Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes
Open Access
- 1 February 2008
- journal article
- Published by American Society of Hematology in Blood
- Vol. 111 (3), 1060-1066
- https://doi.org/10.1182/blood-2007-06-098061
Abstract
Vorinostat (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.Keywords
This publication has 43 references indexed in Scilit:
- Phase 1 and pharmacologic study of MS-275, a histone deacetylase inhibitor, in adults with refractory and relapsed acute leukemiasBlood, 2006
- Phase 1/2 study of the combination of 5-aza-2′-deoxycytidine with valproic acid in patients with leukemiaBlood, 2006
- Thioredoxin in cancer—Role of histone deacetylase inhibitorsSeminars in Cancer Biology, 2006
- Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL)Blood, 2006
- Antileukemia activity of the combination of an anthracycline with a histone deacetylase inhibitorBlood, 2006
- Common markers of proliferationNature Reviews Cancer, 2006
- A Cell Proliferation Signature Is a Marker of Extremely Poor Outcome in a Subpopulation of Breast Cancer PatientsCancer Research, 2005
- Revised Recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid LeukemiaJournal of Clinical Oncology, 2003
- Novel biologically based therapies for Waldenstrom's macroglobulinemiaSeminars in Oncology, 2003
- Gene expression profiling predicts clinical outcome of breast cancerNature, 2002