TY - JOUR
T1 - Phase 1/2 study of the combination of 5-aza-2′-deoxycytidine with valproic acid in patients with leukemia
AU - Garcia-Manero, Guillermo
AU - Kantarjian, Hagop M.
AU - Sanchez-Gonzalez, Blanca
AU - Yang, Hui
AU - Rosner, Gary
AU - Verstovsek, Srdan
AU - Rytting, Michael
AU - Wierda, William G.
AU - Ravandi, Farhad
AU - Koller, Charles
AU - Xiao, Lianchun
AU - Faderl, Stefan
AU - Estrov, Zeev
AU - Cortes, Jorge
AU - O'Brien, Susan
AU - Estey, Elihu
AU - Bueso-Ramos, Carlos
AU - Fiorentino, Jackie
AU - Jabbour, Elias
AU - Issa, Jean Pierre
PY - 2006/11/15
Y1 - 2006/11/15
N2 - 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). Over-all 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. This trial was registered at www.clinicaltrials.gov as #NCT00075010.
AB - 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). Over-all 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. This trial was registered at www.clinicaltrials.gov as #NCT00075010.
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U2 - 10.1182/blood-2006-03-009142
DO - 10.1182/blood-2006-03-009142
M3 - Article
C2 - 16882711
AN - SCOPUS:33750530675
SN - 0006-4971
VL - 108
SP - 3271
EP - 3279
JO - Blood
JF - Blood
IS - 10
ER -