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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

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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.

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Acknowledgements

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. government.

Funding

This study was supported by the National Cancer Institute of the National Institutes of Health under the NCI-Cancer Therapy Evaluation Program (NCI-CTEP). Amer M Zeidan was supported by a Leukemia and Lymphoma Society Scholar in Clinical Research award. Tae Kon Kim was supported by a Conquer Cancer Foundation of ASCO Career Development Award.

Author information

Authors and Affiliations

  1. Section of Hematology, Department of Internal Medicine, Yale Cancer Center, Yale School of Medicine, Yale University, New Haven, CT, USA

    Jan Philipp Bewersdorf, Rory M. Shallis, Anne Caldwell, Wei Wei, Nikolai A. Podoltsev, Stephanie Halene, Tae Kon Kim & Amer M. Zeidan

  2. Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Jan Philipp Bewersdorf

  3. Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA

    Elad Sharon, Richard F. Little, Richard Piekarz & Steven D. Gore

  4. Division of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN, USA

    Silvia Park, Rahul Ramaswamy & Tae Kon Kim

  5. Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA

    Caroline E. Roe & Jonathan M. Irish

  6. Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA

    Caroline E. Roe, Jonathan M. Irish & Tae Kon Kim

  7. Vanderbilt Center for Immunobiology, Vanderbilt University, Nashville, TN, USA

    Caroline E. Roe, Jonathan M. Irish & Tae Kon Kim

  8. The Division of Hematologic Malignancies and Cellular Therapeutics (HMCT), The University of Kansas Cancer Center, Westwood, KS, USA

    Abdulraheem Yacoub

  9. Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA

    Yazan F. Madanat

  10. Lineberger Cancer Center, University of North Carolina, Chapel Hill, NC, USA

    Joshua F. Zeidner

  11. Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA

    Jessica K. Altman

  12. University of Chicago, Chicago, IL, USA

    Olatoyosi Odenike

  13. Hitchcock Cancer Center, Dartmouth University, Lebanon, NH, USA

    Swaroopa Yerrabothala

  14. University of Utah, Huntsman Cancer Center, Salt Lake City, UT, USA

    Tibor Kovacsovics

  15. 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 M. Zeidan

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  1. Jan Philipp Bewersdorf
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  2. Rory M. Shallis
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  3. Elad Sharon
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  4. Silvia Park
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  5. Rahul Ramaswamy
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  6. Caroline E. Roe
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  7. Jonathan M. Irish
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  8. Anne Caldwell
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  9. Wei Wei
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  10. Abdulraheem Yacoub
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  11. Yazan F. Madanat
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  12. Joshua F. Zeidner
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  13. Jessica K. Altman
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  14. Olatoyosi Odenike
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  15. Swaroopa Yerrabothala
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  16. Tibor Kovacsovics
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  17. Nikolai A. Podoltsev
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  18. Stephanie Halene
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  19. Richard F. Little
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  20. Richard Piekarz
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  21. Steven D. Gore
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  22. Tae Kon Kim
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  23. Amer M. Zeidan
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Contributions

AZ, SG, ES, RL, RP, WW and TKK designed the study. AY, YM, JZ, JA, OO, SY, RMS, TK, NAP, SH, and AMZ treated patients on the clinical trial. SP, RR, CER, JMI, and TKK performed correlative experiments. JPB, AC, WW, TKK, and AMZ analyzed data and wrote the initial draft of the manuscript. All authors reviewed and contributed to subsequent drafts of the manuscripts. All authors approved the final version of the manuscript.

Corresponding authors

Correspondence to Jan Philipp Bewersdorf, Tae Kon Kim or Amer M. Zeidan.

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Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki. The study protocol was approved by the Ethics Committees at all participating sites.

Conflict of interest

RMS received honoraria from BMS and Gilead. AY had an advisory role for Incyte, CTI Pharma, Pharmaessentia, Pfizer, Novartis, ACCELERON PHARMA, Servier, AbbVie, Apellis, Gilead, Notable Labs, and Celgene. JFZ received research funding from AbbVie, Gilead, Arog, Astex, Jazz, Merck, Stemline, Sumitomo Dainippon Pharma, Syndax, and Takeda and had a consultancy/received honoraria from AbbVie, BMS, Genentech, Gilead, Immunogen, Servier, and Shattuck Labs. JKA was a member of Data Monitoring Committee for GlycoMimetics and a had consulting or Advisory Role for AbbVie, Astellas Pharma, BioSight, Bluebird Bio, Curio, Daiichi Sankyo, Gilead, Kura Oncology, Kymera, MDEducation, Rigel, Stemline Therapeutics, and Syros. JKA received research funding (all to institution) from AbbVie, Agios, ALX Oncology, Amgen, Amphivena, Aprea AB, Aptose Biosciences, Astellas, Pharma, BioSight, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Cyclacel, Fujifilm, Immunogen, Kartos Therapeutics, Kura Oncology, Loxo, and Pfizer. YFM has received honoraria/consulting fees from Kura Oncology, BluePrint Medicines, GERON, OncLive, and MD Education. YFM participated in advisory boards and received honoraria from Sierra Oncology, Stemline Therapeutics, Blueprint Medicines, Morphosys, Taiho Oncology, Rigel Pharmaceuticals, and Novartis. YFM received travel reimbursement from Blueprint Medicines, MD Education, and Morphosys. NAP received consulting fees from Pfizer, Agios Pharmaceuticals, Blueprint Medicines, Incyte, Novartis, Celgene/Bristol-Myers Squibb, CTI BioPharma, PharmaEssentia, Constellation Pharmaceuticals, and AbbVie; other financial support for serving on an Independent Data Review Committee for Cogent Biosciences. OO had a consultancy with Abbvie; Impact Biomedicines; Celgene; Novartis; BMS; Taiho Pharmaceutical; CTI; Threadwell therapeutics; and Bristol-Myers Squibb/Celgene and received research funding (all to the institution) from Celgene, Incyte, Astex Pharmaceuticals, NS Pharma, Abbvie, Janssen Oncology, OncoTherapy Science, Agios, AstraZeneca, CTI BioPharma Corp, Kartos Therapeutics, Aprea AB. SH had a consultancy with Forma Therapeutics. TKK received research funding from Nextcure and had a consultancy with Agenus. AMZ participated in advisory boards, and/or had a consultancy with and received honoraria from AbbVie, Pfizer, Celgene/BMS, Jazz, Incyte, Agios, Servier, Boehringer-Ingelheim, Novartis, Astellas, Daiichi Sankyo, Geron, Taiho, Seattle Genetics, Otsuka, BeyondSpring, Takeda, Ionis, Amgen, Janssen, Genentech, Epizyme, Syndax, Gilead, Kura, Chiesi, ALX Oncology, BioCryst, Notable, Orum, Mendus, Zentalis, Schrodinger, Regeneron, Syros, and Tyme. None of these relationships was related to the content of this manuscript. All other authors report no relevant conflicts of interest.

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Informed consent was obtained from all individual participants included in the study.

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Tae Kon Kim and Amer M. Zeidan are co-senior and co-corresponding authors.

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Bewersdorf, J.P., Shallis, R.M., Sharon, E. 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 103, 105–116 (2024). https://doi.org/10.1007/s00277-023-05552-4

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