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.
Highlights
Acute myeloid leukemia (AML) is a heterogeneous group of hematological malignancies with variable responses to therapy
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
Similar positive results have been reported in two Medical Research Council (MRC) trials [14, 15], and, as in the ALFA trial, it appeared that patients with favorable or intermediate cytogenetics, including those with cytogenetically normal acute myeloid leukemia (CN-AML), may benefit from GO, while not those with adverse karyotype
Summary
Acute myeloid leukemia (AML) is a heterogeneous group of hematological malignancies with variable responses to therapy. Prognostic impact within CN-AML has been well established for FLT3 internal tandem duplication (FLT3–ITD), NPM1 and CEBPA mutations. Similar positive results have been reported in two Medical Research Council (MRC) trials [14, 15], and, as in the ALFA trial, it appeared that patients with favorable or intermediate cytogenetics, including those with CN-AML, may benefit from GO, while not those with adverse karyotype. In this context, there is a growing interest in identifying molecular determinants of response to this targeted agent. Our objectives were first to evaluate the prognostic impact of these genetic alterations on clinical outcome, within the subset of CN-AML, and second to analyze potential interactions between these genetic alterations and GO treatment
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