Phase 2 clinical trial of 5-azacitidine, valproic acid, and all-trans retinoic acid in patients with high-risk acute myeloid leukemia or myelodysplastic syndrome

Abstract

In this Phase 2 study, we evaluated the efficacy of combination of 5-azacitidine (AZA), valproic acid (VPA), and all-trans retinoic acid (ATRA) in patients with high-risk acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Treatment consisted of six cycles of AZA and VPA for 7 days, followed by ATRA for 21 days. Sixty-five patients were enrolled (median age, 72 years; 55 AML including 13 relapsed/refractory patients, 10 MDS; 30 unfavorable karyotypes). Best responses included 14 CR and 3 PR (26%), 75% of the responders and 36% of the non-responders achieving an erythroid response. Median overall survival (OS) was 12.4 months. Untreated patients had a longer OS than relapsed/refractory patients. In patients who fulfilled the 6 planned cycles, OS did not appear to depend on CR/PR achievement, suggesting that stable disease while on-treatment would be a surrogate for survival with this approach. During therapy, early platelet response and demethylation of the FZD9, ALOX12, HPN, and CALCA genes were associated with clinical response. Finally, there was no evidence for the restoration of an ATRA-induced differentiation during therapy. Epigenetic modulation deserves prospective comparisons to conventional care in patients with high-risk AML, at least in those presenting previously untreated disease and low blast count.

Fig. 1

Kinetics of peripheral blood neutrophil count, platelet count, and hemoglobin level during the treatment period. The evolution of peripheral blood neutrophil count (/mm³), platelet count (/mm³), and hemoglobin level (g/dL) is shown in the 34 patients who may receive the planned 6 treatment cycles, according to the response (15 CR + PR patients versus 19 non-responding patients).

Fig. 2. Overall survival

(A) OS from study inclusion according to the three eligibility subsets. OS was significantly shorter in patients relapsing after prior intensive chemotherapy (subset 2) than in naïve patients with either AML (subset 1) or high-risk MDS (subset 3) (P= 0.0024). (B) OS following the 6-month evaluation according to the response observed at 6 months. In the 34 patients who received the 6 planned cycles, OS after the 6-month evaluation was not significantly different between responding (N= 15) and non-responding (N= 19) patients.