AML-291: MRD Level After Induction Therapy in NPM1-Mutated Patients Identifies Those at High Risk of Relapse and Defines Indications for HSCT

Abstract

Context Patients with NPM1 AML mutation are included in ELN favorable or intermediate genetic risk categories, although a proportion of these patients will relapse. Thus, it is necessary to identify negative prognostic factors for patientss with NPM1 and to evaluate if ASCT could overcome them. Objective To determine the clinical significance of post-remission MRD level NPM1 mutation and correlation with treatment outcome in AML patients. Design Twenty-seven patients with NPM1mut in CR were included in the study. All patients had WT1 overexpression. Additional genetic abnormalities were revealed in 12 patients ([hyperexpression of BAALC (n=4), IDH1/2 (n=4), FLT3ITD (n=8), DNMT3AR882C (n=1), ASXL1(n=1), RUNX1(n=1), aberrant karyotype (n=4)]. Monitoring of minimal residual disease was studied after induction («7+3) and consolidation courses («HiDAC»). Thirteen patients underwent HSCT. Median follow-up was 12 months (2.2–109 months). Results CIR (median 7.25 months vs not reached), RFS (median 7.25 months vs not reached) and OS (median 7.25 vs 41.80 months) were shorter in patients with NPM1mut reduction after an induction course less than 3.85 log (specificities 81.8%, sensitivities 100%) (p=0.001, p=0.0036, and p=0.05, respectively). Patients with NPM1+FLT3- status had similar results with this cut-off (median RFS 9.6 months vs not reached, p=0.037). Cutoff levels of NPM1mut 4.2 log (specificities 83.3%, sensitivities 83.3%) after the first consolidation course separated the cohort into two prognostic groups (14 and 13 patients) as well: median CIR 7.25 vs 41.80 months (p=0.02) and median OS 13 months vs not reached, p=0.05, respectively). MRD status after consolidation therapy in comparison to the MRD status after induction therapy has improved only in two patients but with relapse in 17.7 months and 9.7 months. HSCT improved CIR and OS in the group of patients with cut-off less than 3. 85 log (p=0.016, p=0.03). In the multivariate model with MRD cut-off, age, genetic abnormalities, FLT3 status, and WBC only post-induction cut-off level NPM1 were independent prognostic factors for RFS (HR:0.07; 95% CI: 0,006–0.955; p=0.04). Conclusions NPM1mut-positive patients have adverse prognosis if the post-induction reduction of expression of these genes is less than 3.85 log. This cut-off separated ELN favorable NPM1mut AML patients. Unfavorable prognosis of MRD cut-off-positive patients during AML treatment could be overcome with HSCT in the first CR.