In the European LeukemiaNet favourable risk category, allogeneic haematopoietic stem cell transplantation (alloSCT) is not indicated in first complete remission for patients with acute myeloid leukaemia (AML) with NPM1 mutations (ELNfav NPM1 AML), although a proportion of these patients will relapse. Given the prognostic importance of measurable residual disease (MRD), CETLAM-12 considered a pre-emptive intervention in patients with molecular failure (MF). We analyzed 110 ELNfav NPM1 AML patients achieving complete remission (CR) after induction chemotherapy. Two-year cumulative incidence of relapse (CIR), overall survival (OS) and leukaemia-free survival (LFS) were 17%, 81Á5% and 82%, respectively. Fortysix patients required additional therapy for MF (n = 33) or haematological relapse (HemR; n = 13), resulting in a molecular LFS (molLFS) and a cumulative incidence of MF at two years of 61% and 38% respectively. Two-year OS for these 46 patients was 66%, with a different outcome between patients with MF (86%) and HemR (42%) (P = 0Á002). Quantitative NPM1 detection at different timepoints was predictive of molLFS; an MRD ratio (NPM1mut/ ABL1 9 100) cutoff of 0Á05 after first consolidation identified two cohorts with a two-year molLFS of 77% and 40% for patients below and above 0Á05, respectively. In conclusion, MRD-based pre-emptive intervention resulted in a favourable outcome for ELNfav NPM1 AML patients.

The 2017 European LeukemiaNet (ELN 2017) guidelines for the diagnosis and management of acute myeloid leukemia (AML) have become fundamental guidelines to assess the prognosis and post-remission therapy of patients. However, they have been retrospectively validated in few studies with patients included in different treatment protocols. We analyzed 861 patients included in the CETLAM-12 risk-adapted protocol, which indicates cytarabine-based consolidation for patients allocated to the ELN 2017 favorable-risk group, while it recommends allogeneic stem cell transplantation as a post-remission strategy for the ELN 2017 intermediate- and adverse-risk groups. We retrospectively classified patients according to the ELN 2017, with 327 (48%), 109 (16%) and 245 (36%) patients allocated to the favorable, intermediate and adverse risk group, respectively. The 2 and 5 year-overall survival (OS) were 77 and 70% for favorable risk patients, 52 and 46% for intermediate risk patients, and 33 and 23% for adverse risk patients, respectively. Furthermore, we identified a subgroup of patients within the adverse group (inv(3)/t(3;3), complex karyotype and/or TP53 mutation/17p abnormality) with a particularly poor outcome, with a 2-year OS of 15%. Our study validates the ELN 2017 risk stratification in a large cohort of patients treated with an ELN-2017 risk-adapted protocol, based on alloSCT after remission for non-favorable ELN subgroups, and identifies a genetic subset with a very poor outcome which warrants investigation of novel strategies.

The negative prognostic impact of FLT3-ITD in patients with acute myeloid leukemia with mutated NPM1 (AML-NPM1) is restricted to patients with a higher FLT3-ITD allelic ratio (≥0.5; FLT3high) and considered negligible in wild-type (FLT3wt)/low ITD ratio (FLT3low) patients. Since the co-mutation of DNMT3A (DNMT3Amut) has been suggested to negatively influence the prognosis of AML-NPM1, we analyzed DNMT3Amut impact in FLT3-ITD subsets (absent, low and high ratio). A total of 164 patients diagnosed with AML-NPM1 who received intensive chemotherapy according to two consecutive protocols (AML-03 and AML-12) were selected: 76 harboring FLT3-ITD (46%), 79 DNMT3Amut (48%), and 39 (24%) showing both mutations. Overall, DNMT3A mutational status did not show prognostic impact with comparable OS (mut vs. wt 62±6% vs. 56±6%; p=0.2), RR (22±11% vs. 31±11%; p=0.2) and LFS (65±6 vs. 54±6, p=0.1). Prognostic stratification established by FLT3-ITD (FLT3wt= FLT3low> FLT3high) was independent of DNMT3A mutational status. Measurable residual disease (MRD) based on NPM1 quantitative-PCR kinetics was available in 94 patients. DNMT3Amut was associated with a higher number of mutated NPM1 transcripts following induction (p=0.012) and first consolidation (C1; p<0.001). All DNMT3Amut patients were MRD positive following C1 (p<0.001) and exhibit significant MRD persistence after second and third consolidations (MRD positive vs. negative p=0.027 and p=0.001). Finally, DNMT3Amut patients presented a trend to greater risk of molecular relapse (p=0.054). When molecular failure was proven, patients underwent an allogeneic transplant. In conclusion, DNMT3Amut did not modify overall prognosis exerted by FLT3-ITD in AML-NPM1 despite delayed MRD clearance, possibly due to MRD-driven pre-emptive intervention.

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Midostaurin added to intensive chemotherapy is the standard of care for acute myeloid leukemia (AML) with FLT3 mutations (FLT3mut). We analyzed the impact of midostaurin in 227 FLT3mut-AML patients included in the AML-12 prospective trial for fit patients ≤70 years (#NCT04687098). Patients were divided into an early (2012–2015) and late (2016–2020) cohorts. They were uniformly treated except for the addition of midostaurin in 71% of late group patients. No differences were observed in response rates or the number of allotransplants between groups. Outcome was improved in the late period: 2-year relapse incidence decreased from 42% vs 29% in early vs late group (p = 0.024) and 2-year overall survival (OS) improved from 47% vs 61% (p = 0.042), respectively. The effect of midostaurin was evident in NPM1mut patients (n = 151), with 2-yr OS of 72% (exposed) vs 50% (naive) patients (p = 0.011) and mitigated FLT3-ITD allelic ratio prognostic value: 2-yr OS with midostaurin was 85% and 58% in low and high ratio patients (p = 0.049) vs 67% and 39% in naive patients (p = 0.005). In the wild-type NPM1 subset (n = 75), we did not observe significant differences between both study periods. In conclusion, this study highlights the improved outcome of FLT3mut AML fit patients with the incorporation of midostaurin.

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Objectives High‐dose total body irradiation (TBI) is considered a cornerstone of myeloablative conditioning for allogeneic stem cell transplantation (allo‐SCT). We retrospectively compared the main outcomes of an HLA matched or 1‐allele mismatched related or unrelated allo‐SCT in adult patients affected by acute leukemia (AL) or myelodysplastic syndromes (MDS). Methods Fifty‐nine patients received cyclophosphamide (Cy)‐TBI (13.5 Gy) and graft‐versus‐host disease (GVHD) prophylaxis with a calcineurin‐inhibitor plus methrotrexate (CyTBI group) and 28 patients received fludarabine‐TBI (8.8–13.5 Gy) and GVHD prophylaxis with PTCy and tacrolimus (FluTBI‐PTCy group). Results Median follow‐up for survivors was 82 and 22 months. The 12‐month probability of overall survival and progression‐free survival were similar (p = .18, p = .7). The incidence of Grades 2–4 and 3–4 acute GVHD, and the incidence of moderate‐to‐severe chronic GVHD were higher in the CyTBI group (p = .02, p < .01and p = .03). Nonrelapse mortality (NRM) at 12 months posttransplant was higher in the CyTBI group (p = 0.05), while the incidence of relapse was similar in both groups (p = 0.7). The number of GVHD‐free and relapse‐free patients without systemic immunosuppression (GRFS) at 1‐year posttransplant was higher in the FluTBI‐PTCy group (p = 0.01). Conclusions The study confirms the safety and efficacy of a novel FluTBI‐PTCy platform with reduced incidence of severe acute and chronic GVHD, and early improvement of NRM.

We report a de novo aleukemic form of MCL with a complex monosomic karyotype with LOH for multiple chromosomes and TP53 mutation. Additionally, whereas D816V KIT was not found, the c‐Kit transmembrane domain p.M541L variant was detected which is the most common SNP of KIT gene in humans with controversial pathogenic role. In these cases, it is crucial to perform a rapid broad molecular study for an accurate diagnosis which could help to initiate targeted therapy.