Ipilimumab plus decitabine for patients with MDS or AML in posttransplant or transplant-naïve settings

Recurrence of acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) after transplant has exceedingly poor outcome. In a prior study at our center, single agent CTLA-4 checkpoint inhibitor (ipilimumab) generated remissions in cases of AML with low disease burden at relapse with induction of graft-versus-host disease. We asked if we could augment the rate of remission with combination decitabine plus ipilimumab in patients regardless of disease burden and if the alloreactive environment generated after transplant was required for response. In the context of a phase 1 multi-site clinical trial supported by the NCI/ETCTN, we enrolled and treated 48 patients with decitabine/ipilimumab in cohorts separated by transplantation status to assess for safety and preliminary efficacy. We also collected blood/bone marrow from each patient at the same time points before, on-therapy and at time of relapse when relevant to study the local and systemic tumor immune infiltrates. We discovered that immune-related adverse events were frequent and manageable in most patients, the recommended phase 2 dose was the same regardless of transplant status, and we identified responders in both cohorts. Multiplex immunofluorescence (MIF) analyses of paired sequential bone marrows revealed increases in CD4+ T cells after ipilimumab, but we did not consistently observe increases in activated CD8+ T cells among responders. Immune monitoring using Cytof revealed increases in T regulatory cells after ipilimumab but no correlation with response. Transcriptome-based analyses and MIF revealed differences in AML patients with leukemia cutis (skin) compared to those with marrow involvement, including infiltration of memory T cells and higher expression of CTLA-4 and FOXP3. Altogether, detailed immune and molecular correlatives identified potential mechanisms of response and resistance to combination therapy in advanced MDS/AML patients.