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

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 im-

A phase II multiple dose clinical trial of histone deacetylase inhibitor ITF2357 in patients with relapsed or progressive multiple myeloma

“…Phase I-II clinical trials are underway or have been recently performed with SAHA in patients with advanced hematological malignancies, including MM [6][7][8][9][10][11][12][13]. Overall, these studies showed that SAHA was tolerable, although its toxicity profile was not negligible.…”

“…One class of HDACIs is the hydroxamate derivatives family of compounds whose prototype is suberoyl anilide hydroxamic acid (SAHA) [5], which is being tested clinically in several hematological malignancies and has obtained FDA approval for the treatment of cutaneous T-cell lymphoma [6][7][8][9][10][11][12][13][14][15]. Our group has recently reported that ITF2357, an orally effective member of the family of hydroxamate-derived HDACIs, is a potent inducer of apoptosis and death of MM cells in vitro [16].…”

miR-449a targets HDAC-1 and induces growth arrest in prostate cancer

“…Let-7 family members also target HMGA2, an oncogene known for its involvement in promoting the epithelial-mesenchymal transition (EMT) (Shell et al, 2007). miR-15 and miR-16 promote apoptosis by suppressing expression of the antiapoptotic Bcl-2 protein and are commonly deleted in chronic lymphocytic leukemia (CLL), which leads to high levels of Bcl-2 expression (a prognostic indicator in CLL) (Volinia et al, 2006;Garcia-Manero et al, 2008). miR34a has been shown in multiple studies to be regulated by the frequently mutated/deleted gatekeeper gene, p53.…”

Epigenetic aspects of MDS and its molecular targeted therapy

“…The inhibition of histone-modifying enzymes will be another potential epigenetic target for MDS therapy. There are HDIs currently in clinical trials; however, less data is available for their use in MDS, though anecdotal responses have been reported [75]. Recently, it has also been reported that DNA methylation per se is not a permanent lock for silencing gene expression, but rather a combination of DNA methylation inhibitors with other drugs (such as HDIs) can be used to reactivate gene expression [76,77].…”