Molecular Minimal Residual Disease Monitoring In Npm1-Mutated Acute Myeloid Leukemia: A Single Institution Experience

Abstract

Introduction: The NPM1mut identification by RQ-PCR at diagnosis is important for AML risk stratification and represents a reliable marker to track minimal residual disease (MRD) and to early detect relapse. We retrospectively analyzed clinical and biological features of NPM1mut AML pts consecutively treated with intensive therapy in our Institution to evaluate the role of MRD monitoring in relation to overall survival (OS) and disease free survival (DFS). Methods: We analyzed 104 NPM1mut AML pts eligible for intensive therapy, diagnosed between 2008 and 2018. Median age was 52 years (y) (range, 8-75). NPM1mut was detected in the bone marrow (BM) by RQ-PCR at diagnosis and at different time points. MRD levels were expressed as a percentage (ratio of the NPM1 copies-cp to the housekeeping gene ABL cp × 100); MRD positivity was defined as any level above 0.01%. FLT3mut was detected in 50 pts (48.1%) (7 FLT3-TKD; 43 FLT3-ITD). All pts received intensive treatment according to local institutional standard. After induction and consolidation, pts received either high-dose (HD) chemotherapy followed by autologous stem cell transplantation (ASCT) or 2/3 further cycles of HDAra-C if not eligible for ASCT. Results: Eighty-nine pts achieved a complete remission (CR) (85.6%), 7 proved refractory (6.7%), while 8 died during induction (7.7%). After induction, MRD was available for 50 pts (61.7%): 8 (16%) were MRD negative (-) (7 FLT3wt; 1 FLT3mut) and 42 (84%) were MRD positive (+) (18 FLT3wt; 24 FLT3mut); MRD evaluation after I consolidation was performed in 52 pts (64.2%): 16 (30.8%) were MRD- (9 FLT3wt; 7 FLT3mut), 36 (69.2%) were MRD+ (16 FLT3wt; 20 FLT3mut). For the whole cohort, the 5y-OS was 40.8% (95% CI, 31.5-52.9%) and 5y-DFS was 38.2% (95% CI, 28.8-50.7%). Achieving an MRD- after induction or I consolidation, identified pts with better 5y-DFS than pts with persisting MRD+ (85.6% and 65.5% vs 40% and 26%; p= 0.015, p= 0.032). This also translated into significant differences in 5y-OS (100% and 75.8% vs 44% and 30.5%; p= 0.009, p= 0.045); 5y-cumulative incidence of relapse (CIR) was 43.7% (95% CI: 30.2-54.6%). No statistically significant differences were observed in OS (p= 0.535) and DFS (p= 0.224) according to FLT3 status. However, the CIR was higher in FLT3mut pts (p= 0.063). In the whole cohort, ASCT were 24, allogenic (allo)SCT were 26. Reasons for alloSCT in CR1 were: 1) FLT3-ITDmut; 2) secondary-AML; 3) raising MRD levels, 4) slow clearance of MRD reduction; 5) primary refractory pts. MRD- pts before alloSCT showed a trend towards better OS (p= 0.074) and DFS (p= 0.065) than MRD+ pts. Conclusions: Our study underlines the clinical relevance of achieving an early molecular response in NPM1mut AML. MRD monitoring is a valuable tool for the early identification of pts who might benefit from alloSCT/new drugs and pts with molecular relapse. The most relevant time points for collecting samples and the prognostic MRD thresholds remain to be defined.