5-Azacytidine Efficacy in Higher Risk Myelodysplastic Valproic Acid at Therapeutic Plasma Levels May Increase

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/m for 7 days 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. Epigenetic transcriptional silencing of genes important for carcinogenesis, including cell cycle, apoptosis, DNA repair, and detoxification are likely to contribute to the leukemogenic event underlying myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML). The transcriptional silencing of known or candidate tumor suppressor genes depends not only on DNA methylation, but also on additional epigenetic events such as bimethylation and trimethylation of histone lysine residues and recruitment of methylated DNA-binding proteins (1). Methyl CpG-binding Authors' Affiliations: Istituto di Ematologia, Universita' Cattolica S. Cuore, Rome, Italy; UF Ematologia, AOU Careggi, Università di Firenze, Florence, Italy; Istituto di Ematologia “Seràgnoli”, Universita' di Bologna, Bologna, Italy; Ematologia e Trapianto di Cellule Staminali, IRCCS, Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture, Potenza, Italy; Dipartimento di Medicina Interna, Universita' di Milano-Bicocca, Monza, Italy; Ematologia Centro Oncologico Businco, Cagliari, Italy; Ematologia, Ospedale Civico, Pescara, Italy; Dipartimento di Biotecnologia e Ematologia, Universita' La Sapienza, Rome, Italy; Ematologia, Ospedale S. Eugenio, Rome, Italy; Ematologia-Unita' di Trapianto di Midollo Osseo, IRCCS Regina Elena, Milan, Italy; Istituto di Ematologia, Universita' Tor Vergata, Rome, Italy; Ematologia Universita' di Genova, Genoa, Italy; Ematologia, Istituto Oncologico Regina Elena, Rome, Italy; Gimema Data Center, Rome, Italy for the GIMEMA AL WP-Commissione MDS, Rome, Italy; and Department of Hematology, University of Bari, Bari, Italy Received 2/28/09; revised 4/21/09; accepted 4/30/09; published OnlineFirst