Efficacy, Safety, and Biomarkers of Response to Azacitidine and Nivolumab in Relapsed/Refractory Acute Myeloid Leukemia: A Nonrandomized, Open-Label, Phase II Study

Background: Preclinical models showed that blocking PD-1/ PD-L1pathways enhanced anti-leukemic responses. Azacitidineup-regulates PD-1 and interferon-gammasignaling. Methods: In this single arm trial, patients with relapsed/refractory (R/R) AML were treated with azacitidine75mg/m2 Days 1-7 intravenously/subcutaneously with nivolumab3mg/kg intravenously on Day 1 and 14, every 4-6 weeks. Findings: Seventy-patients were treated. The median age was 70-years (range,22-90). The median number of prior therapies was 2 (range,1-7). The overall response rate (ORR) was 33% including 15 (22%) complete remission (CR)/complete remission with insufficient recovery of counts (CRi), 1 partial response, and 7 patients with hematologic improvement (HI) maintained >6 months. Six-patients (9%) had stable disease >6 months. The ORR was 58% and 22%, in HMA-naive (n=25) and HMA pre-treated (n=45) patients, respectively. Grade 3-4 immune-related adverse events occurred in 8 (11%) patients. Pretherapy bone marrow and peripheral blood CD3 and CD8 were significantly predictive for response on flow-cytometry. CTLA-4was significantly up-regulated on CD4+Teff in non-responders after 2 and 4 doses of nivolumab. Interpretation: Azacitidine- nivolumabtherapy produced an encouraging response rate and overall survival in patients with R/R-AML, particularly in HMA-naive and Salvage-1 patients. Pretherapy bone marrow aspirateand peripheral blood CD3 percentage may be biomarkers for patient selection.