title: 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.
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.
authors.affiliation: Laboratory of Hematology, Biology and Pathology Center, CHRU of Lille, Lille.
authors.forename: Aline
authors.initials: A
authors.lastname: Renneville
authors.forename: Raouf Ben
authors.initials: RB
authors.lastname: Abdelali
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chevret
authors.forename: Olivier
authors.initials: O
authors.lastname: Nibourel
authors.forename: Meyling
authors.initials: M
authors.lastname: Cheok
authors.forename: Cécile
authors.initials: C
authors.lastname: Pautas
authors.forename: Rémy
authors.initials: R
authors.lastname: Duléry
authors.forename: Thomas
authors.initials: T
authors.lastname: Boyer
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Cayuela
authors.forename: Sandrine
authors.initials: S
authors.lastname: Hayette
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Raffoux
authors.forename: Hassan
authors.initials: H
authors.lastname: Farhat
authors.forename: Nicolas
authors.initials: N
authors.lastname: Boissel
authors.forename: Christine
authors.initials: C
authors.lastname: Terre
authors.forename: Hervé
authors.initials: H
authors.lastname: Dombret
authors.forename: Sylvie
authors.initials: S
authors.lastname: Castaigne
authors.forename: Claude
authors.initials: C
authors.lastname: Preudhomme
mesh_terms: D000368:Aged; D000617:Aminoglycosides / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015331:Cohort Studies; D003582:Cytogenetics; D005260:Female; D000079982:Gemtuzumab; D006801:Humans; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000090243:Nucleophosmin; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D012307:Risk Factors; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000617:Aminoglycosides; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C000716967:NPM1 protein, human; D000090243:Nucleophosmin; D000079982:Gemtuzumab