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Acute Lymphoblastic Leukemia
DNMT3A mutation is associated with increased age and adverse outcome in adult T-cell acute lymphoblastic leukemia
Ferrata Storti Foundation
Haematologica 2019 Volume 104(8):1617-1625
Jonathan Bond,1,2,3 Aurore Touzart,1 Stéphane Leprêtre,4 Carlos Graux,5 Mario Bargetzi,6,7 Ludovic Lhermitte,1 Guillaume Hypolite,1 Thibaut Leguay,8 Yosr Hicheri,9 Gaëlle Guillerm,10 Karin Bilger,11 Véronique Lhéritier,12 Mathilde Hunault,13 Françoise Huguet,14 Yves Chalandon,6,15 Norbert Ifrah,13 Elizabeth Macintyre,1 Hervé Dombret,16 Vahid Asnafi1 and Nicolas Boissel16
1Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM), Institut National de Recherche Médicale (INSERM) U1151, and Laboratory of Onco- Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants- Malades, Paris, France; 2Systems Biology Ireland, School of Medicine, University College Dublin, Ireland; 3National Children's Research Centre, Children's Health Ireland at Crumlin, Dublin, Ireland; 4INSERM U1245 and Department of Hematology, Centre Henri Becquerel and Normandie Université UNIROUEN, Rouen, France; 5Department of Hematology, Université Catholique de Louvain (UCL), Centre Hospitalier Universitaire (CHU) Namur - Godinne site, Yvoir, Belgium; 6University Medical Department, Division of Oncology, Hematology and Transfusion Medicine, Kantonsspital Aarau, Aarau, Switzerland; 7Swiss Group for Clinical Cancer Research (SAKK), Bern, Switerland; 8Department of Hematology, CHU de Bordeaux, France; 9Hematology Service, Hôpital St Eloi, Montpellier, France; 10Hematology Service, CHU de Brest, Brest, France; 11Hematology Service, CHU Hautepierre, Strasbourg, France; 12Group for Research on Adult Acute Lymphoblastic Leukemia, Coordination Office, Centre Hospitalier Lyon Sud, Lyon, France; 13PRES LUNAM, CHU Angers Service des Maladies du Sang and CRCINA INSERM, Angers, France; 14Department of Hematology, CHU de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France; 15Department of Oncology, Hematology Division, University Hospital, Geneva, Switzerland and 16Université Paris Diderot, Institut Universitaire d’Hématologie, EA-3518, AP-HP, University Hospital Saint-Louis, Paris, France
ABSTRACT
The prognostic implications of DNMT3A genotype in T-cell acute lymphoblastic leukemia are incompletely understood. We performed comprehensive genetic and clinico-biological analyses of T-cell acute lymphoblastic leukemia patients with DNMT3A mutations treated during the GRAALL-2003 and -2005 studies. Eighteen of 198 cases (9.1%) had DNMT3A alterations. Two patients also had DNMT3A mutations in non- leukemic cell DNA, providing the first potential evidence of age-related clonal hematopoiesis in T-cell acute lymphoblastic leukemia. DNMT3A mutation was associated with older age (median 43.9 years vs. 29.4 years, P<0.001), immature T-cell receptor genotype (53.3% vs. 24.4%, P=0.016) and lower remission rates (72.2% mutated vs. 94.4% non-mutated, P=0.006). DNMT3A alterations were significantly associated with worse clinical outcome, with higher cumulative incidence of relapse (HR 2.33, 95% CI: 1.05-5.16, P=0.037) and markedly poorer event-free survival (HR 3.22, 95% CI: 1.81-5.72, P<0.001) and overall survival (HR 2.91, 95% CI: 1.56-5.43, P=0.001). Adjusting for age as a covariate, or restricting the analy- sis to patients over 40 years, who account for almost 90% of DNMT3A- mutated cases, did not modify these observations. In multivariate analysis using the risk factors that were used to stratify treatment during the GRAALL studies, DNMT3A mutation was significantly associated with shorter event-free survival (HR 2.33, 95% CI: 1.06 – 4.04, P=0.02). Altogether, these results identify DNMT3A genotype as a predictor of aggressive T-cell acute lymphoblastic leukemia biology. The GRAALL-2003 and -2005 studies were registered at http://www.ClinicalTrials.gov as #NCT00222027 and #NCT00327678, respectively.
Correspondence:
NICOLAS BOISSEL
nicolas.boissel@aphp.fr
Received: May 24, 2018. Accepted: January 10, 2019. Pre-published: January 17, 2019.
doi:10.3324/haematol.2018.197848
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