5-azacytidine(5- AC), all-trans retinoic acid (ATRA), and valproic acid (VPA) in patients with acute myelogenous leukemia (AML): Molecular and clinical implications

B48 Background: The combination of a hypomethylating agent with a histone deacetylase inhibitor (HDACI) has synergistic activity. The combination of ATRA with either a hypomethylating agent or a HDACI restores ATRA sensitivity in resistant cells. The combination of VPA and ATRA has activity in patients with AML. Based on this, we developed a phase I/II study of the combination of 5-AC, VPA and ATRA for patients with AML.Methods: The dose of 5-AC was fixed: 75 mg/m 2 sq daily x 7. ATRA dose was: 45 mg/m 2 orally daily x 5 starting on day 3. Three dose levels of VPA were studied: 50, 62.5 and 75 mg/kg orally daily x 7. The phase I portion of the study followed a 3+3 design. Phase II was single arm with stopping rules. Patients with relapsed/refractory AML and patients older than 60 years with untreated disease and adequate renal, hepatic functions and performance status were eligible.Results: Thirty one patients were registered and 27 were evaluable. Median age was 60 years (5-78). Median number of prior therapies was 2 (0-5). Twenty three patients (85%) had abnormal cytogenetics. At a VPA dose of 50 mg/kg, 1 of 6 patients developed grade 3 non-hematological toxicity; at 62.5 mg/kg, 2 of 7, and at 75 mg/kg, 3 of 6. The dose limiting toxicity was neurotoxicity including confusion and somnolence. Six patient had a CR (ANC 10 9 /L, plat 100 x 10 9 /L, and a bone marrow with 5% or less blasts), 2 patients had a CRP (same criteria as of CR but without complete platelet recovery), and 1 a complete marrow response (marrow blasts