Lack of association ofIDH1, IDH2andDNMT3Amutations with outcome in older patients with acute myeloid leukemia treated with hypomethylating agents

Th e discovery of somatic mutations within genes primarily involved in epigenetic regulation has been one of the major success stories of the genomics era. Within the past 5 years, this novel class of recurrent mutations has been elucidated, consisting of critical regulators of post-translational events including DNA methylation and histone modifi cation. Th e updated list of mutated epigenetic modifi ers in myeloid malignancies now includes the genes isocitrate dehydrogenase 1 ( IDH1 ) [1], IDH2 [2], tet methylcytosine dioxygenase 2 ( TET2 ) [3], enhancer of zeste homolog 2 ( EZH2 ) [4], mixed lineage leukemia ( MLL ) [5], additional sex combs-like 1 ( ASXL1 ) [6] and DNA methyltransferase 3A ( DNMT3A ) [7,8]. Importantly, many of these epigenetic mutations have subsequently been identifi ed to have prognostic importance for patients with acute myeloid leukemia (AML), particularly within the sizeable cohort of patients with diploid karyotype or otherwise intermediate-risk cytogenetics, and specifi cally within those intermediate-risk patients with wild-type FMS-related tyrosine kinase 3 ( FLT3 ) status. DNMT3A mutations, for instance, identifi ed in approximately 20% of adult patients with AML, have been shown to lead to both an increased risk of relapse and decreased overall survival (OS), correlate with advanced age and a higher white blood cell count at diagnosis, and are associated with mutations in FLT3 , nucleophosmin 1 ( NPM1 ) and IDH1 [7 – 10]. TET2 mutations, with a frequency of 7 – 20% in adult AML, also appear to confer an adverse prognosis in intermediate-risk AML [11,12]. IDH1 and IDH2 mutations, taken together, occur in AML with an estimated prevalence of 10 – 30%, also occurring at an increased frequency in patients with normal diploid karyotype (CN-AML), older age and NPM1 mutations [1,2,13]. Th e prognostic signifi cance of IDH mutations has been less apparent, perhaps related to a diff erence in prognosis attributed to the three diff erent allelic mutations observed in AML, namely IDH1 -R132, IDH2 -R140 and IDH2 -R172. While IDH1 -R132 and IDH2 -R172 mutations appear to have a negative or null clinical impact within the cohort of patients with CN-AML [14], IDH2 -R140 mutations or any IDH mutation in conjunction with an NPM1 mutation rather unexpectedly confers a favorable outcome in patients with otherwise intermediate-risk AML [10,15]. Despite the clinically signifi cant prognostic information gained through identifi cation of epigenetic mutations, less insight is currently available to determine how these mutations should aff ect therapeutic decisions. Recent retrospective data in adults aged 18 – 60 with de novo AML has notably suggested that the dose-intensity of induction therapy may be especially important for patients with AML with DNMT3A , NPM1 or 11q23 abnormalities involving MLL [10]. Nonetheless, AML is primarily a disease of the elderly, with a median age at diagnosis above 65 and with a median survival of less than 1 year in elderly patients receiving treatment [16]. Given the poor overall response and often increased toxicity associated with intensive chemotherapy in elderly AML, much attention has been paid to the potential role of the hypomethylating agents (HMAs), 5-azacitadine and decitabine, as front-line therapy for elderly patients with AML. With this approach, an improved median survival of 24.5 months (versus 16 months with conventional care) was seen in the subgroup of 113 elderly patients with AML receiving azacitidine in the AZA-001 trial [17]. An improved remission rate (complete remission [CR] or complete remission with incomplete platelet count recovery [CRp]) of 18% and median survival of 8 months was seen in a multicenter phase III study of front-line decitabine versus standard of care (supportive care or low-dose cytarabine) for older patients with AML [18], suggesting that therapy with HMAs may be benefi cial for elderly patients with AML.