiotherapy. None of the patients had received BV or anti-PD-1 antibodies before the third relapse due to non-availability of these agents (Figure 1B). Curative treatment attempts were increasingly replaced by palliative approaches in the fourth-line treatment. With treatments summarized in Figure 1C and a median observation time of 63.3 months for OS after the third relapse, 45 patients (65.2%) had died and 60 (87.0%) had a fourth PFS event (Figure 1D and E). Twelve months after the third relapse, PFS and OS were 73.2% [95% confidence interval (CI) 62.6% to 83.8%] and 50.8% (95% CI 38.9% to 62.8%), respectively. At 18 months, 65.6% (95% CI 54.2% to 77.0%) were still alive and the PFS rate was 29.5% (95% CI 18.5% to 40.5%). Studies evaluating newer agents in rrHL lack a control group or head-to-head comparison due to the relative rarity of the disease. The pivotal phase II studies with anti-PD1 antibodies in multiply rrHL revealed overall 12-month OS rates of 96.1% (95% CI not available) for patients treated with pembrolizumab and 92% (95% CI 88% to 95%) for those receiving nivolumab, respectively [4.Armand P. Engert A. Younes A. et al.Nivolumab for relapsed/refractory classic Hodgkin lymphoma after failure of autologous hematopoietic cell transplantation: extended follow-up of the multicohort single-arm phase II CheckMate 205 trial.J Clin Oncol. 2018; 36: 1428-1439Crossref PubMed Scopus (415) Google Scholar, 5.Zinzani P.L. Chen R. Lee H.J. et al.Two-year follow-up of Keynote-087 Study: pembrolizumab monotherapy in relapsed/refractory classic Hodgkin lymphoma.Blood. 2018; 132: 2900Crossref Google Scholar]. This compares with an OS rate of 73.2% (95% CI 62.6% to 83.8%) in the present study. Respecting obvious limitation with cross-study comparisons as well as different patient populations, the OS data observed with anti-PD1 antibodies so far compare favorably with the outcome with conventional therapy in the present analysis. Taken together, we provide a comprehensive analysis with long-term follow-up describing outcomes of cHL patients treated with conventional therapies for the third relapse in recent decades. This study on a rare patient population in need for innovative therapies as reflected by unfavorable PFS and OS may serve as a reference when evaluating novel targeted therapies. The study was supported by Merck & Co., Inc., Kenilworth, NJ, USA (no grant number applies).