PD-1 blockade with pembrolizumab for classical Hodgkin lymphoma after autologous stem cell transplantation

Abstract

Autologous stem cell transplantation (ASCT) remains the standard of care for patients with relapsed/refractory (RR) classical Hodgkin lymphoma (cHL) who respond to salvage chemotherapy. However, relapse after ASCT remains a frequent cause of treatment failure, with poor subsequent prognosis. Because cHL is uniquely vulnerable to programmed cell death-1 (PD-1) blockade, PD-1 blockade given as consolidation after ASCT could improve ASCT outcomes. We therefore conducted a multicohort phase 2 study of pembrolizumab in patients with RR cHL after ASCT, hypothesizing that it would improve the progression-free survival (PFS) at 18 months after ASCT (primary end point) from 60% to 80%. Pembrolizumab was administered at 200 mg IV every 3 weeks for up to 8 cycles, starting within 21 days of post-ASCT discharge. Thirty patients were treated on this study. The median age was 33 years, and 90% were high-risk by clinical criteria. Seventy-seven percent completed all 8 cycles. Toxicity was manageable, with 30% of patients experiencing at least 1 grade 3 or higher adverse event (AE), and 40% at least 1 grade 2 or higher immune-related AE. Two patients were lost to follow-up in complete remission at 12 months. The PFS at 18 months for the 28 evaluable patients was 82%, meeting the primary end point. The 18-month overall survival was 100%. In conclusion, pembrolizumab was successfully administered as post-ASCT consolidation in patients with RR cHL, and resulted in a promising PFS in a high-risk patient cohort, supporting the testing of this strategy in a randomized trial. This trial was registered at www.clinicaltrials.gov as #NCT02362997.

Conflict of interest statement

Conflict-of-interest disclosure: P.A. provided consulting services to Merck & Co, Bristol-Myers Squibb, Pfizer, Affimed, Adaptive, and Infinity, and received research funding (institutional) from Merck & Co, Bristol-Myers Squibb, Affimed, Adaptive, Roche, Tensha, Otsuka, and Sigma Tau. Y.-B.C. provided consulting services to Magenta, Takeda, Kiadis, Incyte, and Regimmune. D.C.F. received honoraria from Merck & Co. A.F.H. provided consulting services to Bristol-Myers Squibb, Genentech, Merck & Co, Kite Pharma/Gilead, Adaptive Biotechnologies, and Seattle Genetics, and received research funding from Bristol-Myers Squibb, Genentech, Immune Design, AstraZeneca, Merck & Co, Pharmacyclics, Seattle Genetics, Kite Pharma, and Gilead Sciences. C.A.J. provided consulting services to Kite Pharma, Novartis, Pfizer, Humanigen, Precision Bioscience, Bayer, and Celgene, and received research funding from Pfizer and Kite Pharma. E.D.J. provided consulting services to Merck & Co, AstraZeneca, and Seattle Genetics, and received research funding from Pharmacyclics and Celgene. A.S.L. provided consulting services to Bristol-Myers Squibb and received honoraria from, and served on speakers’ bureaus for, Seattle Genetics, Humanigen, and Research to Practice. J.R. provided consulting services to Avrobio, Celgene, Draper Labs, LifeVault Bio, Regenerex, and TScan Therapeutics, and received research funding from Prometheus Laboratories, Neovii Biotech, Nektar, Merck & Co, and Kite Pharma. Y.N. received research funding from Otsuka, AstraZeneca, Affimed, Celgene, Sanofi Aventis, and Novartis. S.J.R. received research funding from Bristol-Myers Squibb, Merck & Co, Kite Pharma/Gilead, and Affimed Pharmaceuticals. M.A.S. provided consulting services to Bristol-Myers Squibb and received research funding from Bayer, Bristol-Myers Squibb, and Merck & Co. The remaining authors declare no competing financial interests.

© 2019 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

PFS. (A) All patients on study. (B) Patients with at least 1 clinical risk factor (primary refractory or relapse within 1 year, residual FDG-avid disease at ASCT, >1 salvage regimen, extranodal disease or B symptoms at relapse).

Figure 2.

Multiplex immunofluorescence. Comparison of BL and PP biopsy for patient with available tissue. (A) Increased PD-L1 on HRS (PAX5+, red arrows) cells and macrophages (CD68+). White arrow indicates PAX5+ B cell. Original magnification ×200; inset, original magnification ×200. (B) Increase in PD-1 on infiltrating T cells (CD3+). Original magnification ×200; inset, original magnification ×200. Stains: DAPI (Invitrogen); PDL1: 9A11 (Dana-Farber Cancer Institute [DFCI]/Cell Signaling Technology [CST]), Opal 520; PD1: EH33 (DFCI/CST), Opal 690; CD3: PolyC (Dako), Opal 570; CD68: PGM1 (Dako), Opal 540; PAX5: 24/PAX-5 (BD Transduction), Opal 620.