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

Abstract

Two articles in this week’s issue focus on the use of ipilimumab and decitabine for patients with myelodysplasia (MDS) and acute myeloid leukemia (AML) before and after hematopoietic stem cell transplantation (HSCT) for high-risk disease. In the first article, Garcia et al report on the results of a phase 1 trial of the combination in 54 patients, demonstrating overall response rate of 52% in patients who are HSCT-naïve and 20% in patients post-HSCT; responses are usually short-lived. In the second article, Penter and colleagues characterize gene expression responses to therapy and conclude that decitabine acts directly to clear leukemic cells while ipilimumab acts on infiltrating lymphocytes in marrow and extramedullary sites. Responses are determined by leukemic cell burden and by the frequency and phenotype of infiltrating lymphocytes. Increasing bone marrow regulatory T cells is identified as a potential contributor to checkpoint inhibitor escape.

Phase II trial of hypomethylating agent combined with nivolumab for acute myeloid leukaemia relapse after allogeneic haematopoietic cell transplantation—Immune signature correlates with response

“…27 Decitabine combined with ipilimumab resulted in a CR/CRi in 5/25 (20%) patients with post-allo-HCT relapse. 53 Our data align with the literature and demonstrate that long-lasting responses to PD-1 blockade, even in combination with HMA and DLI, are seen primarily in individual patients. We propose that HMA/ nivolumab can be applied as a "bridging" approach to the subsequent treatment, such as a second allo-HCT.…”

“…In comparison, CTLA‐4 blockade with ipilimumab induced a CR in 5/12 (42%) patients with myelodysplastic syndrome/AML 27 . Decitabine combined with ipilimumab resulted in a CR/CRi in 5/25 (20%) patients with post‐allo‐HCT relapse 53 . Our data align with the literature and demonstrate that long‐lasting responses to PD‐1 blockade, even in combination with HMA and DLI, are seen primarily in individual patients.…”

Mechanisms of response and resistance to combined decitabine and ipilimumab for advanced myeloid disease

“…Overall, response rates (defined as CR/CRi at any timepoint during the study) were 20% (5 of 25, arm A) vs 52% (12 of 23, arm B). 10 Longitudinal sampling of peripheral blood and bone marrow was obtained at study entry ('Screening'), following decitabine priming (end of lead-in, ~day 30), after introduction of ipilimumab (Cycle 1, ~day 60) and at pre-defined later timepoints including at the end of treatment ('EOT', day 48 -531).…”

“…Based on this concept, we recently reported the clinical results of the phase I ETCTN/CTEP 10026 study, which tested combined decitabine with ipilimumab both in relapsed AML following HSCT (Arm A) and in transplant-naïve AML/MDS (Arm B). 9,10 Arm A was motivated by clinical responses in extramedullary AML post-HSCT treated with ipilimumab monotherapy (ETCTN/CTEP 9204). 5,11 The objective response rates of ETCTN/CTEP 10026 revealed 5 of 25 (Arm A) and 12 of 23 (Arm B) patients achieving CR/CRi.…”

Novel immune directed therapies in myelodysplastic syndromes and acute myeloid leukemia

“…First, there appear to be a sizeable minority of patients who will experience excess toxicity during therapy, such as the development of pneumonitis, and there is a signal for early mortality with atezolizumab and azacitidine [39]. Several studies explored combinations of pembrolizumab, nivolumab, or ipilimumab with DNTMI, although again it was not clear that there was advantage over azacitidine monotherapy [35,[40][41][42][43]. Indeed, a randomized phase II study of azacitidine with or without the PD-L1 inhibitor durvalumab showed no difference in activity between the two arms [44].…”