Abstract 2827: Characterization of acute myeloid leukemia PDX models with hotspot gene mutations for therapeutic evaluation

Abstract Introduction: Acute myeloid leukemia (AML) is the most common acute type of leukemia in adults characterized by chromosomal abnormalities and gene mutations. While inhibitors have shown promise targeting FLT3 mutations, resistance to these inhibitors can emerge. Similarly, inhibitors targeting IDH1 and IDH2 mutations showed promise, yet the emergence of drug resistance poses a significant challenge. In this study, a panel of AML PDX models with multiple gene alterations was established to support the development of new therapies. Methods: The systemic AML PDX models were established using patients’ peripheral blood (PB) or bone morrow (BM) injected intravenously and expanded in vivo by using splenic tumor cells. One AML PDX model derived from patient skin was established subcutaneously. Expression of human CD45+ in PB cells for systemic models or tumor volume for the subcutaneous model was used to monitor the tumor burden. Leukemic loads (hCD45+ cells) were measured in PB, spleen (SP), and BM. Tumors were categorized following tumor immunophenotyping, histology, and RNA sequencing/Whole Exome Sequencing. For in vivo efficacy studies, animals were grouped 3-5 weeks after systemic tumor cells inoculation and treated with AC220 (1, 2 or 10 mg/kg, p. o. , QD), Cytarabine (Ara-c, 2mg/kg, i. p. , QD), 5-azacytidine (2mg/kg, i. p. , QD), Sorafenib (10mg/kg, i. p. , QD) and Gilteritinib (10 or 30mg/kg, p. o. , QD). Results: Nine systemic and one subcutaneous AML PDX models carrying hotspot mutations (e. i. FLT3-ITD or TKD, IDH1-R132H and IDH2-R140Q) were established, showing comparable features to the clinic. Systemic AM8231 PDX model harboring FLT3-ITD mutation treated with AC220, a type II FLT3i, showed significant tumor burden reduction in PB at different time points and in SP and BM at termination, as well as a survival increase. Similarly in systemic model AM7577 with FLT3-ITD mutation treated with AC220, significant tumor burden reduction in PB was observed. Whereas using systemic model AM9626 (model with Sorafenib pretreatment history) with coexisting-FLT3-ITD/D835H TKD mutation, no significant efficacy was observed with AC220i, suggesting a FLT3-TKD mediated resistance mechanism. To overcome the resistance, Gilteritinib, a type I FLT3i, was tested in AM9626 and showed significant reduction of hCD45+ cells in PB compared to the control group, even at a lowest dose. As model AM9626 PDX also carries IDH1 mutation, the level of serum 2-HG correlated with the tumor burden. The functional effect of IDH1 inhibitor on the tumor inhibition and 2-HG level is under investigation. Conclusion: The results presented in this study showed the establishment of a panel of AML PDX models, including different subtypes and genomic features reflecting the clinic. Those models will support the preclinical evaluation of new treatments or combination modalities as well as a better understanding of drug resistance mechanisms. Citation Format: Qingzhi Liu, Jinxi Wang, Jinping Liu, Likun Zhang, Ludovic Bourre, Jingjing Wang. Characterization of acute myeloid leukemia PDX models with hotspot gene mutations for therapeutic evaluation abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 2827.