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.
BackgroundDespite great efforts to identify druggable molecular targets for AML, there remains an unmet need for more effective therapies.MethodsAn in silico screening was performed using Connectivity Maps to identify FDA-approved drugs that may revert an early leukaemic transformation gene signature. Hit compounds were validated in AML cell lines. Cytotoxic effects were assessed both in primary AML patient samples and healthy donor blood cells. Xenotransplantation assays were undertaken to determine the effect on engraftment of hit compounds. The mechanism of action responsible for the antileukaemic effect was studied focussing on lysosomes and mitochondria.FindingsWe identified a group of antihistamines (termed ANHAs) with distinct physicochemical properties associated with their cationic-amphiphilic nature, that selectively killed leukaemic cells. ANHAs behaved as antileukaemic agents against primary AML samples ex vivo, sparing healthy cells. Moreover, ANHAs severely impaired the in vivo leukaemia regeneration capacity. ANHAs' cytotoxicity relied on simultaneous mitochondrial and lysosomal disruption and induction of autophagy and apoptosis. The pharmacological effect was exerted based on their physicochemical properties that permitted the passive targeting of both organelles, without the involvement of active molecular recognition.InterpretationDual targeting of lysosomes and mitochondria constitutes a new promising therapeutic approach for leukaemia treatment, supporting the further clinical development.FundThis work was funded by the (RMR), (RMR), the (RMR), the (RMR), (RMR), and (IJC).
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