Do AML patients with DNMT3A exon 23 mutations benefit from idarubicin as compared to daunorubicin? A single center experience

Abstract

Mutations in DNMT3A encoding DNA methyltransferase 3A were recently described in patients with acute myeloid leukemia. To assess their prognostic significance, we determined the mutational status of DNMT3A exon 23 in 288 patients with AML excluding acute promyelocytic leukemia, aged from 18 to 65 years and treated in Toulouse University Hospital. A mutation was detected in 39 patients (13.5%). All DNMT3A exon 23+ patients had intermediate-risk cytogenetics. Mutations significantly correlated with a higher WBC count (p<0.001), NPM1 (p<0.001) and FLT3-ITD mutations (p=0.027). DNMT3A mutations were conserved through xenotransplantation in immunodeficient mice. No difference in outcome between DNMT3A exon 23+ and DNMT3A exon 23- patients was found even if the results were stratified by NPM1 or FLT3-ITD status. However, DNMT3A exon 23+ patients had better median DFS (not reached vs 11.6 months, p=0.009) and OS (not reached vs 14.3 months, p=0.005) as compared to DNMT3A exon 23- patients when treated with idarubicin, whereas patients treated with daunorubicin had similar outcome regardless the DNMT3A status. This study shows that DNMT3A mutations have no impact on outcome but could be a predictive factor for response to idarubicin and thus, could have a direct influence in the way AML patients should be managed.

Molecular Evaluation of DNMT3A and IDH1/2 Gene Mutation: Frequency, Distribution Pattern and Associations with Additional Molecular Markers in Normal Karyotype Indian Acute Myeloid Leukemia Patients

“…More recently, another interesting study reported no impact of DNMT3A mutation on outcome, but could be a predictive factor for response to idarubicin and thus, could have a direct influence in the way AML patients should be managed (LaRochelle et al, 2011). In contrast, the true clinical impact of IDH mutations is still debatable, and it varies considerably among the different type of mutations detected, and also by the presence of concurrent mutation in other clinically relevant genes (Paschka et al, 2010).…”

Hemophagocytic syndrome in patients with acute myeloid leukemia undergoing intensive chemotherapy

“…The diagnostic workup and treatment modalities have been described elsewhere. 13,14 All patients had a central venous catheter placed and were given bacterial digestive tract decontamination, antibiotic therapy for febrile neutropenia (piperacillin-tazobactam/amikacin and imipenem/vancomycin/ciprofloxacin as first-and second-line treatments, respectively) and antifungal prophylaxis with posaconazole. Clinical and biological data were recorded by four of the authors (KD, AS, SB and CR).…”

Clinical impact of DNMT3A mutations in younger adult patients with acute myeloid leukemia: results of the AML Study Group (AMLSG)

“…However, in most studies, patient populations were small and selected. [8][9][10][11][12][13][14][15][16] DNMT3A is located in chromosomal band 2p23 and, together with DNMT3B and DNMT1, is a member of a DNA methyltransferase (MTase) family. 17 It has three conserved domains: the PWWP domain targeting the enzyme to nucleic acids, the cystein-rich PHD zinc-finger domain interacting with unmodified histone H3, and the highly conserved catalytic domain representing the MTase domain in the Cterminal region.…”