Clinical impact of gene mutations and lesions detected by SNP-array karyotyping in acute myeloid leukemia patients in the context of gemtuzumab ozogamicin treatment: Results of the ALFA-0701 trial

// Aline Renneville 1–3 , Raouf Ben Abdelali 1–3 , Sylvie Chevret 4 , Olivier Nibourel 1–3 , Meyling Cheok 3 , Cécile Pautas 5 , Rémy Duléry 6 , Thomas Boyer 1–3 , Jean-Michel Cayuela 7 , Sandrine Hayette 8 , Emmanuel Raffoux 9 , Hassan Farhat 10 , Nicolas Boissel 9 , Christine Terre 11 , Hervé Dombret 9 , Sylvie Castaigne 10 , and Claude Preudhomme 1–3 1 Laboratory of Hematology, Biology and Pathology Center, CHRU of Lille, Lille 2 University of Lille Nord de France, Lille 3 Inserm, U837, Team 3, Cancer Research Institute of Lille, Lille 4 UMR-717, Inserm; Paris Diderot university, Saint-Louis Hospital, APHP, Paris 5 Department of Hematology, Henri Mondor Hospital, APHP, Créteil 6 Department of Hematology, Huriez Hospital, CHRU of Lille, Lille 7 Laboratory of Hematology, Saint-Louis Hospital, APHP, Paris 8 Laboratory of Molecular Biology and UMR5239 CNRS, Lyon Sud Hospital, Pierre-Bénite 9 EA 3518, University of Paris 7; Department of Adult Hematology, Saint-Louis Hospital, APHP, Paris 10 Department of Hematology, Versailles Hospital, Le Chesnay 11 Laboratory of Cytogenetics, Versailles Hospital, Le Chesnay; all in France. Correspondence: Claude Preudhomme, e-mail: claude.preudhomme@chru-lille.fr A.R. and R.B.A., H.D., S.Ca. and C.Pr. equally contributed to this work. Keywords: acute myeloid leukemia, SNP array lesions, gene mutations, gemtuzumab ozogamicin, prognosis. Received : October 30, 2013      Accepted : December 12, 2013      Published : January 20, 2014 ABSTRACT We recently showed that the addition of fractionated doses of gemtuzumab ozogamicin (GO) to standard chemotherapy improves clinical outcome of acute myeloid leukemia (AML) patients. In the present study, we performed mutational analysis of 11 genes ( FLT3 , NPM1 , CEBPA , MLL, WT1 , IDH1/2 , RUNX1 , ASXL1 , TET2 , DNMT3A ), EVI1 overexpression screening, and 6.0 single-nucleotide polymorphism array (SNP-A) analysis in diagnostic samples of the 278 AML patients enrolled in the ALFA-0701 trial. In cytogenetically normal (CN) AML (n=146), 38% of the patients had at least 1 SNP-A lesion and 89% of the patients had at least 1 molecular alteration. In multivariate analysis, the independent predictors of higher cumulative incidence of relapse were unfavorable karyotype (P = 0.013) and randomization in the control arm (P = 0.007) in the whole cohort, and MLL partial tandem duplications (P = 0.014) and DNMT3A mutations (P = 0.010) in CN-AML. The independent predictors of shorter overall survival (OS) were unfavorable karyotype (P < 0.001) and SNP-A lesion(s) (P = 0.001) in the whole cohort, and SNP-A lesion(s) (P = 0.006), DNMT3A mutations (P = 0.042) and randomization in the control arm (P = 0.043) in CN-AML. Interestingly, CN-AML patients benefited preferentially more from GO treatment as compared to AML patients with abnormal cytogenetics (hazard ratio for death, 0.52 versus 1.14; test for interaction, P = 0.04). Although the interaction test was not statistically significant, the OS benefit associated with GO treatment appeared also more pronounced in FLT3 internal tandem duplication positive than in negative patients.