Phase II Study of Immune Checkpoint Blockade with Pembrolizumab after High Dose Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia

To address the role of immune dysregulation in AML, we conducted a phase II study of high-dose cytarabine followed by pembrolizumab 200 mg IV on day 14 to examine whether programmed death-1 inhibition improves clinical responses in relapsed/refractory (R/R) AML. Overall responders could receive pembrolizumab maintenance up to two years. Among thirty-seven patients enrolled, the overall response rate, composite complete remission rate (CRc; primary endpoint), and median overall survival (OS) were 46%, 38% and 11.1 months, respectively. Patients with refractory/early relapse and those receiving treatment as first salvage had encouraging outcomes (median OS 13.2 and 11.3 months, respectively). Grade >3 immune-related adverse events were rare (14%) and self-limiting. Patients who achieved CRc had a higher frequency of progenitor exhausted CD8+ T-cells in the bone marrow prior to treatment and a non-significant increase in baseline T-cell diversity. The primary objective of this single-arm open-label phase II study was to estimate the composite CR (CRc: CR + CRi) rate of HiDAC followed by pembrolizumab in R/R AML. The study design was a Simon’s like two-stage design with relaxed stopping for futility. Relaxed stopping refers to inclusion of PR in the first stage as some of these PRs may convert to a CR during maintenance phase. The null hypothesis that the true CRc rate for HiDAC followed by pembrolizumab is 20% was tested against a one-sided alternative hypothesis. In the first stage, 19 patients were enrolled. If the number of patients who achieved a CRc plus the number of patients with PR was equal to <4 in these 19 patients, the study would be stopped for futility. Otherwise, 18 additional patients were enrolled for a total of 37 patients. The null hypothesis will be rejected if >12 CRc’s are observed in 37 patients. Assuming that the PR rate has a uniform distribution, this design yields a type 1 error rate of at most 5% and power of at least 84% when the true CR rate for HiDAC followed by pembrolizumab is 40%. Secondary endpoints of this study included rates of unacceptable toxicity as defined in Safety Assessment, toxicity of HiDAC + pembrolizumab induction phase and pembrolizumab maintenance, objective overall response rates (ORR: CR + CRi + PR + MLFS), OS defined as day 1 of treatment until date of last known follow-up, relapse-free survival (RFS) defined as time from CRc until relapse or death, progression-free survival (PFS) defined as time from ORR until relapse, progression, or death, and event-free survival (EFS) defined as day 1 of treatment until no response, relapse or death. Survival measurements were summarized by Kaplan-Meier methodology. ** Submitters declare that they do not have consent to deposit the raw data in GEO and the raw data will be made available through the University of North Carolina at Chapel Hill (UNC) **