NPM1 AML account for 30% of adult AML, frequently harbor targetable mutations in FLT3 or IDH1 and often express targetable CD33.

Most patients achieve complete remission (CR), but half of them relapse. NPM1 residual disease (MRD) is the gold standard for monitoring patients. Molecular relapses are defined by NPM1 MRD positivity and absence of blasts on bone marrow cytology. Retrospective studies suggest that pre-emptive treatments before cytologic relapse lead to better long-term outcome. However, there is currently no recommendation for second-line treatments due to frequent and unpredictable clonal evolution at relapse, and a technological barrier preventing characterization of the rare residual leukemic cells. Genetic and phenotypic evaluation of single-cell leukemic cells at molecular relapse is thus necessary to optimize treatment decisions.

We therefore aim to upgrade the Tapestri multi-omics protocol (Mission Bio) to capture all the biomarkers of resistance and response to second-line treatments in NPM1 AML. In addition to somatic mutations identification and surface protein detection, we want to quantify intra-cellular proteins involved in apoptosis resistance, metabolic dependencies and intra-cellular signalling pathways.

Through this seed funding, we expect to demonstrate the feasibility of this approach, to apply for national funding to evaluate its relevance in a national prospective clinical trial.