Data from Synergistic Activity of Combined FLT3-ITD and MDM2 Inhibition with Quizartinib and Milademetan in <i>FLT3</i>-ITD Mutant/<i>TP53</i> Wild-type Acute Myeloid Leukemias

<div>AbstractPurpose:<p>Acute myeloid leukemia (AML) is characterized by frequent mutations in FMS-like tyrosine kinase 3 (<i>FLT3</i>), overexpression of murine double minute 2 (MDM2), and <i>TP53</i> wild-type (WT). Monotherapies targeting FLT3 frequently result in the development of resistant disease. In this study, we investigated the antileukemic efficacy of co-targeting FLT3 and MDM2 with quizartinib and milademetan (Q/M) in <i>FLT3</i> internal tandem duplication (<i>FLT3</i>-ITD) AML cell lines, xenograft and patient-derived xenograft (PDX) models, and a phase I clinical trial.</p>Experimental Design:<p>Preclinical studies used human and murine cell lines carrying <i>FLT3</i>-ITD and/or tyrosine kinase domain mutations, <i>TP53</i> WT/knockdown, leukemia cell xenograft models, and a PDX model. Assays were conducted using milademetan (DS-3032b) and murine-specific MDM2 inhibitor (DS-5272). An open-label, phase I, dose-escalation clinical trial (ClinicalTrials.gov NCT03552029) was conducted.</p>Results:<p>Dual inhibition of <i>FLT3</i>-ITD and MDM2 synergistically induced apoptosis in <i>FLT3</i>-ITD/<i>TP53</i> WT AML and venetoclax-resistant cell lines, reduced tumor burden, and improved survival in xenograft and PDX models of <i>FLT3</i>-ITD AML. Phase I clinical data indicated favorable safety and tolerability for the Q/M combination treatment. Complete responses with incomplete hematologic recovery were achieved in 40% of patients with relapsed/refractory AML. Unsupervised single-cell proteomic analysis showed that Q/M treatment decreased the expression of prosurvival proteins (p-ERK, p-AKT, and Mcl-1) and activated protein signaling downstream of p53 including p53 upregulated modulator of apoptosis. YTHDF2 was increased after therapy in resistant cells. The Q/M combination demonstrated higher activity in CD34⁺ versus CD34⁻ leukemia blasts.</p>Conclusions:<p>Preclinical and mechanistic rationale and preliminary clinical data support the future development of MDM2/FLT3-targeting strategies for FLT3-mutant AML.</p></div>

Duke Scholars

Author Harry Paul Erba Medicine, Hematologic Malignancies and Cellular Therapy