Experience with the Combination of a Hypomethylating Agent and Valproic Acid in Pediatric Acute Myelogenous Leukemia
Abstract Combination epigenetic therapy consists of the combination of a hypomethylating agent (5-aza-2′-deoxycitidine [decitabine] or 5-azacitidine) with a histone deacetylase (HDAC) inhibitor. We have performed two studies combining either decitabine (n=55) or 5-azacitidine (n=54) with valproic acid (VPA). VPA is a neurotropic agent with weak HDAC inhibitory capacity in the mM range. Both studies were open to children with relapsed or refractory AML age 2 or older. Of the 109 patients, 10 (9%) were considered pediatric patients (pts). Seven patients were treated with a fixed dose of intravenous decitabine (DAC) and escalating doses of VPA, and three patients were treated with 5-azacytidine, VPA and all-trans retinoic acid (ATRA). All of the pediatric pts were refractory to a minimum of two chemotherapy regimens for AML or had multiple relapses of AML. The median age was 17 (range 5–21), 5 (50%) were diploid, and the median WBC at presentation was 3.4 (range 0.9 to 16.3). Five of the 10 pts derived benefit from the combination. In the DAC plus VPA trial, three pts achieved a complete marrow response, defined as a hypocellular marrow with less than 5% blasts without recovery of peripheral counts. An additional pt had a partial response with 6% marrow blasts after therapy and improvement in transfusion requirements. In the 5AZA/VPA/ATRA trial, 1 complete marrow response was observed. No complete remission (CR) was observed. No differences were observed in terms of LINE methylation (measured using a bisulfite pyrosequencing assay) pretreatment in pediatric versus adult patients (44.7% [40–65] pediatric versus 46.3 [37–65] adult, p=0.3) or after therapy with the combination treatment. There was a trend towards higher bound VPA levels in the adult group on days 5 or 7 (median 72 [0–202] in adult versus 32 [2–114], p=0.49). Pediatric pts treated with DAC/VPA had less acetylation compared to adult pts (14% vs 35%) and showed no evidence of mRNA activation of p21. Overall, administration of DAC/VPA or 5AZA/VPA/ATRA was safe with no grade 3 or 4 toxicity and no induction mortality in the pediatric group. Combination epigenetic therapy has potential clinical activity in pediatric pts with highly pre-treated relapsed or refractory AML and should be studied in pediatric specific clinical trials.