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

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.

Graphical abstract

Figure 1.

Kaplan-Meier survival curves assessed in all patients. OS curve (blue) and PFS curve (red) for all patients on trial (n = 28).

Figure 2.

OS and PFS by lymphoid vs myeloid disease. (A) OS by lymphoid (blue) vs myeloid (red) disease. (B) PFS by lymphoid (blue) vs myeloid (red) disease.

Figure 3.

Assessment of immunologic correlative studies. (A) Time course of immune cell populations at baseline and on treatment through cycle 8 (C8), including total T cell (CD3⁺), CD4⁺, and CD8⁺ T cell, B cell (CD20⁺), NK cell (CD56⁺CD3⁻), and DC (HLA-DR⁺LINEAGE⁻). Each dot represents median value. *P ≤ .05 compared with the baseline value. (B) Baseline %PD-1 expression in T-cell subsets in patients who went on to achieve response (CR/PR; green), SD (yellow), or progressive disease (PD) (orange) as best response. Red color represents the maximum value, and the blue color represents the minimum value in each row. (C) CD4 and CD8 T-cell subsets at cycle 4 according to response status, including T_reg and T_con. Red color represents the maximum value, and the blue color represents the minimum value in each row. (D) % of morphologic and cytogenetic bone marrow involvement as well as immune activity from CD3⁺CD8⁺ T-cell and donor-cell chimerism in a responding patient with CMML at baseline (green), day +75 post nivolumab (red), and day +112 post nivolumab (blue). The % of trisomy 21 is 100% of 10 XY recipient metaphase cells that were evaluated by the clinical cytogenetics laboratory, while the % of CTLs was 20% of the total marrow population. (E) Next-generation sequencing analysis of variant allele fraction for clones and subclones in this same CMML patient at time of diagnosis, after therapy with a hypomethylating agent (HMA), and after nivolumab therapy. The level of donor single nucleotide variants post PBSCT and nivolumab therapy is depicted in orange.