Prognostic impact of co-mutations in adults with IDH1/2-mutated acute myeloid leukemia

Acute myeloid leukemia (AML) is characterized by the accumulation of cytogenetic and molecular abnormalities. Isocitrate dehydrogenase 1 and 2 (IDH1/2) mutations occur in 11% to 20% of adults with AML. The outcome of IDH1/2-mutated AML is heterogeneous and affected by co-mutational patterns. We retrospectively analyzed 118 patients with IDH1/2-mutated AML who were retrieved from 1597 patients newly diagnosed with AML and treated with intensive chemotherapy. Univariate analysis revealed the NPM1 mutation was a favorable factor (p = 0.019) for overall survival (OS), whereas the DNMT3A mutation was consistently associated with a poor outcome (3-year OS, 52.0%; 3-year relapse-free survival [RFS], 44.8%; and 3-year cumulative incidence of relapse [CIR], 42.6%). Interestingly, the DNMT3A mutation still identified patients with a poorer prognosis, even when measurable residual disease (MRD) was negative after 2 courses of chemotherapy. In a multivariate regression model, age, DNMT3A mutation and MRD positivity were retained as independent adverse markers for OS, RFS, and CIR. In the absence of the DNMT3A or FLT3-ITD mutations, the NPM1 mutation identified patients with a very favorable OS (3-year OS, 96.3% and 86.3%, respectively). Finally, hematopoietic stem cell transplantation in first complete remission significantly improved RFS (p = 0.015) and there was a trend toward improvement in OS (p = 0.282) for patients with the DNMT3A mutation but it did not benefit 2 subgroups with the IDH1/2+/NPM1+/DNMT3A- and IDH1/2+/NPM1+/FLT3-ITD- genotypes. In summary, this study provides a reference for risk stratification and treatment implications for patients with IDH1/2-mutated AML as well as for comparison with results of IDH inhibitor- or venetoclax-based combination therapy.