Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome

Andres O. Soriano, Hui Yang, Stefan Faderl, Zeev Estrov, Francis Giles, Farhad Ravandi, Jorge Cortes, William G. Wierda, Souzanne Ouzounian, Andres Quezada, Sherry Pierce, Elihu H. Estey, Jean Pierre J. Issa, Hagop M. Kantarjian, Guillermo Garcia-Manero

Research output: Contribution to journalArticle

Abstract

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/m2 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/m2 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.

Original languageEnglish (US)
Pages (from-to)2302-2308
Number of pages7
JournalBlood
Volume110
Issue number7
DOIs
StatePublished - Oct 1 2007
Externally publishedYes

Fingerprint

Azacitidine
Myelodysplastic Syndromes
Valproic Acid
Tretinoin
Acute Myeloid Leukemia
Safety
Acetylation
Histone Deacetylase Inhibitors
Maximum Tolerated Dose
DNA Methylation
Histones
Toxicity
Blood
Clinical Trials
Survival
DNA

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome. / Soriano, Andres O.; Yang, Hui; Faderl, Stefan; Estrov, Zeev; Giles, Francis; Ravandi, Farhad; Cortes, Jorge; Wierda, William G.; Ouzounian, Souzanne; Quezada, Andres; Pierce, Sherry; Estey, Elihu H.; Issa, Jean Pierre J.; Kantarjian, Hagop M.; Garcia-Manero, Guillermo.

In: Blood, Vol. 110, No. 7, 01.10.2007, p. 2302-2308.

Research output: Contribution to journalArticle

Soriano, AO, Yang, H, Faderl, S, Estrov, Z, Giles, F, Ravandi, F, Cortes, J, Wierda, WG, Ouzounian, S, Quezada, A, Pierce, S, Estey, EH, Issa, JPJ, Kantarjian, HM & Garcia-Manero, G 2007, 'Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome', Blood, vol. 110, no. 7, pp. 2302-2308. https://doi.org/10.1182/blood-2007-03-078576
Soriano, Andres O. ; Yang, Hui ; Faderl, Stefan ; Estrov, Zeev ; Giles, Francis ; Ravandi, Farhad ; Cortes, Jorge ; Wierda, William G. ; Ouzounian, Souzanne ; Quezada, Andres ; Pierce, Sherry ; Estey, Elihu H. ; Issa, Jean Pierre J. ; Kantarjian, Hagop M. ; Garcia-Manero, Guillermo. / Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome. In: Blood. 2007 ; Vol. 110, No. 7. pp. 2302-2308.
@article{98a0ce6e8ab84565b05ff91bf58babaa,
title = "Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome",
abstract = "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/m2 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/m2 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.",
author = "Soriano, {Andres O.} and Hui Yang and Stefan Faderl and Zeev Estrov and Francis Giles and Farhad Ravandi and Jorge Cortes and Wierda, {William G.} and Souzanne Ouzounian and Andres Quezada and Sherry Pierce and Estey, {Elihu H.} and Issa, {Jean Pierre J.} and Kantarjian, {Hagop M.} and Guillermo Garcia-Manero",
year = "2007",
month = "10",
day = "1",
doi = "10.1182/blood-2007-03-078576",
language = "English (US)",
volume = "110",
pages = "2302--2308",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "7",

}

TY - JOUR

T1 - Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome

AU - Soriano, Andres O.

AU - Yang, Hui

AU - Faderl, Stefan

AU - Estrov, Zeev

AU - Giles, Francis

AU - Ravandi, Farhad

AU - Cortes, Jorge

AU - Wierda, William G.

AU - Ouzounian, Souzanne

AU - Quezada, Andres

AU - Pierce, Sherry

AU - Estey, Elihu H.

AU - Issa, Jean Pierre J.

AU - Kantarjian, Hagop M.

AU - Garcia-Manero, Guillermo

PY - 2007/10/1

Y1 - 2007/10/1

N2 - 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/m2 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/m2 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.

AB - 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/m2 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/m2 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.

UR - http://www.scopus.com/inward/record.url?scp=34948845116&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34948845116&partnerID=8YFLogxK

U2 - 10.1182/blood-2007-03-078576

DO - 10.1182/blood-2007-03-078576

M3 - Article

C2 - 17596541

AN - SCOPUS:34948845116

VL - 110

SP - 2302

EP - 2308

JO - Blood

JF - Blood

SN - 0006-4971

IS - 7

ER -