PD1-positive T-cells are significantly increased in the bone marrow (BM) of patients with relapsed acute myeloid leukemia (AML) when compared with healthy adults. Epigenetic therapy upregulates PD1 and PD-L1 in myelodysplastic syndromes and AML, which may, in turn, be associated with emergence of resistance and poorer survival.
This single-center phase 1b/2 study was conducted to determine the recommended phase 2 dose (RP2D), efficacy, and safety of nivolumab (NIVO) in combination with 5-azacitidine (AZA) in patients with relapsed AML.1
Patients were eligible if they have AML and failed prior therapy, have adequate performance status (ECOG ≤2), and organ function. The first 6 patients received AZA on days 1 to 7 with NIVO on days 1 and 14. Courses were repeated approximately every 4 weeks. One of 6 patients had a dose-limiting toxicity (grade 3 pneumonitis), which established a 3-mg/kg dose as the RP2D. Twenty-two additional patients have been treated at 3 mg/kg.
To date, 28 patients (15 de novo, 13 secondary AML) with a median age of 72 years are enrolled. They include 8 patients with diploid, 14 with adverse, and 6 with miscellaneous cytogenetics. Median number of prior therapies is 2, including hypomethylating agent–based regimens, high- or intermediate-dose cytarabine-based regimens, and targeted therapies. Baseline BM samples from all patients were analyzed for common myeloid mutations by next-generation sequencing. The most frequently detected mutations wereDNMT3A, ASXL1, CEBPA, RAS, and TP53.
Among the 28 patients receiving NIVO + AZA, 6 (21%) achieved complete remission (CR) or CR with incomplete hematologic recovery, 2 (7%) had hematologic improvement (HI) with blast reduction, 3 (11%) had HI only. Five patients had stable disease and 12 progressed. Median number of cycles to any response was 2 (1-8). Grade 2 to 4 immune toxicities were observed in 10 (36%) patients: 8 pneumonitis, 4 nephritis, and 1 skin rash, as well as 1 episode of grade 3 transaminitis. Time to onset of toxicities ranged from 4 days to 3.5 months. All responded to steroids, and 9 of 10 patients were successfully rechallenged with NIVO + AZA. The median progression-free survival and overall survival for 22 evaluable patients, as reported in the abstract, was 3.5 months and 5.9 months, respectively.
Researchers concluded that combination use of NIVO + AZA is effective in patients with relapsed AML. Immune-mediated toxicities occur, but can be adequately managed with early recognition and systemic steroids.
