Session: 617. Acute Myeloid Leukemia: Biology, Cytogenetics, and Molecular Markers in Diagnosis and Prognosis: Poster I
Hematology Disease Topics & Pathways:
AML, Diseases, MDS, Technology and Procedures, MPN, Clinically relevant, Myeloid Malignancies, molecular testing, NGS
We applied a newly developed platform technology to perform targeted single-cell DNA sequencing on over 140,000 cells and generated high-resolution maps of clonal architecture from AML tumor samples. Marrow and/or peripheral blood samples were collected prior to, during treatment, and at clinical progression to the FLT3 inhibitor gilteritinib given on a clinical trial for relapsed/refractory AML with FLT3 mutation. Single-cell sequencing of multiple patient samples demonstrated that relapse clones acquired oncogenic RAS mutations. We utilized the high-throughput and sensitivity of our single-cell approach to more definitively assess where in the course of treatment these RAS mutated clones were acquired. Oncogenic RAS harboring clones, comprising between 0.4%, and 0.1% of tumor populations, were identified in patient samples either prior to or shortly after onset of treatment. Significantly, these RAS variant alleles were not detectable with targeted bulk sequencing. Throughout the course of treatment with the FLT3 inhibitor gilteritinib, the RAS mutant clones selectively expanded and were responsible for resistance to therapy and relapse. These findings point to the presence of underlying genetic heterogeneity in AML and demonstrate the utility of sensitively assaying clonal architecture to better inform patient stratification and therapy selection.
Disclosures: Eastburn: Mission Bio, Inc.: Employment, Equity Ownership. Durruthy-Durruthy: Mission Bio, Inc.: Employment, Equity Ownership. Smith: Astellas Pharma: Research Funding. Perl: Arog: Consultancy; Actinium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; NewLink Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria; Takeda Oncology: Honoraria; Asana Biosciences: Honoraria; Seattle Genetics: Honoraria.
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