Valproic acid at therapeutic plasma levels may increase 5-azacytidine efficacy in higher risk myelodysplastic syndromes

Maria Teresa Voso, Valeria Santini, Carlo Finelli, Pellegrino Musto, Enrico Pogliani, Emanuele Angelucci, Giuseppe Fioritoni, Giuliana Alimena, Luca Maurillo, Agostino Cortelezzi, Francesco Buccisano, Marco Gobbi, Lorenza Borin, Anna Di Tucci, Gina Zini, Maria Concetta Petti, Giovanni Martinelli, Emiliano Fabiani, Paola Fazi, Marco VignettiAlfonso Piciocchi, Vincenzo Liso, Sergio Amadori, Giuseppe Leone

Research output: Contribution to journalArticlepeer-review


Purpose: Epigenetic changes play a role and cooperate with genetic alterations in the pathogenesis of myelodysplastic syndromes (MDS). We conducted a phase II multicenter study on the combination of the DNA-methyltransferase inhibitor 5-azacytidine (5-AZA) and the histone deacetylase inhibitor valproic acid (VPA) in patients with higher risk MDS. Experimental Design: We enrolled 62 patients with MDS (refractory anemia with excess blasts, 39 patients; refractory anemia with excess blasts in transformation, 19 patients; and chronic myelomanocytic leukemia (CMML), 4 patients) and an International Prognostic Scoring System (IPSS) rating of Intermediate-2 (42 patients) or high (20 patients). VPA was given to reach a plasma concentration of >50 μg/mL, then 5-AZA was added s.c. at 75 mg/m2 for 7days in eight monthly cycles. Results: The median overall survival was 14.4 months. At a median follow-up of 12 months (range, 0.7-21.0), the disease progressed in 20 patients, with 21% cumulative incidence of progression. Of 26 patients who completed eight cycles, 30.7% obtained complete or partial remission, 15.4% had a major hematologic improvement, whereas 38.5% showed stable disease. Drug-related toxicity was mild. Favorable prognostic factors for survival were IPSS Intermediate-2 and plasma VPA of ≥50 μg/mL (log rank = 0.013 and 0.007, respectively). Analysis of polymorphisms important for the metabolism of the drugs used in the trial showed that carriers of the CYP2C19*2 variant of cytochrome P450 required higher VPA doses to achieve the target VPA plasma concentration of 50 μg/mL on day 1 of 5-AZA treatment (P = 0.0021). Conclusion: Our data show that the 5-AZA/VPA combination is active and safe in patients with MDS with a poor prognosis. Achievement of VPA therapeutic levels may indeed increase 5-AZA efficacy.

Original languageEnglish
Pages (from-to)5002-5007
Number of pages6
JournalClinical Cancer Research
Issue number15
Publication statusPublished - Aug 1 2009

ASJC Scopus subject areas

  • Cancer Research
  • Oncology


Dive into the research topics of 'Valproic acid at therapeutic plasma levels may increase 5-azacytidine efficacy in higher risk myelodysplastic syndromes'. Together they form a unique fingerprint.

Cite this