Phase I Study of Suberoylanilide Hydroxamic Acid (SAHA) and Decitabine in Patients with Relapsed, Refractory or Poor Prognosis Leukemia.

Few effective treatment strategies are available for patients with relapsed and refractory leukemias and their prognosis remains poor. Epigenetic therapy by targeting epigenetic pathways is currently under investigation as a potential strategy to reverse transcriptional silencing of tumor suppressor genes leading to the reversal of the neoplastic phenotype. 5-Aza-2′-deoxycytidine (DAC, Decitabine) and suberoylanilide hydroxamic acid (SAHA, Vorinostat) can affect epigenetic change in leukemic cells through promoter CpG island hypomethylation and inhibition of histone deacetylation, respectively. We have conducted a phase I study of combination of DAC plus SAHA (using a sequential dosing schedule) in patients with relapsed, refractory, or high risk leukemias. Five cohorts (Dose levels 0 – 4) of 6 patients each received escalating doses of decitabine (10, 10, 15, 20 and 25 mg/m² IV daily x 5) followed by SAHA (100 mg PO tid x 14 in the first cohort and 200 mg PO tid x 14 in all subsequent cohorts). From 7/06 to 8/07, 31 patients (21 M, 10 F) have been accrued with the last cohort receiving DAC 25 mg/m² daily x 5 followed by SAHA 200 mg tid x 14. Median age was 62 years (range, 22 – 82). Twenty one patients (68%) had refractory AML (5 with prior MDS), 1 (3%) refractory acute biphenotypic leukemia, 3 (10%) relapsed MDS, 3 (10%) refractory ALL, 1 (3%) untreated high risk MDS, and 2 (6%) Philadelphia chromosome-negative myeloproliferative disease. Median number of prior regimens was 2 (range, 0 – 8). One patient did not receive therapy due to rapid disease progression and 30 were evaluable for assessment of toxicity. Median number of cycles of DAC + SAHA administered was 2 (range, 0 – 6). One patient had pulmonary embolism and one grade 3 diarrhea, both considered to be dose limiting. Other adverse events included syncope, neutropenic fever, diarrhea, fatigue, renal failure, rash, nausea, thrombosis, and angioedema. Of the 30 evaluable pts, 1 patient achieved complete remission lasting 5.5 weeks, 4 had significant reductions in the bone marrow blasts, 4 had stable disease, 7 are too early for response evaluation, and 14 had no response/disease progression. We conclude that the sequential combination of DAC and SAHA is safe and has activity in advanced leukemia. Correlative studies evaluating DNA promoter methylation and histone acetylation will be presented.