Acute Myeloid Leukaemia with Normal Cytogenetics and NPM1-Mutation: Impact of Mutation Topography on Outcomes

Abstract Background About one-half of adults with acute myeloid leukaemia with normal cytogenetics (CN-AML) have a nucleophosmin-1 (NPM1) mutation. There is controversy regarding their prognosis and best therapy. Methods We studied 150 consecutive subjects with these features using targeted regional sequencing. The co-variates in the multi-variable analyses including clinical baseline data and genetic mutations. Prognostic stratification based on identified risk factors was performed, and subjects were assigned to two post-remission therapies with and without a transplant. Subsequently, we evaluated the effect of post-remission therapy. Results In multi-variable analyses a positive MRD-test after the 2nd consolidation cycle (Hazard Ratio [HR] = 6.00; 95% Confidence Interval [CI] [3.31, 10.85]; P < 0.001), DNMT3A mutation (HR = 3.01 [1.57, 5.78]; P < 0.001), FLT3-ITD mutation with high variant allele frequency (VAF) (HR = 4.40 [1.89, 10.24]; P < 0.001) and DEAD/H-box helicase 11 (DDX11) mutations (HR = 4.38 [2.38, 8.04]; P < 0.001) were independently correlated with higher cumulative incidence of relapse (CIR) and worse leukaemia-free survival (LFS) (HR = 5.76 [3.16, 10.48]; P < 0.001; HR = 3.32 [1.78, 6.20]; P < 0.001; HR = 4.03 [1.82, 8.94]; P < 0.001; HR = 4.24 [1.99, 9.01]; P < 0.001). Subjects with ≥ 1 high-risk co-variate who received an allogeneic haematopoietic cell transplant had a lower CIR and better LFS compared with subjects not receiving a transplant. Allocation to a transplant was not random and our censoring was imperfect so this observation needs validation. Conclusions In conclusion, we identified co-variates associated with CIR and LFS in subjects of NPM1-mutated CN-AML. Trial registration The trial is registered at Clinicaltrials. gov (NCT01455272, NCT02185261) and in chictr.org (ChiCTR-OCH-10000940).