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.

Autor: Bewersdorf JP; Section of Hematology, Department of Internal Medicine, Yale Cancer Center, Yale School of Medicine, Yale University, New Haven, CT, USA. jan.bewersdorf@yale.edu.; Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. jan.bewersdorf@yale.edu., Shallis RM; Section of Hematology, Department of Internal Medicine, Yale Cancer Center, Yale School of Medicine, Yale University, New Haven, CT, USA., Sharon E; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA., Park S; Division of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN, USA., Ramaswamy R; Division of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN, USA., Roe CE; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA.; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.; Vanderbilt Center for Immunobiology, Vanderbilt University, Nashville, TN, USA., Irish JM; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA.; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.; Vanderbilt Center for Immunobiology, Vanderbilt University, Nashville, TN, USA., Caldwell A; Section of Hematology, Department of Internal Medicine, Yale Cancer Center, Yale School of Medicine, Yale University, New Haven, CT, USA., Wei W; Section of Hematology, Department of Internal Medicine, Yale Cancer Center, Yale School of Medicine, Yale University, New Haven, CT, USA., Yacoub A; The Division of Hematologic Malignancies and Cellular Therapeutics (HMCT), The University of Kansas Cancer Center, Westwood, KS, USA., Madanat YF; Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA., Zeidner JF; Lineberger Cancer Center, University of North Carolina, Chapel Hill, NC, USA., Altman JK; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA., Odenike O; University of Chicago, Chicago, IL, USA., Yerrabothala S; Hitchcock Cancer Center, Dartmouth University, Lebanon, NH, USA., Kovacsovics T; University of Utah, Huntsman Cancer Center, Salt Lake City, UT, USA., Podoltsev NA; Section of Hematology, Department of Internal Medicine, Yale Cancer Center, Yale School of Medicine, Yale University, New Haven, CT, USA., Halene S; Section of Hematology, Department of Internal Medicine, Yale Cancer Center, Yale School of Medicine, Yale University, New Haven, CT, USA., Little RF; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA., Piekarz R; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA., Gore SD; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA., Kim TK; Section of Hematology, Department of Internal Medicine, Yale Cancer Center, Yale School of Medicine, Yale University, New Haven, CT, USA. tae.k.kim@vumc.org.; Division of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN, USA. tae.k.kim@vumc.org.; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA. tae.k.kim@vumc.org.; Vanderbilt Center for Immunobiology, Vanderbilt University, Nashville, TN, USA. tae.k.kim@vumc.org., Zeidan AM; Section of Hematology, Department of Internal Medicine, Yale Cancer Center, Yale School of Medicine, Yale University, New Haven, CT, USA. amer.zeidan@yale.edu.; Hematology Section, Department of Internal Medicine, Yale School of Medicine, Yale University, 333 Cedar Street, PO Box 208028, New Haven, CT, 06520-8028, USA. amer.zeidan@yale.edu.
Jazyk: angličtina
Zdroj: Annals of hematology [Ann Hematol] 2024 Jan; Vol. 103 (1), pp. 105-116. Date of Electronic Publication: 2023 Dec 01.
DOI: 10.1007/s00277-023-05552-4
Abstrakt: 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.
(© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Databáze: MEDLINE
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