Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes

Blood - Tập 111 - Trang 1060-1066 - 2008
Guillermo Garcia-Manero1, Hui Yang1, Carlos Bueso-Ramos1, Alessandra Ferrajoli1, Jorge Cortes1, William G. Wierda1, Stefan Faderl1, Charles Koller1, Gail Morris1, Gary Rosner1, Andrey Loboda2, Valeria R. Fantin2, Sophia S. Randolph2, James S. Hardwick2, John F. Reilly2, Cong Chen2, Justin L. Ricker2, J. Paul Secrist2, Victoria M. Richon2, Stanley R. Frankel2
1Departments of Leukemia, Hematopathology, and Biostatistics, University of Texas M. D. Anderson Cancer Center, Houston and
2Merck, Whitehouse Station, NJ

Tóm tắt

AbstractVorinostat (suberoylanilide hydroxamic acid, SAHA) is a histone deacetylase inhibitor active clinically in cutaneous T-cell lymphoma and preclinically in leukemia. A phase 1 study was conducted to evaluate the safety and activity of oral vorinostat 100 to 300 mg twice or thrice daily for 14 days followed by 1-week rest. Patients with relapsed or refractory leukemias or myelodysplastic syndromes (MDS) and untreated patients who were not candidates for chemotherapy were eligible. Of 41 patients, 31 had acute myeloid leukemia (AML), 4 chronic lymphocytic leukemia, 3 MDS, 2 acute lymphoblastic leukemia, and 1 chronic myelocytic leukemia. The maximum tolerated dose (MTD) was 200 mg twice daily or 250 mg thrice daily. Dose-limiting toxicities were fatigue, nausea, vomiting, and diarrhea. Common drug-related adverse experiences were diarrhea, nausea, fatigue, and anorexia and were mild/moderate in severity. Grade 3/4 drug–related adverse experiences included fatigue (27%), thrombocytopenia (12%), and diarrhea (10%). There were no drug-related deaths; 7 patients had hematologic improvement response, including 2 complete responses and 2 complete responses with incomplete blood count recovery (all with AML treated at/below MTD). Increased histone acetylation was observed at all doses. Antioxidant gene expression may confer vorinostat resistance. Further evaluation of vorinostat in AML/MDS is warranted.

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