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
- PMID: 38036712
- DOI: 10.1007/s00277-023-05552-4
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.
© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Similar articles
-
Addition of histone deacetylase inhibitors does not improve prognosis in patients with myelodysplastic syndrome and acute myeloid leukemia compared with hypomethylating agents alone: A systematic review and meta-analysis of seven prospective cohort studies.Leuk Res. 2018 Aug;71:13-24. doi: 10.1016/j.leukres.2018.06.007. Epub 2018 Jun 9. Leuk Res. 2018. PMID: 29936305
-
Results of phase 2 randomized study of low-dose decitabine with or without valproic acid in patients with myelodysplastic syndrome and acute myelogenous leukemia.Cancer. 2015 Feb 15;121(4):556-61. doi: 10.1002/cncr.29085. Epub 2014 Oct 21. Cancer. 2015. PMID: 25336333 Free PMC article. Clinical Trial.
-
Epigenetic priming with decitabine followed by low dose idarubicin and cytarabine in acute myeloid leukemia evolving from myelodysplastic syndromes and higher-risk myelodysplastic syndromes: a prospective multicenter single-arm trial.Hematol Oncol. 2020 Oct;38(4):531-540. doi: 10.1002/hon.2755. Epub 2020 Jun 24. Hematol Oncol. 2020. PMID: 32469434
-
Lost in translation? Ten years of development of histone deacetylase inhibitors in acute myeloid leukemia and myelodysplastic syndromes.Expert Opin Investig Drugs. 2016;25(3):307-17. doi: 10.1517/13543784.2016.1146251. Expert Opin Investig Drugs. 2016. PMID: 26807602 Review.
-
Histone deacetylase inhibitors for the treatment of myelodysplastic syndrome and acute myeloid leukemia.Leukemia. 2011 Feb;25(2):226-35. doi: 10.1038/leu.2010.276. Epub 2010 Nov 30. Leukemia. 2011. PMID: 21116282 Review.
References
-
- Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, Schoch R, Gattermann N, Sanz G, List A, Gore SD, Seymour JF, Bennett JM, Byrd J, Backstrom J, Zimmerman L, McKenzie D, Beach C, Silverman LR, International Vidaza High-Risk MDSSSG (2009) Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol 10(3):223–232. https://doi.org/10.1016/S1470-2045(09)70003-8 - DOI - PubMed - PMC
-
- Zeidan AM, Stahl M, Hu X, Wang R, Huntington SF, Podoltsev NA, Gore SD, Ma X, Davidoff AJ (2018) Long-term survival of older patients with MDS treated with HMA therapy without subsequent stem cell transplantation. Blood 131(7):818–821. https://doi.org/10.1182/blood-2017-10-811729 - DOI - PubMed - PMC
-
- Sekeres MA, Othus M, List AF, Odenike O, Stone RM, Gore SD, Litzow MR, Buckstein R, Fang M, Roulston D, Bloomfield CD, Moseley A, Nazha A, Zhang Y, Velasco MR, Gaur R, Atallah E, Attar EC, Cook EK et al (2017) Randomized phase II study of azacitidine alone or in combination with lenalidomide or with vorinostat in higher-risk myelodysplastic syndromes and chronic myelomonocytic leukemia: North American Intergroup Study SWOG S1117. J Clin Oncol 35(24):2745–2753. https://doi.org/10.1200/JCO.2015.66.2510 - DOI - PubMed - PMC
-
- Prébet T, Gore SD, Esterni B, Gardin C, Itzykson R, Thepot S, Dreyfus F, Rauzy OB, Recher C, Adès L, Quesnel B, Beach CL, Fenaux P, Vey N (2011) Outcome of high-risk myelodysplastic syndrome after azacitidine treatment failure. J Clin Oncol 29(24):3322–3327. https://doi.org/10.1200/jco.2011.35.8135 - DOI - PubMed - PMC
-
- Nazha A, Sekeres MA, Komrokji R, Steensma DP, Kantarjian H, Roboz G, Fenaux P, Prebet T, Azarnia N, Zbyszewski PS, Fruchtman SM, Santini V, Silverman LR, Platzbecker U, Garcia-Manero G (2017) Validation of a post-hypomethylating agent failure prognostic model in myelodysplastic syndromes patients treated in a randomized controlled phase III trial of rigosertib vs. best supportive care. Blood Cancer J 7(12):644–644. https://doi.org/10.1038/s41408-017-0018-7 - DOI - PubMed - PMC
Publication types
MeSH terms
Substances
Associated data
LinkOut - more resources
Full Text Sources
Medical
Research Materials
Miscellaneous