Results of a phase I/II study of the combination of 5-aza-2’-deoxycytidine and valproic acid in patients with acute myeloid leukemia and myelodysplastic syndrome

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Abstract
6544 Background: The combination of the hypomethylating agent DAC and the histone deacetylase inhibitor VPA has synergistic in vitro antileukemia activity. Methods: In the phase I, a fixed dose of DAC (15 mg/m2 IV qd x 10) was combined with VPA at 3 doses levels: 20, 35, and 50 mg/kg po x 10 days concomitant with DAC. The phase II had a target response rate of 30%. The study is to stop if 0/10, ≤ 3/20 and ≤ 5/30 patients (pts) respond. Results: 51 pts have been registered in this study: median age 59 years (range 4–80), 47 AML, 4 MDS, median number of prior therapies 2 (range 0–5). 22 pts were treated during the phase I of the study: 1 of 10 patients at a VPA dose of 50 mg/kg developed grade III neurotoxicity, and 5 out of 10 grade II. Neurotoxicity was transient and associated with the use of other neurotropic agents. No other grade III/IV non-hematological toxicities have been observed. Subsequently, VPA 50 mg/kg po daily x 10 days was combined with DAC at the above dose concomitantly for the phase II portion of the study. 40 pts are evaluable for response in both phases of the study. In total, 8 pts achieved CR and 1 CRp (RR 22%), the median number of courses for response were 2 (range 1–3). At a dose level of 20 mg/kg of VPA, 1 of 3 pts achieved CR (maintained for 7+ months). At a dose level of 35 mg/kg, 1 of 9 pts achieved a CR (maintained for 6+ months). Both pts also achieved a complete cytogenetic response. At a dose level of 50 mg /kg, 6 out 28 pts (evaluable for the phase II portion) have achieved CR and 1 a CRp (RR 25%). All pts achieved response after 1 course of therapy and no pt has relapsed (1+ to 7+ months). Three out 4 pts (75%) with untreated disease have achieved CR. The expectation for this group of elderly pts with abnormal CG was 42%. Pts that achieved a response had higher VPA bound levels (127 vs 104 μg/ml, p=0.02). Histone H3 or H4 acetylation was observed in 37% of pts receiving VPA at a 50 mg/kg compared to 11% at lower doses (p=0.002). The median decrease in LINE methylation was 10% (range 2–21%). P21 mRNA induction was observed in 40% of pts. Conclusion: The combination of DAC and VPA has significant activity in pts with AML and MDS that is associated with changes in histone acetylation, and DNA hypomethylation.

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