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

Abstract

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 2 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.

Synergistic induction of PI-PLCβ1 signaling by azacitidine and valproic acid in high-risk myelodysplastic syndromes

“…Currently, the combination of DNA methyltransferase inhibitors, such as AZA, with HDAC inhibitors, like VPA, has been recognized as clinically useful and associated with a high response rate in patients with MDS at higher risk of AML evolution and unfavorable prognosis. 16,17 However, the biological role of these combination therapies remains to be defined, as the extent to which clinical activity and response depend on epigenetic modulations, as well as the cellular targets or the pathways involved, are still not fully understood. 18 PI-PLCb1 is a well-known enzyme involved in cell proliferation and differentiation.…”

“…14,15 Combination of the DNA methyltransferase inhibitor AZA and the HDAC inhibitor valproic acid (VPA) in patients having MDS and belonging to the International Prognostic Scoring System risk group intermediate-2/high is active and associated with a high response rate in these MDS patients, usually with unfavorable prognosis. 16,17 However, at present, there are no valuable parameters, either diseaseassociated or patient-associated, predictive of response to DNA methyltransferase inhibitors or to the combination of DNA methyltransferase inhibitors and HDAC inhibitors, which could be also useful to monitor the efficacy of the treatment, even though current studies focusing on hypomethylation and gene reexpression in MDS are trying to asses the optimal epigenetic drug targets, and the molecular mechanisms underlying clinical response to demethylating therapy. 18,19 Lipid signaling in disease is an important field of investigation, and phosphoinositides have been demonstrated to be involved in leukemogenesis.…”

Epigenetic aspects of MDS and its molecular targeted therapy

“…Recently, it has also been reported that DNA methylation per se is not a permanent lock for silencing gene expression, but rather a combination of DNA methylation inhibitors with other drugs (such as HDIs) can be used to reactivate gene expression [76,77]. Furthermore, there is increasing evidence that such combinations have encouraging results [78,79]. Therefore, it is likely that the rational design of combinations of several drugs targeting epigenetic pathways will be required for the treatment of MDS (Fig.…”

Targeting the epigenome for treatment of cancer

“…HDACis can also be combined with DNMTis, given their ability to more effectively reactivate those TSGs, including CDKN2A and MLH1, that are silenced in association with histone hypoacetylation and promoter hyper-methylation (Cameron et al, 1999). Moreover, this combination synergizes in induction of cancer cell death in vitro and appears to have enhanced clinical efficacy in early clinical studies (Zhu et al, 2001;Garcia-Manero et al, 2006;Gore et al, 2006;Blum et al, 2007;Braiteh et al, 2008;Voso et al, 2009;Stathis et al, 2011).…”

“…The incorporation of DNMTis is DNA replication-dependent, meaning that slowly proliferating cancer cells could survive DNMTi treatment (Issa and Kantarjian, 2009). Responsiveness to DNMTis and HDACis is critically determined by pharmacogenetic factors that affect the uptake and metabolism of these agents (Voso et al, 2009;Geutjes et al, 2011). Such issues could potentially be avoided with the new DNMTis as they do not require metabolic activation or DNA replication for their incorporation.…”