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

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. ClinicalTrials.gov ID, NCT00339196

New insights in the management of elderly patients with acute myeloid leukemia

“…In the clofarabine CLASSIC II study [27 ], the complete remission rate was 38% and median OS was 9.5 months. In the azacitidine VIVEDEP study, the complete remission rate was 22% and the median OS reached 12.4 months [28]. At first sight, these median OS are in the same range than that reported after intensive chemotherapy.…”

Myoepithelial and luminal breast cancer cells exhibit different responses to all-trans retinoic acid

“…The previously established LM38-LP cell line (passage [15][16][17][18][19][20][21][22][23][24][25], derived from a BALB/c murine mammary papillary adenocarcinoma with tumourigenic and metastatic capacities [8], was used throughout this study. This cell line is composed of two main subpopulations, antigenically characterized as luminal epithelial (LEP) and myoephitelial (MEP), which remain up to the 30th passage [12].…”

“…Due to their role in growth regulation and differentiation, natural and synthetic retinoids are widely evaluated in clinical trials for cancer treatment and prevention [18][19][20]. Besides, since retinoic acid is known to act as a key regulator of embryonic stem cell behaviour, retinoids may not only induce apoptosis, but also differentiation of cancer stem cells.…”

RETRACTED ARTICLE: 5-Azacitidine for treating acute myelogenous leukemia

“…Azacitidine-based combinations have recently been investigated in early phase clinical trials in relapsing/refractory AML [76][77][78] and in retrospective cohorts of limited size [60,69,79,80]. Subgroups of relapsed/refractory patients likely to benefit from such azacitidine-based regimens have not been identified to date.…”