A multicenter phase Ib trial of the histone deacetylase inhibitor entinostat in combination with pembrolizumab in patients with myelodysplastic syndromes/neoplasms or acute myeloid leukemia refractory to hypomethylating agents (1).
This study was an investigator-initiated, multicenter phase Ib trial investigating the combination of entinostat, a histone deacetylase inhibitor (HDACi), and pembrolizumab, an anti-PD1 antibody, in patients with myelodysplastic syndromes/neoplasms (MDS) or acute myeloid leukemia (AML) refractory to hypomethylating agents. The study's population consisted of patients suffering from MDS or AML who had previously failed to respond to hypomethylating agents. The intervention under investigation was a combination therapy of entinostat and pembrolizumab. The study followed a 3 + 3 dose escalation design, with entinostat administered orally on days 1 and 15, and pembrolizumab administered intravenously on day 1 of a 21-day cycle.
A total of 28 patients were enrolled in the trial, comprising 25 MDS and 3 AML patients. During the dose escalation phase involving 13 patients, dose-limiting toxicities (DLTs) were observed, including one case of grade 5 pneumonia/bronchoalveolar hemorrhage and two cases of grade 3 pharyngeal mucositis and anorexia. The study proceeded with dose level 1 for expansion, enrolling an additional 15 patients. Hematologic adverse events were commonly observed, alongside significant non-hematologic adverse events such as infection, hypoxia/respiratory failure, and dyspnea.
The results of the study indicated limited clinical efficacy of the combination therapy in this patient population. No protocol-defined responses were observed among the 28 enrolled patients, although two patients achieved marrow complete remission (mCR). A systems immunology approach employing mass cytometry and machine learning analysis revealed that patients with mCR had an increase in classical monocytes and macrophages, but there was no significant change in myeloid-derived suppressor cells (MDSCs).
The clinical significance of these findings lies in the limited efficacy and substantial toxicity associated with the combination of entinostat and pembrolizumab in patients with advanced MDS and AML. The absence of an effect on MDSCs might contribute to the explanation of the limited efficacy of this therapeutic combination. This trial highlights the challenges in developing effective treatments for patients with MDS and AML refractory to hypomethylating agents and underscores the need for continued research in this area.
Bewersdorf JP, Shallis RM, Sharon E, Park S, Ramaswamy R, Roe CE, et al. A multicenter phase Ib trial of the histone deacetylase inhibitor entinostat in combination with pembrolizumab in patients with myelodysplastic syndromes/neoplasms or acute myeloid leukemia refractory to hypomethylating agents. Ann Hematol. 2024;103(1):105-16.