Acute myeloid leukemia (AML) is a disease of the elderly, affecting patients with a median age of 65--70 years. Cytotoxic chemotherapy remains the mainstay of treatment in younger patients (often defined as those below the age of 60 years), but is associated with lower complete remission (CR) rates and greater toxicity in older patients (X60 years), resulting in poor long-term outcomes and a median overall survival (OS) of o1 year. 1 Thus, there is a need for novel, effective and well-tolerated treatment approaches, especially for older patients.

Epigenetic changes, including aberrant DNA methylation, can result in silencing of tumor suppressor genes and likely contribute to the pathogenesis of AML. 2 Aberrant DNA methylation can be reversed pharmacologically by inhibitors of DNA methyltransferase (DNMT) enzymes. 2 Two azanucleotide DNMT inhibitors, azacitidine and decitabine, are approved for the treatment of patients with myelodysplastic syndromes, and are also being studied in AML. 3 Our group has recently reported promising results with a well-tolerated 10-day schedule of low-dose decitabine, including a CR rate of 47% and a median OS of 1 year in older patients with untreated AML who were considered unfit for or refused intensive chemotherapy. 4 Recurrent DNMT3A gene mutations were recently discovered in AML, 5--7 and are associated with worse outcomes. 6--8 It has been reported that at least some DNMT3A mutations, including those at the mutational hotspot codon R882, impair the protein’s methyltransferase activity. 5, 7 Although the biological mechanisms linking DNMT3A mutations to leukemogenesis are not yet fully understood, an obvious question from the clinical standpoint is whether DNMT3A mutations influence the response to treatment with hypomethylating agents. We therefore evaluated DNMT3A mutation status in a cohort of 46 predominantly older patients with previously untreated AML, who were enrolled in two clinical trials and received decitabine at an initial dose of 20mg/m2 iv over 1 h for 10 days, as described in detail earlier. 4 Patients received decitabine either as a single agent (n= 39; clinicaltrials. gov identifier NCT00492401 (ref. 6)) or in combination with bortezomib (0.7--1.3 mg/m2 iv on days 5, 8, 12 and 15; n= 7; NCT00703300). All patients who had genomic DNA from pretreated bone marrow specimens available were included in this analysis. DNMT3A exons 18, 19, 21, 22 and 24--26 (GeneBank accession number NM_175629), where approximately 90% of mutations are located, 6 were studied using PCR and direct sequencing. Patients were also characterized for FLT3-internal tandem duplications (FLT3-ITD) and tyrosine kinase domain mutations (FLT3-TKD), and