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Clinical Trial
. 2014 Feb 28;5(4):916-32.
doi: 10.18632/oncotarget.1536.

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 , Raouf Ben Abdelali, Sylvie Chevret, Olivier Nibourel, Meyling Cheok, Cécile Pautas, Rémy Duléry, Thomas Boyer, Jean-Michel Cayuela, Sandrine Hayette, Emmanuel Raffoux, Hassan Farhat, Nicolas Boissel, Christine Terre, Hervé Dombret, Sylvie Castaigne, Claude Preudhomme
Affiliations
Clinical Trial

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 et al. Oncotarget. .

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.

Trial registration: ClinicalTrials.gov NCT00927498.

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Figures

Figure 1
Figure 1
(A) Circos plot diagram illustrating the pairwise co-occurrence of gene mutations in cytogenetically normal acute myeloid leukemia. (B) Bar coding representing the co-occurrence of molecular alterations and SNP-A lesions in cytogenetically normal acute myeloid leukemia. Each patient is represented by a virtual column. Colored cells indicate the presence of a mutation in the gene(s) described in that row on the left. Abbreviations: SNP-A, single-nucleotide polymorphism array; mut, mutation; ITD, internal tandem duplication; TKD, tyrosine kinase domain; PTD, partial tandem duplication.
Figure 2
Figure 2
Kaplan-Meier estimates of overall survival according to SNP-array profile and gene mutational status. (A) in the whole patient cohort analyzed by SNP-A, 2–year OS was estimated at 68% (95%CI, 54–75) in those without SNP-A lesion versus 37% (95%CI, 27.5–47) in those with SNP-A lesion (P < 0.0001 by the log-rank test); (B) in CN-AML patients analyzed by SNP-A, 2–year OS was estimated at 70% (95%CI, 56–80) in those without SNP-A lesion versus 46% (95%CI, 29–61) in those with SNP-A lesion (P = 0.0027 by the log-rank test); (C) in CN-AML patients tested for DNMT3A mutation, 2–year OS was estimated at 68% (95%CI, 55–78) in those without mutation versus 41% (95%CI, 24–57) in those with mutation (P = 0.0045 by the log-rank test).
Figure 3
Figure 3
Forest plots of patient subsets and pooled data for (A) cumulative incidence of relapse and (B) overall survival in all patients, and (C) cumulative incidence of relapse and (D) overall survival in patients with cytogenetically normal acute myeloid leukemia. P-values obtained with the Gail and Simon interaction tests are also indicated.
Figure 4
Figure 4
Kaplan-Meier estimates of overall survival according to FLT3–ITD status and treatment arm. (A) Overall survival according to FLT3–ITD status and treatment arm in all patients. In FLT3–ITD positive patients, 2–year OS was estimated at 46% (95%CI, 23–66) in the control arm versus 62% (95%CI, 32–82) in the GO arm (P = 0.07 by the log-rank test); In FLT3–ITD negative patients, 2–year OS was estimated at 44% (95%CI, 32–55) in the control arm versus 53% (95%CI, 42–63) in the GO arm (P = 0.30 by the log-rank test). (B) Overall survival according to FLT3–ITD status and treatment arm in patients with cytogenetically normal acute myeloid leukemia. In FLT3–ITD positive patients, 2–year OS was estimated at 36% (95%CI, 14–59) in the control arm versus 64% (95%CI, 29–85) in the GO arm (P = 0.023 by the log-rank test); in FLT3–ITD negative patients, 2–year OS was estimated at 55% (95%CI, 36–71) in the control arm versus 70% (95%CI, 53–82) in the GO arm (P = 0.20 by the log-rank test). Abbreviations: CN-AML: cytogenetically normal acute myeloid leukemia; ITD, internal tandem duplication.
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