Prior research suggests that blocking PD-1/PD-L1 pathways may enhance antileukemic responses in patients with acute myeloid leukemia (AML). Because azacytidine upregulates PD-1 in AML, the combination of a PD-1 inhibitor with azacytidine is a rational choice for investigation. In this study, azacytidine 75 mg/m2 on days 1 to 7, with nivolumab 3 mg/kg on days 1 and 14, was established as the recommended phase 2 dose. Courses were repeated every 4 to 5 weeks indefinitely, and responses were evaluated at the end of 3 courses. In this single-arm study, results were compared against a historical cohort of patients receiving hypomethylator combination salvage treatment.
To date, 70 patients have been enrolled; baseline characteristics were median age of 70 years, median of 2 prior regimens, and secondary AML and poor-risk cytogenetics, in 43% and 34% of enrolled patients, respectively. Common mutations included TP53 (n = 16), DNMT3A (n = 12), TET2 (n = 11), and ASXL1 (n = 11). The overall response rate was 32%, including 15 (21%) patients who achieved complete remission (CR) or CR with incomplete blood count recovery (CRi) and 7 (14%) with hematologic improvement. In addition, 17 (24%) patients had ≥50% bone marrow blast reduction, and 26 (37%) had stable disease after 6 months or progressive disease. Median overall survival for evaluable patients was 6.2 months in patients receiving azacytidine and nivolumab versus 4.1 months for patients receiving historical hypomethylator combination salvage protocols. Immune toxicities occurred in 18 patients; all responded rapidly to steroids, and 16 of 18 patients were successfully rechallenged.
Patients who achieved CR/CRi had higher pretherapy total CD3 and CD8+ T-cell levels in the bone marrow. Responders also demonstrated progressive increase in CD8+ and CD4+ infiltrate in the bone marrow. However, both responders and nonresponders had increases in CTLA-4+ CD8+ cells on therapy. The researchers concluded that full-dose azacytidine and nivolumab are tolerable and appears to produce durable responses in first salvage AML. CTLA-4 was upregulated on therapy, suggesting potential for dual checkpoint blockade.
Daver NG, et al. ASCO Abstract 7026.