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Prognostic Significance of Concomitant Gene Mutations in Intensively Treated Patients with IDH1/2 Mutated AML

2020 Year in Review - AML - Leukemia

Approximately 20% of patients with acute myeloid leukemia (AML) have disease that carries ≥1 somatic mutations in IDH. However, the data on the prognostic value of identifying co-occurring mutations for each IDHmut subgroup in patients planned to undergo allogeneic stem-cell transplantation (allo-SCT) are inconsistent. The clinical use of isocitrate dehydrogenase (IDH) inhibitors in AML have made the prognostic implications of gene mutational profiles even less clear. This study aimed to determine the significance of covariates in each IDH mut subtype for prognosis. In addition, this study evaluated AML patients with unfavorable risk profile—per European LeukemiaNet (ELN) 2010 criteria—undergoing intensive chemotherapy to determine the outcome of subsequent allo-SCT.

Patients with IDH-mutated AML (262 total: 101 IDH1mut, 115 IDH2R140mut, 46 IDH2R172mut) from the ALFA-0702 (N = 133; median age, 50 years) and ALFA-1200 (N = 129; median age, 67 years) trials were analyzed retrospectively. Data from sequencing of 37 genes were available for each patient. If a patient with unfavorable ELN-2010 risk profile that achieved complete remission or complete remission with incomplete platelet recovery (CR/CRp) had a sibling or matched unrelated donor, they were considered eligible for allo-SCT. The correlation between IDH subtype and covariates and the significance of the tested correlations were determined. 

IDH1mut was associated with NRASmut (Q-statistic value = .0008). Among IDH1 subtypes, associations varied somewhat. IDH1R132C was associated with a lower white blood cell count (WBC) (Q = .03); however, IDH1R132H was associated more strongly with NRASmut (Q = .003), NPM1mut (Q = .007), and higher WBC (Q = .007). Among IDH1mut patients who were also NPM1mut , 80% achieved CR/CRp versus 66% of IDH1mut patients who were not also NPM1mut (P <.001).At median follow-up of 40.3 months, median overall survival (OS) was not reached, while median event-free survival (EFS) was 15.1 months. For IDH1mut patients, NPM1mut was the only predictor of longer OS (hazard ratio [HR], 0.31; P = .0007). For NPM1wt patients, 5-year OS was 35% versus 68% for NPM1mut . In DNMT3Awt patients, the effect of NPM1mut in terms of OS was more apparent (HR, 0.21; P = .004).

IDH2R140mut was associated with NPM1mut (Q = .003), FLT3-ITD (Q = .02), and SRSF2mut (Q = .002) as well as higher WBC (Q = .005). A total of 105 (91%) IDH2R140 patients achieved CR/CRp. If patients were also NPM1mut , 100% (58/58) achieved CR/CRp versus 82% (47/57) for patients who were not, but this difference was not significant. At median follow-up of 40.7 months, median OS was not reached, and median EFS was 25.8 months. NPM1mut (HR, 0.43; P = .01) and DNMT3Amut (HR, 2.14; P = .014) were determined to be independent prognostic factors. For NPM1wt patients, 5-year OS was 40% versus 67% for NPM1mut . Again, in DNMT3Awt patients, the better OS outcome associated with NPM1mut was more apparent (HR, 0.22; P = .001).

IDH2R172mut was associated with BCORmut (Q = .009), lower WBC (Q = .009), fewer SRSF2mut (Q = .003), FLT3-ITD (Q = .009), and no NPM1mut (Q <.0001). Of all IDH2R172mut patients, 78% achieved CR/CRp. At median follow-up of 43.9 months, median OS was 61.5 months and median EFS was 13.96 months. It was determined that WBC (HR, 2.8; P = .039) and platelet count (HR, 0.17; P = .003) were independent prognostic factors.

At the time of achievement of their first CR, 69 (55%) patients in the unfavorable risk category received allo-SCT, at which point the distribution of the various mutations was as follows: IDH1R132C, 23 patients (33.3%); IDH2R140mut, 27 patients (39.2%); and IDH2R172mut, 19 patients (27.5%). For the entire cohort, allo-SCT was associated with prolonged EFS (HR, 0.64; P = .088); it was also associated with prolonged OS in IDH1 patients (HR, 0.44; P = .065).

In conclusion, NPM1mut is the best prognostic factor in patients who are IDH1mut and IDH2R140mut. It may prove useful as a stratification factor in clinical trials evaluating IDH inhibitors when administered with intensive chemotherapy.

Reference

Duchmann M, Micol JB, Duployez N, et al. Prognostic Significance of Concomitant Gene Mutations in Intensively Treated Patients with IDH1/2 Mutated AML. Presented at: 25th European Hematology Association Congress Virtual; June 11-21, 2020. Abstract S146.

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Last modified: July 22, 2021