title: 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.
authors.affiliation: Département d'Hématologie, Hôpital Saint-Louis, Assistance Publique - Hôpitaux de Paris (AP-HP), and Université Denis Diderot - Paris 7, EA 3518, Institut Universitaire d'Hématologie (IUH), Paris.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Raffoux
authors.affiliation: UMR-S-940, Université Denis Diderot-Paris 7, IUH, Paris.
authors.forename: Audrey
authors.initials: A
authors.lastname: Cras
authors.affiliation: Département d'Hématologie, Hôpital Purpan, Toulouse.
authors.forename: Christian
authors.initials: C
authors.lastname: Recher
authors.affiliation: UMR-S-707, Université Pierre et Marie Curie - Paris 6, Hôpital Saint-Antoine, AP-HP, Paris.
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Boëlle
authors.affiliation: Département d'Hématologie, Hôpital Saint-Louis, Assistance Publique - Hôpitaux de Paris (AP-HP), and Université Denis Diderot - Paris 7, EA 3518, Institut Universitaire d'Hématologie (IUH), Paris.
authors.forename: Adrienne
authors.initials: A
authors.lastname: de Labarthe
authors.affiliation: Département d'Hématologie, Hôpital Dupuytren, Limoges.
authors.forename: Pascal
authors.initials: P
authors.lastname: Turlure
authors.affiliation: Département d'Hématologie, Hôpital Nord, Amiens.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Marolleau
authors.affiliation: Département d'Hématologie, Centre Hospitalier Universitaire, Caen.
authors.forename: Oumedaly
authors.initials: O
authors.lastname: Reman
authors.affiliation: Département d'Hématologie, Hôpital Avicenne, AP-HP, Bobigny.
authors.forename: Claude
authors.initials: C
authors.lastname: Gardin
authors.affiliation: UMR-S-940, Université Denis Diderot-Paris 7, IUH, Paris.
authors.forename: Maud
authors.initials: M
authors.lastname: Victor
authors.affiliation: Département d'Hématologie, Hôpital Henri Mondor, AP-HP, Créteil.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Maury
authors.affiliation: Département d'Hématologie, Hôpital Mignot, Versailles.
authors.forename: Philippe
authors.initials: P
authors.lastname: Rousselot
authors.affiliation: Département d'Hématologie, Hôpital Percy, Clamart.
authors.forename: Jean-Valère
authors.initials: JV
authors.lastname: Malfuson
authors.affiliation: Département d'Hématologie, Hôpital Saint-Louis, Assistance Publique - Hôpitaux de Paris (AP-HP), and Université Denis Diderot - Paris 7, EA 3518, Institut Universitaire d'Hématologie (IUH), Paris.
authors.forename: Odile
authors.initials: O
authors.lastname: Maarek
authors.affiliation: Département d'Hématologie, Hôpital Saint-Louis, Assistance Publique - Hôpitaux de Paris (AP-HP), and Université Denis Diderot - Paris 7, EA 3518, Institut Universitaire d'Hématologie (IUH), Paris.
authors.forename: Marie-Thérèse
authors.initials: MT
authors.lastname: Daniel
authors.affiliation: Département d'Hématologie, Hôpital Avicenne, AP-HP, Bobigny.
authors.forename: Pierre
authors.initials: P
authors.lastname: Fenaux
authors.affiliation: Département d'Hématologie, Hôpital Saint-Louis, Assistance Publique - Hôpitaux de Paris (AP-HP), and Université Denis Diderot - Paris 7, EA 3518, Institut Universitaire d'Hématologie (IUH), Paris.
authors.forename: Laurent
authors.initials: L
authors.lastname: Degos
authors.affiliation: UMR-S-940, Université Denis Diderot-Paris 7, IUH, Paris.
authors.forename: Christine
authors.initials: C
authors.lastname: Chomienne
authors.affiliation: Département de Biostatistiques et d'Informatique Médicale, Hôpital Saint-Louis, AP-HP, Paris, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chevret
authors.affiliation: Département d'Hématologie, Hôpital Saint-Louis, Assistance Publique - Hôpitaux de Paris (AP-HP), and Université Denis Diderot - Paris 7, EA 3518, Institut Universitaire d'Hématologie (IUH), Paris.
authors.forename: Hervé
authors.initials: H
authors.lastname: Dombret
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000927:Anticonvulsants / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001374:Azacitidine / Q000008:administration & dosage; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D057890:Epigenomics; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000235:genetics; D016133:Polymerase Chain Reaction; D015996:Survival Rate; D016896:Treatment Outcome; D014212:Tretinoin / Q000008:administration & dosage; D014635:Valproic Acid / Q000627:therapeutic use*
chemical_list: D000927:Anticonvulsants; D004273:DNA, Neoplasm; D014212:Tretinoin; D014635:Valproic Acid; D001374:Azacitidine