A multicenter, phase I study of nivolumab for relapsed hematologic malignancies after allogeneic transplantation.

CTLA-4 blockade augments the graft-vs-tumor effect in relapsed hematologic malignancies (HMs) after allogeneic hematopoietic cell transplantation (alloHCT). PD-1/PDL-1 interactions also contribute to functional T cell impairment, but retrospective studies of anti-PD-1 therapy following alloHCT reported substantial toxicity from GVHD. Here, we report the results of a prospective clinical trial of PD-1 blockade for relapsed HMs after alloHCT (ClinicalTrials.gov, NCT01822509). The primary objectives in this phase I multicenter, investigator-initiated study were 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 de-escalation 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 (range 27-76), and median time from alloHCT to enrollment was 21 months (range 5.6-108.5). Two of six 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 PFS and OS 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 de-escalation, with only modest anti-tumor activity. Further studies of anti-PD-1 therapy post alloHCT may require specific toxicity mitigation strategies.