PD-1 Inhibition for Relapse after Allogeneic Transplantation in Acute Myeloid Leukemia and Myelodysplastic Syndrome.

Relapse of AML and MDS remains the primary source of mortality after allogeneic transplantation (HCT). Targeting PD-1 is an approach for reversing T cell exhaustion and restoring the graft-versus-leukemia (GVL) effect that has logistical advantages versus donor lymphocyte infusion. In a prospective phase 1B clinical trial, pembrolizumab monotherapy was administered every three weeks to sixteen AML (n=12) and MDS (n=4) patients in relapse after HCT to assess Graft-versus-Host Disease (GVHD), clinical response and survival. The median time to relapse after HCT was 5.5 months and the median pre-treatment bone marrow blast percentage was 21.5%. The overall response rate (ORR) was 31.3% for patients receiving pembrolizumab monotherapy, consisting of three complete remissions (18.8%) and two partial remissions (13.5%). The median duration of response was 610 days. A significantly greater proportion of patients with mixed CD3 chimerism had clinical response compared to those with full donor chimerism (50% vs. 0%; p=0.03). Immune toxicities were frequent with 37.5% patients developing severe (grade III-IV) GVHD after pembrolizumab, of which the majority had resistance to corticosteroids and contributed to death in four patients (25%). The one-year overall survival was 37.5% and event-free survival was 31.3%. For AML, one-year overall survival was 50.0%. In this trial, PD-1 inhibition led to durable remissions in a third of patients experiencing early relapse after HCT suggesting this approach may augment the GVL response. Responses were exclusively observed in the setting of mixed CD3 donor chimerism. Immune toxicities (GVHD) were a barrier to successful treatment outcome. NCT03286114.