Phase 1/2 study of the combination of 5-aza-2′-deoxycytidine with valproic acid in patients with leukemia

Guillermo Garcia-Manero, Hagop M. Kantarjian, Blanca Sanchez-Gonzalez, Hui Yang, Gary Rosner, Srdan Verstovsek, Michael Rytting, William G. Wierda, Farhad Ravandi, Charles Koller, Lianchun Xiao, Stefan Faderl, Zeev Estrov, Jorge Cortes, Susan O'Brien, Elihu Estey, Carlos Bueso-Ramos, Jackie Fiorentino, Elias Jabbour, Jean Pierre Issa

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3271-3279
Number of pages9
JournalBlood
Volume108
Issue number10
DOIs
StatePublished - Nov 15 2006

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decitabine
Valproic Acid
Leukemia
Histones
Acetylation
Histone Deacetylase Inhibitors
Methylation
Platelets
Epigenomics
Recovery
DNA
Myelodysplastic Syndromes
Acute Myeloid Leukemia
Cytogenetics
Blood Platelets

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Garcia-Manero, G., Kantarjian, H. M., Sanchez-Gonzalez, B., Yang, H., Rosner, G., Verstovsek, S., ... Issa, J. P. (2006). Phase 1/2 study of the combination of 5-aza-2′-deoxycytidine with valproic acid in patients with leukemia. Blood, 108(10), 3271-3279. https://doi.org/10.1182/blood-2006-03-009142

Phase 1/2 study of the combination of 5-aza-2′-deoxycytidine with valproic acid in patients with leukemia. / Garcia-Manero, Guillermo; Kantarjian, Hagop M.; Sanchez-Gonzalez, Blanca; Yang, Hui; Rosner, Gary; Verstovsek, Srdan; Rytting, Michael; Wierda, William G.; Ravandi, Farhad; Koller, Charles; Xiao, Lianchun; Faderl, Stefan; Estrov, Zeev; Cortes, Jorge; O'Brien, Susan; Estey, Elihu; Bueso-Ramos, Carlos; Fiorentino, Jackie; Jabbour, Elias; Issa, Jean Pierre.

In: Blood, Vol. 108, No. 10, 15.11.2006, p. 3271-3279.

Research output: Contribution to journalArticle

Garcia-Manero, G, Kantarjian, HM, Sanchez-Gonzalez, B, Yang, H, Rosner, G, Verstovsek, S, Rytting, M, Wierda, WG, Ravandi, F, Koller, C, Xiao, L, Faderl, S, Estrov, Z, Cortes, J, O'Brien, S, Estey, E, Bueso-Ramos, C, Fiorentino, J, Jabbour, E & Issa, JP 2006, 'Phase 1/2 study of the combination of 5-aza-2′-deoxycytidine with valproic acid in patients with leukemia', Blood, vol. 108, no. 10, pp. 3271-3279. https://doi.org/10.1182/blood-2006-03-009142
Garcia-Manero G, Kantarjian HM, Sanchez-Gonzalez B, Yang H, Rosner G, Verstovsek S et al. Phase 1/2 study of the combination of 5-aza-2′-deoxycytidine with valproic acid in patients with leukemia. Blood. 2006 Nov 15;108(10):3271-3279. https://doi.org/10.1182/blood-2006-03-009142
Garcia-Manero, Guillermo ; Kantarjian, Hagop M. ; Sanchez-Gonzalez, Blanca ; Yang, Hui ; Rosner, Gary ; Verstovsek, Srdan ; Rytting, Michael ; Wierda, William G. ; Ravandi, Farhad ; Koller, Charles ; Xiao, Lianchun ; Faderl, Stefan ; Estrov, Zeev ; Cortes, Jorge ; O'Brien, Susan ; Estey, Elihu ; Bueso-Ramos, Carlos ; Fiorentino, Jackie ; Jabbour, Elias ; Issa, Jean Pierre. / Phase 1/2 study of the combination of 5-aza-2′-deoxycytidine with valproic acid in patients with leukemia. In: Blood. 2006 ; Vol. 108, No. 10. pp. 3271-3279.
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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

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AU - Jabbour, Elias

AU - Issa, Jean Pierre

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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.

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