Phase 1/2 study of the combination of 5-aza-2'-deoxycytidine with valproic acid in patients with leukemia.
We conducted a phase 1/2 study of the combination of 5-aza-2'-deoxycytidine (decitabine) and the histone deacetylase inhibitor valproic acid (VPA) in patients with advanced leukemia, including older untreated patients. A group of 54 patients were treated with a fixed dose of decitabine (15 mg/m(2) by IV daily for 10 days) administered concomitantly with escalating doses of VPA orally for 10 days. A 50 mg/kg daily dose of VPA was found to be safe. Twelve (22%) patients had objective response, including 10 (19%) complete remissions (CRs), and 2 (3%) CRs with incomplete platelet recovery (CRp). Among 10 elderly patients with acute myelogenous leukemia or myelodysplastic syndrome, 5 (50%) had a response (4CRs, 1CRp's). Induction mortality was observed in 1 (2%) patient. Major cytogenetic response was documented in 6 of 8 responders. Remission duration was 7.2 months (range, 1.3-12.6+ months). Overall survival was 15.3 months (range, 4.6-20.2+ months) in responders. Transient DNA hypomethylation and global histone H3 and H4 acetylation were induced, and were associated with p15 reactivation. Patients with lower pretreatment levels of p15 methylation had a significantly higher response rate. In summary, this combination of epigenetic therapy in leukemia was safe and active, and was associated with transient reversal of aberrant epigenetic marks.
Garcia-Manero
Guillermo
G
Department of Leukemia, Box 428, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA. ggarciam@mdanderson.org
Kantarjian
Hagop M
HM
Sanchez-Gonzalez
Blanca
B
Yang
Hui
H
Rosner
Gary
G
Verstovsek
Srdan
S
Rytting
Michael
M
Wierda
William G
WG
Ravandi
Farhad
F
Koller
Charles
C
Xiao
Lianchun
L
Faderl
Stefan
S
Estrov
Zeev
Z
Cortes
Jorge
J
O'brien
Susan
S
Estey
Elihu
E
Bueso-Ramos
Carlos
C
Fiorentino
Jackie
J
Jabbour
Elias
E
Issa
Jean-Pierre
JP
D000107:Acetylation / Q000187:drug effects; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D044127:Epigenesis, Genetic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy; D012074:Remission Induction / Q000379:methods; D016019:Survival Analysis; D014635:Valproic Acid / Q000008:administration & dosage* / Q000494:pharmacology
D056572:Histone Deacetylase Inhibitors; D006657:Histones; D014635:Valproic Acid; D000077209:Decitabine; D001374:Azacitidine