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

Abstract

Patients with myelodysplastic syndromes/neoplasms (MDS) or acute myeloid leukemia (AML) with hypomethylating agent failure have a poor prognosis. Myeloid-derived suppressor cells (MDSCs) can contribute to MDS progression and mediate resistance to anti-PD1 therapy. As histone deacetylase inhibitors (HDACi) decrease MDSCs in preclinical models, we conducted an investigator-initiated, NCI-Cancer Therapy Evaluation Program-sponsored, multicenter, dose escalation, and expansion phase Ib trial (NCT02936752) of the HDACi entinostat and the anti-PD1 antibody pembrolizumab. Twenty-eight patients (25 MDS and 3 AML) were enrolled. During dose escalation (n=13 patients), there was one dose-limiting toxicity (DLT) on dose level (DL) 1 (G5 pneumonia/bronchoalveolar hemorrhage) and two DLTs at DL 2 (G3 pharyngeal mucositis and G3 anorexia). Per the 3 + 3 dose escalation design, DL 1 (entinostat 8 mg PO days 1 and 15 + pembrolizumab 200 mg IV day 1 every 21 days) was expanded and another 15 patients were enrolled. Hematologic adverse events (AEs) were common. The most common non-hematologic ≥G3 AEs were infection (32%), hypoxia/respiratory failure (11%), and dyspnea (11%). There were no protocol-defined responses among the 28 patients enrolled. Two patients achieved a marrow complete remission (mCR). Using a systems immunology approach with mass cytometry and machine learning analysis, mCR patients had increased classical monocytes and macrophages but there was no significant change of MDSCs. In conclusion, combining entinostat with pembrolizumab in patients with advanced MDS and AML was associated with limited clinical efficacy and substantial toxicity. Absence of an effect on MDSCs could be a potential explanation for the limited efficacy of this combination. ClinicalTrial.gov Identifier: NCT02936752.

Keywords: AML; Entinostat; MDS; Myeloid-derived suppressor cells; Pembrolizumab.

Figure 1.

Mass cytometric analysis reveals changes in the bone marrow of patients over the course of treatment with entinostat and pembrolizumab. A.T-REX (Tracking Responders Expanding) analysis of all cells from six patients is shown. A central UMAP dimensionality reduction plot, performed only using cell surface markers, shaded by T-REX change depicts phenotypically similar cells in regions of great expansion (dark red, ≥95% from EOC3) or great contraction (dark blue, ≥95% from pre-) over time following treatment with entinostat and pembrolizumab. Red or blue population interpretations are shown for major expanding or contracting populations identified by T-REX. Boxes indicate clusters of similar cells identified by T-REX, with marker enrichment modelling (MEM) labels inside each box providing a phenotypic description of these clusters. All measured features were included in MEM labels, which only show features enriched by at least +4 or more on a scale from 0 to 10. A traditional immune cell identity is assigned by an expert to each cluster or group of clusters (large text above boxes). B. Individual dimensionality reduction (UMAP) plots compare the global bone marrow signature before and at the end of cycle three of therapy. mCR: marrow complete remission, SD: stable disease, PD: progression of disease

Figure 2.

Changes in abundance of biaxially gated MDSC subsets in patient bone marrow over the course of treatment with entinostat and pembrolizumab. MDSC subsets are defined as lineage negative/CD11b+/HLA-DR^low/CD66b+ (granulocytic MDSCs) or lineage negative/CD11b+/HLA-DR^low/CD14+ (monocytic MDSCs). MDSCs were generally stable over the course of therapy, with generally modest decreases of the granulocytic phenotype. Two patients, patient 3 and patient 6, had marked increases in monocytic MDSCs in their bone marrow over the course of treatment. Changes in abundance major immune lineages in patient bone marrow over the course of treatment with entinostat and pembrolizumab. A general decrease in detection of T and NK cells is observed, especially CXCR5+ T follicular helper cells (Tfh).