PD-1 blockade for diffuse large B-cell lymphoma after autologous stem cell transplantation

Abstract

Disease relapse remains the leading cause of failure after autologous stem cell transplantation (ASCT) for patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). We conducted a phase 2, multicenter, single-arm study of the anti-PD-1 monoclonal antibody pembrolizumab given after ASCT in patients with chemosensitive DLBCL, hypothesizing that it would improve the progression-free survival (PFS) at 18 months after ASCT (primary endpoint) 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. Twenty-nine patients were treated on this study; 62% completed all 8 cycles. Seventy-nine percent of patients experienced at least one grade 3 or higher adverse event, and 34% experienced at least one grade 2 or higher immune-related adverse event. Overall, 59% of patients were alive and progression free at 18 months, which did not meet the primary endpoint. The 18-month overall survival was 93%. In conclusion, pembrolizumab was successfully administered as post-ASCT consolidation in patients with R/R DLBCL, but the PFS did not meet the protocol-specific primary objective and therefore does not support a larger confirmatory study. This trial was registered at www.clinicaltrials.gov as #NCT02362997.

Conflict of interest statement

Conflict-of-interest disclosure: M.J.F. has served as a consultant for Novartis, Xenetic, Foundation Medicine, Arcellx, Nkarta, Incyte, and June/Celgene; and received honoraria from Kite/Gilead. P.A. has served as a consultant for Merck, Bristol-Myers Squibb, Pfizer, Affimed, Adaptive, Infinity, ADC Therapeutics, Celgene, and MorphoSys; received research funding (institution) from Merck, Bristol-Myers Squibb, Affimed, Adaptive, Roche, Tensha, Otsuka, Sigma-Tau, Genentech, and IGM; and has received honoraria from Bristol-Myers Squibb and Merck. A.F.H. has served as a consultant for Bristol-Myers Squibb, Genentech, Merck & Co., Kite Pharma/Gilead, Adaptive Biotechnologies, and Seattle Genetics; and has received research funding from Bristol-Myers Squibb, Genentech, Immune Design, AstraZeneca, Merck & Co., Pharmacyclics, Seattle Genetics, Kite Pharma, and Gilead Sciences. Y.N. has received research funding from Otsuka, AstraZeneca, Affimed, Celgene, Sanofi Aventis, and Novartis. A.S.L. has served as a consultant for Bristol-Myers Squibb; and has received honoraria/speakers bureau fees from Seattle Genetics, Humanigen, and Research to Practice. C.A.J. has served as a consultant for Kite, Novartis, Pfizer, Humanigen, Precision Bioscience, Bayer, and Celgene; and has received research funding from Pfizer and Kite. E.D.J. has served as a consultant for Merck, AstraZeneca, and Seattle Genetics; and received research funding from Pharmacyclics and Celgene. J.R. has served as a consultant for Avrobio, Celgene, Draper Labs, Falcon Therapeutics, LifeVault Bio, Talaris Therapeutics, and TScan Therapeutics; and has received research funding from Equillium and Kite Pharma. S.J.R. has received research funding from Bristol-Myers Squibb, Merck, Kite/Gilead, and Affimed Pharmaceuticals. M.A.S. has served as a consultant for Bristol-Myers Squibb; and has received research funding from Bayer, Bristol-Myers Squibb, and Merck. Y.-B.C. has served as a consultant for Magenta, Takeda, Kiadis, Incyte, and AbbVie. The remaining authors declare no competing financial interests.

© 2020 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

PFS, overall survival, and examples of tumor characteristics pre- and posttreatment. PFS in all evaluable patients (n = 29) (A) and patients stratified according to disease response before ASCT (partial remission [PR], n = 11; CR, n = 18) (B). (C) Representative IHC for pretransplant (pre) samples and posttransplant (post) relapse biopsy samples (original magnification ×200) showing CD3 (white), PD-1 (red), and 4′,6-diamidino-2-phenylindole (DAPI; blue) with corresponding quantification of CD3+ infiltrates and PD-1 staining in 4 patients. (D) Representative IHC for pretransplant samples and posttransplant relapse biopsy samples (original magnification ×200) showing Pax5 (pink), CD68 (orange), PD-L1 (green), and DAPI (blue) with corresponding quantification of CD68+PD-L1+ infiltrates in 4 patients.