Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome.
The combination of a DNA hypomethylating agent with a histone deacetylase inhibitor has synergistic antileukemia activity and may restore sensitivity to all-trans retinoic acid (ATRA). We conducted a phase 1/2 study of the combination of 5-azacitidine (5-AZA), valproic acid (VPA), and ATRA in patients with acute myeloid leukemia or high-risk myelodysplastic syndrome. 5-AZA was administered subcutaneously at a fixed dose of 75 mg/m(2) daily for 7 days. VPA was dose-escalated and given orally daily for 7 days concomitantly with 5-AZA. ATRA was given at 45 mg/m(2) orally daily for 5 days, starting on day 3. A total of 53 patients were treated. Their median age was 69 years (range, 5-84 years). The maximum tolerated dose of VPA in this combination was 50 mg/kg daily for 7 days. Dose-limiting toxicity was reversible neurotoxicity. The overall response rate was 42%. In previously untreated older patients, the response rate was 52%. Median number of courses to response was 1 (range, 1-3 courses). Median remission duration was 26 weeks, and median survival has not been reached. A significant decrease in global DNA methylation and induction of histone acetylation were achieved. VPA blood levels were higher in responders (P < .005). In conclusion, the combination studied is safe and has significant clinical activity. This clinical trial was registered at www.clinicaltrials.gov as no. NCT00326170.
Soriano
Andres O
AO
Department of Leukemia, University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA.
Yang
Hui
H
Faderl
Stefan
S
Estrov
Zeev
Z
Giles
Francis
F
Ravandi
Farhad
F
Cortes
Jorge
J
Wierda
William G
WG
Ouzounian
Souzanne
S
Quezada
Andres
A
Pierce
Sherry
S
Estey
Elihu H
EH
Issa
Jean-Pierre J
JP
Kantarjian
Hagop M
HM
Garcia-Manero
Guillermo
G
D000107:Acetylation; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001374:Azacitidine / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D064420:Drug-Related Side Effects and Adverse Reactions; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D014212:Tretinoin / Q000009:adverse effects / Q000627:therapeutic use*; D014635:Valproic Acid / Q000009:adverse effects / Q000627:therapeutic use*
D006657:Histones; D012333:RNA, Messenger; D014212:Tretinoin; D014635:Valproic Acid; D001374:Azacitidine