Chromosomal Abnormalities and Prognosis in NPM1-Mutated Acute Myeloid Leukemia: A Pooled Analysis of Individual Patient Data From Nine International Cohorts

Purpose: Nucleophosmin 1 (NPM1) mutations are associated with a favorable prognosis in acute myeloid leukemia (AML) when an internal tandem duplication (ITD) in the fms-related tyrosine kinase 3 gene (FLT3) is absent (FLT3-ITD^neg) or present with a low allelic ratio (FLT3-ITD^low). The 2017 European LeukemiaNet guidelines assume this is true regardless of accompanying cytogenetic abnormalities. We investigated the validity of this assumption.

Methods: We analyzed associations between karyotype and outcome in intensively treated patients with NPM1^mut/FLT3-ITD^neg/low AML who were prospectively enrolled in registry databases from nine international study groups or treatment centers.

Results: Among 2,426 patients with NPM1^mut/FLT3-ITD^neg/low AML, 2,000 (82.4%) had a normal and 426 (17.6%) had an abnormal karyotype, including 329 patients (13.6%) with intermediate and 83 patients (3.4%) with adverse-risk chromosomal abnormalities. In patients with NPM1^mut/FLT3-ITD^neg/low AML, adverse cytogenetics were associated with lower complete remission rates (87.7%, 86.0%, and 66.3% for normal, aberrant intermediate, and adverse karyotype, respectively; P < .001), inferior 5-year overall (52.4%, 44.8%, 19.5%, respectively; P < .001) and event-free survival (40.6%, 36.0%, 18.1%, respectively; P < .001), and a higher 5-year cumulative incidence of relapse (43.6%, 44.2%, 51.9%, respectively; P = .0012). These associations remained in multivariable mixed-effects regression analyses adjusted for known clinicopathologic risk factors (P < .001 for all end points). In patients with adverse-risk chromosomal aberrations, we found no significant influence of the NPM1 mutational status on outcome.

Conclusion: Karyotype abnormalities are significantly associated with outcome in NPM1^mut/FLT3-ITD^neg/low AML. When adverse-risk cytogenetics are present, patients with NPM1^mut share the same unfavorable prognosis as patients with NPM1 wild type and should be classified and treated accordingly. Thus, cytogenetic risk predominates over molecular risk in NPM1^mut/FLT3-ITD^neg/low AML.