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

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 IDH^mut 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 IDH1^mut, 115 IDH2R140^mut, 46 IDH2R172^mut) 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. 

IDH1^mut was associated with NRAS^mut (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 NRAS^mut (Q = .003), NPM1^mut (Q = .007), and higher WBC (Q = .007). Among IDH1^mut patients who were also NPM1^mut , 80% achieved CR/CRp versus 66% of IDH1^mut patients who were not also NPM1^mut (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 IDH1^mut patients, NPM1^mut was the only predictor of longer OS (hazard ratio [HR], 0.31; P = .0007). For NPM1^wt patients, 5-year OS was 35% versus 68% for NPM1^mut . In DNMT3A^wt patients, the effect of NPM1^mut in terms of OS was more apparent (HR, 0.21; P = .004).

IDH2R140^mut was associated with NPM1^mut (Q = .003), FLT3-ITD (Q = .02), and SRSF2^mut (Q = .002) as well as higher WBC (Q = .005). A total of 105 (91%) IDH2R140 patients achieved CR/CRp. If patients were also NPM1^mut , 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. NPM1^mut (HR, 0.43; P = .01) and DNMT3A^mut (HR, 2.14; P = .014) were determined to be independent prognostic factors. For NPM1^wt patients, 5-year OS was 40% versus 67% for NPM1^mut . Again, in DNMT3A^wt patients, the better OS outcome associated with NPM1^mut was more apparent (HR, 0.22; P = .001).

IDH2R172^mut was associated with BCOR^mut (Q = .009), lower WBC (Q = .009), fewer SRSF2^mut (Q = .003), FLT3-ITD (Q = .009), and no NPM1^mut (Q <.0001). Of all IDH2R172^mut 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%); IDH2R140^mut, 27 patients (39.2%); and IDH2R172^mut, 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, NPM1^mut is the best prognostic factor in patients who are IDH1^mut and IDH2R140^mut. 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.