Oncotarget

Research Papers:

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

Olivier LaRochelle, Sarah Bertoli, François Vergez, Jean Emmanuel Sarry, Véronique Mansat-De Mas, Sophie Dobbelstein, Nicole Dastugue, Anne-Claire Strzelecki, Cindy Cavelier, Laurent Creancier, Arnaud Pillon, Anna Kruczynski, Cecile Demur, Audrey Sarry, Françoise Huguet, Anne Huynh, Christian Récher _ and Eric Delabesse

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Oncotarget. 2011; 2:850-861. https://doi.org/10.18632/oncotarget.347

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Abstract

Olivier LaRochelle1*, Sarah Bertoli2*, François Vergez1,3*, Jean-Emmanuel Sarry3, Véronique Mansat-De Mas1,3,4, Sophie Dobbelstein1, Nicole Dastugue1, Anne-Claire Strzelecki1, Cindy Cavelier1, Laurent Creancier5, Arnaud Pillon5, Anna Kruczynski5, Cécile Demur1,3, Audrey Sarry2, Françoise Huguet2, Anne Huynh2, Christian Récher2,3,4* and Eric Delabesse1,3,4*

1 Laboratoire d’Hématologie, CHU de Toulouse, Hôpital Purpan

2 Service d’Hématologie, CHU de Toulouse, Hôpital Purpan, 31059 Toulouse, France

3 INSERM UMR1037-Cancer Research Center of Toulouse, CNRS ERL 5294, Pavillon Lefebvre BP3028, CHU Purpan, 31024 Toulouse, France

4 Université Toulouse III Paul Sabatier, Toulouse, France

5 Centre de Recherche et Développement Pierre Fabre, 3 avenue Hubert Curien, BP 13562, 31035 Toulouse Cedex 1, France

* These authors contributed equally to the work

Received: November 1, 2011; Accepted: November 1, 2011; Published: November 9, 2011;

Keywords:DNMT3A, acute leukemia, idarubicin, NOD/SCID, xenograft

Correspondence:

Eric Delabesse, email:

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 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.


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