Genetics of acute myeloid leukemia in the elderly: mutation spectrum and clinical impact in intensively treated patients aged 75 years or older

Abstract

A cute myeloid leukemia is a disease of the elderly (median age at diagnosis, 65-70 years). The prognosis of older acute myeloid leukemia patients is generally poor. While genetic markers have become important tools for risk stratification and treatment selection in young and middle-aged patients, their applicability in very old patients is less clear. We sought to validate existing genetic risk classification systems and identify additional factors associated with outcomes in intensively treated patients aged ≥75 years. In 151 patients who received induction chemotherapy in the AMLCG-1999 trial, we investigated recurrently mutated genes using a targeted sequencing assay covering 64 genes. The median number of mutated genes per patient was four. The most commonly mutated genes were TET2 (42%), DNMT3A (35%), NPM1 (32%), SRSF2 (25%) and ASXL1 (21%). The complete remission rate was 44% and the 3-year survival was 21% for the entire cohort. While adverse-risk cytogenetics (MRC classification) were associated with shorter overall survival (P=0.001), NPM1 and FLT3-ITD mutations (present in 18%) did not have a significant impact on overall survival. Notably, none of the 13 IDH1-mutated patients (9%) reached complete remission. Consequently, the overall survival of this subgroup was significantly shorter than that of IDH1-wildtype patients (P<0.001). In summary, even among very old, intensively treated, acute myeloid leukemia patients, adverse-risk cytogenetics predict inferior survival. The spectrum and relevance of driver gene mutations in elderly patients differs from that in younger patients. Our data implicate IDH1 mutations as a novel marker for chemorefractory disease and inferior prognosis. (AMLCG-1999 trial: clinicaltrials.gov identifier, NCT00266136).

Figure 1.

Overall survival according to the MRC and ELN risk classifications. (A) Overall survival for patients in the favorable-and intermediate-risk groups (green) compared to the adverse-risk group (red) according to the MRC cytogenetic risk category. (B) Overall survival for patients in the favorable-(green), intermediate-(orange) and adverse-risk groups (red) according to the ELN 2017 genetic category.

Figure 2.

Genetic landscape of old acute myeloid leukemia patients. (A) Driver gene mutations in 151 AML patients ≥75 years of age at primary diagnosis. The bar chart shows the 15 most commonly mutated genes in the 151 AML patients aged ≥75 years compared to 664 patients aged <60 and 60–74 at primary diagnosis (data from Metzeler et al.). (B) Heatmap showing associations between different driver gene mutations. Each column represents one patient.

Figure 3.

Overall survival according to gene mutations. (A) NPM1 mutations: overall survival in NPM1-mutated (green) compared to NPM1-wildtype patients (red). (B) NPM1-mutated/FLT3-ITD-negative patients: overall survival in NPM1-mutated/FLT3-ITD-wildtype patients (green) compared to other patients (red). (C) FLT3-ITD mutations: overall survival in FLT3-ITD-mutated (red) compared to FLT3-ITD-wildtype patients (green). (D) TP53 mutations: overall survival in TP53-mutated patients (red) compared to TP53-wildtype patients (green). “Mut” denotes mutated and “wt” wildtype.

Figure 4.

IDH1 mutations and survival. (A) Overall survival in IDH1-mutated patients (red line) compared to IDH1-wildtype patients (green line). (B) Overall survival in NPM1-mutated/IDH1-mutated patients (red line) compared to NPM1-mutated/IDH1-wildtype patients (green line). Mut: mutated; wt: wildtype.

Figure 5.

Impact of Eastern Cooperative Oncology Group performance status, Medical Research Council classification and IDH1 mutations on overall survival. Overall survival in patients with an ECOG performance status of 0-2, favorable or intermediate MRC category and IDH1-wildtype compared to patients with an ECOG performance status of 3–4 or MRC adverse category or IDH1 mutation.