| Autor: |
Bewersdorf, Jan Philipp, Shallis, Rory M., Sharon, Elad, Park, Silvia, Ramaswamy, Rahul, Roe, Caroline E., Irish, Jonathan M., Caldwell, Anne, Wei, Wei, Yacoub, Abdulraheem, Madanat, Yazan F., Zeidner, Joshua F., Altman, Jessica K., Odenike, Olatoyosi, Yerrabothala, Swaroopa, Kovacsovics, Tibor, Podoltsev, Nikolai A., Halene, Stephanie, Little, Richard F., Piekarz, Richard |
| Předmět: |
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| Zdroj: |
Annals of Hematology; Jan2024, Vol. 103 Issue 1, p105-116, 12p |
| 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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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