Abstract
One of the greatest challenges in drug development for Acute Myeloid Leukemia (AML) is the low success rate of therapeutic candidates in clinical trials. This is mainly due to insufficient preclinical testing using cell lines or transgenic murine models that do not reflect the molecular abnormalities of most AMLs. Here we generated a patient-derived xenograft (PDX) resource within highly immunocompromised mice that recapitulates the risk groups and genetic diversity found in large clinical trials. Bone marrow or blood samples from 50 patients were tested for engraftment in NSGS, NRGS, or NSG, that was defined by blast morphology, established donor chimerism, splenomegaly, anemia or thrombocytopenia. Regression analysis identified donor age as predictor for engraftment success. The overall engraftment success rate in NSGS/NRGS was 70%, with accelerated AML progression when compared to NSG. Pairwise analysis revealed a higher percentage of patient-derived CD34+ CD38- cells in NSG when compared to NSGS/NRGS. From the engrafting AMLs, 30 were randomly selected and molecularly characterized by transcriptional and mutational sequencing. The identities and frequencies of the mutations were similar to those observed in large AML trials, with NPM1 and DNMT3A mutations most frequently found. We validated the clinical significance of the generated AML PDX resource by performing a randomized, Phase II-like preclinical trial on standard chemotherapy (5+3: cytarabine and doxorubicin; 19 individual AMLs; 6 NRGS per treatment group). Relapse was determined by the underlying AML kinetics and closely correlated with prognosis subgroup. Altogether, the generated AML PDX resource faithfully recapitulates the risk groups and molecular abnormalities found in comprehensive clinical trials, and is therefore a valuable tool for adequately powered Phase II-like preclinical trials in AML.
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