CTEP 10026, a multicenter, investigator-initiated phase 1 study, assessed the safety and clinical activity of the hypomethylating agent (HMA) decitabine (DAC) plus the checkpoint inhibitor ipilimumab (IPI) in patients with relapsed/refractory (R/R) myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML), with prior allogeneic hematopoietic stem-cell transplantation (allo-HSCT; arm A) and without prior allo-HSCT (arm B).
Patients were aged ≥18 years with R/R MDS (≥5% blasts), R/R AML, or untreated secondary AML. Prior HMA was initially permitted; however, the protocol was amended to exclude those with disease progression on HMA therapy within 12 weeks of study entry. Patients in arm A (post–allo-HSCT) were required to be >3 months post–donor-cell infusion, without prior acute graft-versus-host disease (GVHD) grade ≥3, be >2 weeks off immunosuppressive therapy, and have donor T-cell chimerism ≥20%. Patients received treatment in 28-day cycles with a lead-in single-agent DAC (cycle 0) followed by combination DAC + IPI for up to 1 year. DAC infusion was given at 20 mg/m2 on days 1 to 5, and IPI infusion was given at 3 mg/kg (dose level [DL]0), 5 mg/kg (DL1) or 10 mg/kg (DL2) on day 1 of cycles 1 to 4, 5, 7, 9 and 11. Dose-limiting toxicity was defined as grade ≥3 nonhematologic adverse event (AE), acute GVHD, and steroid-refractory, immune-related AE within 8 weeks of the initial IPI dose.
At the time of data cutoff, 37 of 47 (79%) patients received ≥1 doses of DAC + IPI. The median age for arm A was 67 years (range, 29-79) versus 75 years (range, 34-85) for arm B. Of the 37 patients, 36 had AML and 11 had MDS. The median number of prior regimens was 3 (range, 0-5) for arm A and 1 (range, 0-3) for arm B. In arms A and B, 17 and 14 patients had received prior HMA therapy, respectively. Next-generation sequencing revealed mutations most commonly in ASXL1 (n = 8); RUNX1 (n = 6), STAG2 and NRAS (n = 5 each); DNMT3A and TP53 (n = 4 each).
In arm A, 25 patients received DAC + IPI (7 at DL0, 3 at DL1, and 6 at DL2). The most common grade 3/4 nonhematologic AEs were aspartate aminotransferase elevation (n = 3), gamma-glutamyl transpeptidase elevation (n = 1), and respiratory failure (n = 1). There were 2 grade 5 nonhematologic AEs, stroke (n = 1) and sepsis (n = 1). Eight patients experienced immune-related AEs. Most immune-related AEs were reversible with steroids. Four patients achieved responses (3 with complete response [CR] and 1 with marrow CR). Two of the responders had immune-related AEs. The median time to response was 1.7 months.
In arm B, 22 patients received DAC + IPI. The most common nonhematologic grade 3/4 AEs were fatigue, lung infection, and dyspnea (n = 4 each); hyperglycemia, muscle weakness, and hypertension (n = 3 each); acute kidney injury, hyponatremia, hypoxia, and creatinine increase (n = 2 each); as well as respiratory failure (n = 1). Six patients experienced grade ≥2 immune-related AEs. Objective responses were detected in 9 patients (4 CR, 2 CR with incomplete hematologic recovery [CRi], and 3 marrow CR). Two responders had immune-related AEs. The median time to response was 3.9 months. In conclusion, patients with R/R or secondary MDS/AML treated with DAC + IPI exhibited encouraging clinical activity, with AE profiles as expected. Consistent with IPI 10 mg/kg for melanoma, the rate of immune-related toxicity was common. A high degree of clinical activity was observed in patients who did not receive allo-HSCT, indicating that an alloreactive environment may not be required for patients to benefit from blockade of cytotoxic T-lymphocyte-associated protein-4.
Reference
Garcia JS, Flamand Y, Tomlinson BK, et al. Safety and Efficacy of Decitabine plus Ipilimumab in Relapsed or Refractory MDS/AML in the Post-BMT or Transplant Naïve Settings. Presented at: 62nd American Society of Hematology Annual Meeting & Exposition, December 5-8, 2020. Abstract 170.