A multicenter phase 1 study of nivolumab for relapsed hematologic malignancies after allogeneic transplantation

Matthew S. Davids, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
Haesook T. Kim, Department of Data Sciences, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, MA.
Caitlin Costello, Division of BMT, University of California, San Diego Moores Cancer Center, La Jolla, CA.
Alex F. Herrera, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, CA.
Frederick L. Locke, Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL.
Rodrigo O. Maegawa, Eastern Maine Medical Center, Bangor, ME.
Alexandra Savell, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
Michael Mazzeo, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
Adrienne Anderson, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
Alexander P. Boardman, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
Augustine Weber, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
David Avigan, BMT Program, Beth Israel Deaconess Medical Center, and.
Yi-Bin Chen, BMT Program, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA.
Sarah Nikiforow, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
Vincent T. Ho, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
Corey Cutler, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
Edwin P. Alyea, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
Pavan Bachireddy, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
Catherine J. Wu, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
Jerome Ritz, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
Howard Streicher, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD; and.
Edward D. Ball, Division of BMT, University of California, San Diego Moores Cancer Center, La Jolla, CA.
Asad Bashey, Blood and Marrow Transplant Group of Georgia at Northside Hospital, Atlanta, GA.
Robert J. Soiffer, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
Philippe Armand, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

Abstract

Programmed cell death-1 (PD-1)/programmed death ligand-1 blockade may potentially augment graft-vs-tumor effects following allogeneic hematopoietic cell transplantation (alloHCT), but retrospective studies of anti-PD-1 therapy reported substantial toxicity from graft-versus-host-disease (GVHD). Here, we report the results of a prospective clinical trial of PD-1 blockade for relapsed hematologic malignancies (HMs) after alloHCT (NCT01822509). The primary objective in this phase 1 multicenter, investigator-initiated study was to determine maximum tolerated dose and safety. Secondary objectives were to assess efficacy and immunologic activity. Patients with relapsed HMs following alloHCT were eligible. Nivolumab was administered every 2 weeks until progression or unacceptable toxicity, starting with a 1-mg/kg cohort, with planned deescalation based on toxicity to a 0.5-mg/kg cohort. Twenty-eight patients were treated (n = 19 myeloid, n = 9 lymphoid). Median age was 57 years (range 27-76), and median time from alloHCT to enrollment was 21 months (range 5.6-108.5). Two of 6 patients treated at 1 mg/kg experienced dose-limiting toxicity (DLT) from immune-related adverse events (irAEs). Twenty-two patients were treated at 0.5 mg/kg, and 4 DLTs occurred, including 2 irAEs and 2 with fatal GVHD. The overall response rate in efficacy-evaluable patients was 32% (8/25). With a median follow-up of 11 months, the 1-year progression-free survival and overall survival were 23% and 56%, respectively. In this first prospective clinical trial of an anti-PD-1 antibody for post-alloHCT relapse, GVHD and irAEs occurred, requiring dose deescalation, with only modest antitumor activity. Further studies of anti-PD-1 therapy post-alloHCT may require specific toxicity mitigation strategies. This trial was registered at www.clinicaltrials.gov as #NCT01822509.