Outcomes of NPM1-mutated AMLs in first hematological relapse and prognostic value of MRD

Abstract Background & Objectives. The prognosis of NPM1m AML after first hematological relapse and the predictive value of NPM1m MRD with respect to allogeneic hematopoietic cell transplantation (allo-HCT) are not well characterized. Methods. This study retrospectively included pts with NPM1m AML in first hematological relapse receiving salvage therapy at 2 centers between 2009 and 2023 (pre-menin inhibitor era). Pts treated for molecular relapse were excluded. All censored outcomes were studied from first hematological relapse, considering hematological response, first achievement of MRD negativity (in peripheral blood [PB] and/or bone marrow [BM]) and allo-HCT as time-dependent variables. Results. The study includes 103 pts (M/F 45/58, median age 59y [IQR 47–66]). Most (94,2%) had received intensive chemotherapy (IC) as frontline therapy, and only 3.9% had received allo-HCT in first complete remission (CR1). Median time to relapse was 16.2 months (IQR 8.7–27.8). Recurrent mutations at relapse were DNMT3A (57.5%), FLT3 38.2% (ITD 25.2%), IDH1 (24.7%), IDH2 (23.6%), WT1 (20.7%) and NRAS (14.1%). Salvage was IC in 60 (53.1%), low-intensity therapy (LIT) in 31 (27.4%), or single-agent targeted therapy (FLT3 or IDH inhibitors) in 12 (10.6%) pts. The overall response rate was 68.9% (CR 57.3%, CRi 4.9%, PR 2.9%, MLFS 3.9%); 42 pts received allo-HCT after salvage (only 1 with resistant disease). With a median follow-up of 45.1 months, the median OS from hematological relapse was 15.1 months. In univariable analysis, shorter OS was associated with older age (≥65 years [38.8%], p=0.004), early relapse (<12 months from diagnosis [36.9%], p<0.001), non-intensive salvage (LIT or targeted therapy, p<0.001), and to a lesser extent FLT3 mutation at relapse (ITD or TKD, p=0.082). WBC ≥20 G/L (20.8%) at relapse, FLT3-ITD, DNMT3A, IDH1, IDH2, or NRAS mutations were not prognostic. In multivariable Cox regression, age ≥65y (HR=2.03 [95%CI 1.12–3.67]; p=0.019), early relapse (HR=2.94 [1.56-5.56]; p<0.001) and non-intensive salvage (HR=2.38 [1.30-4.35]; p=0.004) but not FLT3 mut (HR=1.39 [0.75–2.60]; p=0.3) retained independent prognostic value. In univariable analysis, achieving any response (CR/CRi/PR/MLFS) was associated with a markedly improved OS (HR=0.12 [0.07–0.20]; p<0.001). This held true in both intensively (p=0.0006) and non-intensively (p<0.001) subgroups. This impact remained significant (p<0.001) in a multivariable analysis accounting for age ≥65 years, timing of relapse, FLT3 status and salvage intensity. In a multivariable model accounting for time to relapse, FLT3 status, overall response and salvage intensity, allo-HCT was independently associated with improved OS (HR=0.17 [0.04–0.62]; p=0.008). MRD was assessed in 63 (55.8%) pts after intensive (n=46) or non-intensive (n=17) salvage at a median of 3 timepoints (IQR 2-4.5), all before allo-HCT. MRD was assessed in the PB, BM or both in 52%, 18.3% and 29.7% timepoints, respectively (resp). Best MRD was obtained in PB (36.5%), BM (31.7%), or both simultaneously (31.7%). The median time from hematological relapse to best MRD was 83 days (IQR 60–124). The cumulative incidence of negative MRD by day 120 was 51.9% and 38.9% after IC and LIT resp (p=0.23). In a multivariable model accounting for timing of relapse, FLT3 status, and salvage intensity, MRD negativity was independently associated with improved OS (HR=0.29 [0.09–0.97]; p=0.043). Of 63 MRD-assessed pts, 39 (61.9%) received allo-HCT (23 with negative MRD) while 16 of the 24 non-transplanted pts achieved MRD negativity after salvage. In a Cox model, both MRD negativity (HR=0.26 [0.08–0.87]; p=0.028) and allo-HCT (HR=0.26 [0.07–0.92]; p=0.036) were independently associated with improved OS with no significant interaction between MRD status and allo-HCT (p=0.26). This remained true when accounting for age, CR1 duration, and salvage intensity. The 16 patients who achieved MRD negativity and did not undergo allo-HCT had a median age of 63y, were mostly (84.6%) FLT3 wild-type, and intensively salvaged in 56.2% cases. Most (83.2%) achieved stringent CR-MRD-. Their median OS from the time of MRD negativity was 61.2 months. Conclusions. In a pre-Menin inhibitor era, achieving MRD negativity is a strong predictor of improved survival in NPM1m AML pts in first hematological relapse but is not a pre-requisite to benefit from allo-HCT, which remains the standard of care in this population.