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-

Decitabine induces hypomethylation and has clinical activity in imatinib refractory chronic myelogenous leukemia. We hypothesize that the inverse correlation between hypomethylation 2 weeks after therapy and response is due to a cell death mechanism of response, whereby resistant cells can withstand more hypomethylation.

BACKGROUND.Resistance to imatinib is a frequent clinical problem in advanced phase chronic myelogenous leukemia (CML). A Phase II study was performed on low‐dose decitabine, a DNA methyltransferase inhibitor, in combination with imatinib in patients with CML in accelerated phase (AP) and myeloid blastic phase (BP).METHODS.Patients received decitabine 15 mg/m2 intravenously daily, 5 days a week for 2 weeks, and imatinib 600 mg orally daily. Global DNA methylation was measured by long interspersed nucleotide element (LINE) bisulfite/pyrosequencing.RESULTS.Twenty‐eight patients were enrolled (25 with imatinib resistance; 18 in AP, 10 in BP). A total of 91 cycles (median, 2.5 cycles per patient) was administered. Complete hematologic responses, partial hematologic responses, and hematologic improvement were observed in 9 (32%), 1 (4%), and 2 (7%) patients. Major and minor cytogenetic responses were observed in 5 (18%) and 3 (11%) patients. The hematologic response rate was higher in patients without BCR‐ABL kinase mutations (10 of 19, 53%) than in those with mutations (1 of 7, 14%). Median duration of hematologic response was 18 (range, 4 to 107+) weeks. Myelosuppression was the major adverse effect, with neutropenic fever in 9 patients (32%). LINE methylation decreased from 71.6% ± 0.9% (mean ± standard error of the mean) to 60.4% ± 2.0% on Day 5, 60.5% ± 1.8% on Day 12, and returned to 68.8% ± 1.4% at peripheral blood recovery. A decrease in LINE methylation tended to be greater in nonresponders than in responders on Days 5 and 12.CONCLUSIONS.Combination therapy with decitabine and imatinib is well tolerated and active in advanced phase CML without BCR‐ABL kinase mutations. Cancer 2007 © 2007 American Cancer Society.

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Cytarabine resistance characterizes relapsed and refractory acute myelogenous leukemia (AML). Restoration of cytarabine sensitivity can potentially improve treatment outcome in this setting. Acquired hypermethylation of gene promoters and associated silencing of gene expression has been implicated in chemo resistance, and drug-induced hypomethylation can improve sensitivity to cytarabine in vitro. We conducted an adaptively randomized study of a combination of azacitidine, a hypomethylating agent, and cytarabine in 34 patients with AML. The combination administered in a concomitant fashion is safe at full doses of azacitidine and cytarabine, without unexpected toxicities. However, in this advanced AML population, it was difficult to deliver more than one cycle of therapy, and minimal anti-leukemia activity was seen in patients with relapsed/refractory disease. Complete remission was achieved in 2 of 6 minimally pre-treated patients. We conclude that the combination of azacitidine and cytarabine is feasible but has limited activity in relapsed/refractory AML.