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 (<i>IDH1/2</i>) mutations occur in 11% to 20% of adults with AML. The outcome of <i>IDH1/2</i>-mutated AML is heterogeneous and affected by co-mutational patterns. We retrospectively analyzed 118 patients with <i>IDH1/2</i>-mutated AML who were retrieved from 1597 patients newly diagnosed with AML and treated with intensive chemotherapy. Univariate analysis revealed the <i>NPM1</i> mutation was a favorable factor (<i>p</i> = 0.019) for overall survival (OS), whereas the <i>DNMT3A</i> 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 <i>DNMT3A</i> 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, <i>DNMT3A</i> mutation and MRD positivity were retained as independent adverse markers for OS, RFS, and CIR. In the absence of the <i>DNMT3A</i> or <i>FLT3</i>-ITD mutations, the <i>NPM1</i> 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 (<i>p</i> = 0.015) and there was a trend toward improvement in OS (<i>p</i> = 0.282) for patients with the <i>DNMT3A</i> mutation but it did not benefit 2 subgroups with the <i>IDH1/2</i>+/<i>NPM1</i>+/<i>DNMT3A</i>- and <i>IDH1/2</i>+/<i>NPM1</i>+/<i>FLT3</i>-ITD- genotypes. In summary, this study provides a reference for risk stratification and treatment implications for patients with <i>IDH1/2</i>-mutated AML as well as for comparison with results of IDH inhibitor- or venetoclax-based combination therapy.