Prognostic significance of concurrent gene mutations in intensively treated patients withIDH-mutated AML: an ALFA study

Abstract

IDH inhibitors are effective in AML, and trials evaluating frontline combinations with intensive chemotherapy (IC) are ongoing. Data on the prognostic significance of co-occurring genetic alterations and allogeneic hematopoietic stem cell transplantation (HSCT) are conflicting in each IDH-mutated subgroup treated by IC, while this information is important for trial design and results interpretation. We retrospectively analyzed 127 IDH1, 135 IDH2R140 and 57 IDH2R172 newly diagnosed AML patients treated with IC in three Acute Leukemia French Association (ALFA) prospective trials. We addressed in each IDH subgroup the prognostic impact of clinical and genetic covariates, and the role of HSCT in eligible patients. In IDH1 patients, presence of NPM1 mutations was the only variable predicting improved OS in multivariate analysis (p < 0.0001). In IDH2R140, normal karyotype (p= 0.008) and NPM1 mutations (p = 0.01) predicted better OS. NPM1 mutations were associated with better DFS (p = 0.0009) whereas presence of DNMT3A mutations was associated with shorter DFS (p = 0.0006). In IDH2R172, platelet count was the only variable retained in the multivariate model for OS (p = 0.002). Among non-favorable ELN-2010 eligible patients, 71 (36%) achieved an HSCT in first complete remission (CR1) and had longer OS (p = 0.03) and DFS (p = 0.02) than not-transplanted patients. Future clinical trial testing frontline IDH inhibitors combined with IC may consider stratification on NPM1 mutational status, the main prognostic factor in IDH1 and IDH2R140 mutated AML. HSCT improve OS of non-favorable IDH1/2-mutated AML and should be fully integrated in the treatment strategy.

Differential impact of IDH1/2 mutational subclasses on outcome in adult AML: results from a large multicenter study

“…The proportions of different IDH variants were comparable to our study. In line with our study, Duchmann et al 39 reported IDH2-R172 to be associated with fewer co-mutations and to be mutually exclusive with NPM1. In their analysis, co-mutations of NPM1 and IDH2-R140 or IDH1-R132…”

“…While Duchmann et al 39 refer to the ELN2010 classification 40 for subgroup analysis, we used the more recent ELN2017 classification. 22 16…”

“…The median variant allele fractionequency (VAF) for IDH mutations was 38% (IQR: [30][31][32][33][34][35][36][37][38][39][40][41][42][43] with no difference in VAF between mutational subgroups (Supplement Tbl.1).…”

Clonal Architecture and Evolutionary Dynamics in Acute Myeloid Leukemias

“…However, gene-gene interactions ('epistasis') are likely to affect the combined output of combinations of driver mutations. Some combinations of mutations may synergize at the molecular level, leading to large gains of fitness and clonal dominance, strong association at the population level, and poorer prognosis, as exemplified in AML by the combination of IDH2 and DNMT3A mutations [25,63,126,127]. During AML progression, fitness gains of mutations tend to be lower, owing to partially overlapping effects (diminishing-returns epistasis [64]), progressive alteration of the cellular signaling networks, and increased immunogenicity [9,128].…”

New Drugs Bringing New Challenges to AML: A Brief Review

“…The biomarkers associated with clinical response remain unclear. In examining the prognostic significance of co-mutations in IDH-mutant AML, the NPM1 mutation was associated with improved OS in IDH1-or IDH2R140-mutated AML treated with intensive chemotherapy, suggesting a potential group of patients who would particularly benefit from the addition of targeted therapy [36].…”