title: 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 less than 0.001), NPM1 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.
authors.affiliation: Laboratoire d'Hématologie, CHU de Toulouse, Hôpital Purpan.
authors.forename: Olivier
authors.initials: O
authors.lastname: LaRochelle
authors.forename: Sarah
authors.initials: S
authors.lastname: Bertoli
authors.forename: François
authors.initials: F
authors.lastname: Vergez
authors.forename: Jean-Emmanuel
authors.initials: JE
authors.lastname: Sarry
authors.forename: Véronique
authors.initials: V
authors.lastname: Mansat-De Mas
authors.forename: Sophie
authors.initials: S
authors.lastname: Dobbelstein
authors.forename: Nicole
authors.initials: N
authors.lastname: Dastugue
authors.forename: Anne-Claire
authors.initials: AC
authors.lastname: Strzelecki
authors.forename: Cindy
authors.initials: C
authors.lastname: Cavelier
authors.forename: Laurent
authors.initials: L
authors.lastname: Creancier
authors.forename: Arnaud
authors.initials: A
authors.lastname: Pillon
authors.forename: Anna
authors.initials: A
authors.lastname: Kruczynski
authors.forename: Cécile
authors.initials: C
authors.lastname: Demur
authors.forename: Audrey
authors.initials: A
authors.lastname: Sarry
authors.forename: Françoise
authors.initials: F
authors.lastname: Huguet
authors.forename: Anne
authors.initials: A
authors.lastname: Huynh
authors.forename: Christian
authors.initials: C
authors.lastname: Récher
authors.forename: Eric
authors.initials: E
authors.lastname: Delabesse
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D004252:DNA Mutational Analysis; D003630:Daunorubicin / Q000627:therapeutic use*; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005091:Exons; D005260:Female; D006801:Humans; D015255:Idarubicin / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D009154:Mutation; D000090243:Nucleophosmin; D011379:Prognosis; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult
chemical_list: D000903:Antibiotics, Antineoplastic; C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; C000716967:NPM1 protein, human; C000715570:Npm1 protein, mouse; D000090243:Nucleophosmin; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D015255:Idarubicin; D003630:Daunorubicin
references.citation: Cancer Cell. 2010 Jan 19;17(1):13-27
references.pmid: 20060365
references.citation: N Engl J Med. 2009 Sep 24;361(13):1235-48
references.pmid: 19776405
references.citation: Hematology Am Soc Hematol Educ Program. 2005;:143-50
references.pmid: 16304372
references.citation: Int J Cancer. 2011 Feb 1;128(3):551-61
references.pmid: 20473858
references.citation: Leukemia. 2000 May;14(5):889-97
references.pmid: 10803522
references.citation: J Clin Oncol. 2003 Dec 15;21(24):4642-9
references.pmid: 14673054
references.citation: Nat Genet. 2011 Mar 13;43(4):309-15
references.pmid: 21399634
references.citation: Oncotarget. 2010 Nov;1(7):606-19
references.pmid: 21317456
references.citation: Trends Mol Med. 2010 Sep;16(9):387-97
references.pmid: 20692206
references.citation: Leukemia. 2010 Jul;24(7):1380-5
references.pmid: 20508614
references.citation: Hematology Am Soc Hematol Educ Program. 2010;2010:47-55
references.pmid: 21239770
references.citation: Blood. 2005 May 1;105(9):3420-7
references.pmid: 15572587
references.citation: N Engl J Med. 2010 Dec 16;363(25):2424-33
references.pmid: 21067377
references.citation: Blood. 2010 Jan 21;115(3):453-74
references.pmid: 19880497
references.citation: J Clin Oncol. 2011 Jul 20;29(21):2889-96
references.pmid: 21670448
references.citation: Blood. 2011 Feb 24;117(8):2358-65
references.pmid: 20693429
references.citation: Blood. 2006 Feb 1;107(3):1166-73
references.pmid: 16234360
references.citation: J Clin Oncol. 2010 Feb 1;28(4):562-9
references.pmid: 20026804
references.citation: Curr Med Chem. 2010;17(33):4052-71
references.pmid: 20939822
references.citation: Pharmacol Rev. 2004 Jun;56(2):185-229
references.pmid: 15169927
references.citation: N Engl J Med. 2008 May 1;358(18):1909-18
references.pmid: 18450602
references.citation: Blood. 2011 Feb 10;117(6):1828-33
references.pmid: 21051557
references.citation: Blood. 2010 Jul 22;116(3):354-65
references.pmid: 20385793
references.citation: J Clin Oncol. 2010 Feb 10;28(5):808-14
references.pmid: 20048183
references.citation: Leukemia. 2009 Nov;23(11):2109-17
references.pmid: 19626050
references.citation: N Engl J Med. 2009 Sep 10;361(11):1058-66
references.pmid: 19657110
references.citation: Nat Genet. 2001 Mar;27(3):263-70
references.pmid: 11242107
references.citation: N Engl J Med. 2009 Sep 24;361(13):1249-59
references.pmid: 19776406
references.citation: J Clin Oncol. 2011 Feb 10;29(5):475-86
references.pmid: 21220609
references.citation: Leukemia. 2008 May;22(5):915-31
references.pmid: 18288131
references.citation: Haematologica. 2010 Jun;95(6):996-1003
references.pmid: 20007135
references.citation: J Clin Invest. 2011 Jan;121(1):384-95
references.pmid: 21157036