Phase I/II study of the combination of 5-azacytidine(5-AC), all-trans retinoic acid (ATRA) and valproic Acid (VPA) in patients with myelodysplastic syndrome (MDS) and leukemia

Abstract

6563 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 MDS. Based on this, we developed a phase I/II study of the combination of 5-AC, VPA and ATRA for patients with MDS or AML. Methods: The dose of 5-AC was fixed: 75 mg/m2 sq daily × 7. ATRA dose was: 45 mg/m2 orally daily × 5 starting on day 3. Three dose levels of VPA were studied: 50, 62.5 and 75 mg/kg orally daily × 7. The phase I portion of the study followed a 3+3 design. Patients with high risk MDS (≥10% blasts) or relapsed/refractory AML and patients older than 60 years with untreated disease and adequate renal, hepatic functions and performance status were eligible. Results: Nineteen patients were registered and 16 were evaluable. Median age was 68 years (5–78). All, but one patient with MDS had AML. Median number of prior therapies was 2 (0–5). Twelve patients (75%) had abnormal cytogenetics. At a VPA dose of 50 mg/kg, 1 of 6 patients developed grade 3 confusion; at 62.5 mg/kg, 0 of 6, and at 75 mg/kg, 2 of 6. One patient had a CR, 2 a complete marrow response (marrow blasts < 5%), and 1 a CRP (same criteria as of CR but without complete platelet recovery), overall response rate was 30% of 13 patients that have completed 1 course. All 4 responses occurred during the first cycle. The CR occurred at a VPA dose of 75mg/kg. The other 3 responses occurred at 62.5 and 75 mg/kg. One out of 2 previously untreated older patients achieved a CR. To assess the hypomethylating effect of 5-AC, we used the LINE assay. Median LINE methylation pretreatment was 62.5% (57–67%), declined to 58% by day 7 and returned to baseline by day 0 of next cycle (p<0.001). Analysis of histone acetylation and gene re-expression are ongoing. Conclusions: The combination of 5-AC with VPA and ATRA is well tolerated. The dose of 62.5 mg/kg daily × 7 is currently being expanded. Significant clinical activity was observed and the effects are potentially mediated by the synergistic action of the combination including induction of DNA hypomethylation and histone acetylation. [Table: see text]