Using gilteritinib and the mammalian target of rapamycin (mTOR) inhibitors to target FLT3 signaling as a treatment for FLT3+ Acute Myeloid Leukemia patients.

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B143
Abstract ID: 4478

Presenting Author:
Malia E Leifheit , Graduate Student at Rush Univ.

Abstract:

Acute myeloid leukemia (AML) is a hematological malignancy characterized by the overproduction of neoplastic myeloid stem cells and accounts for about one-third of leukemia diagnoses annually. FMS-like tyrosine kinase 3 (FLT3) is overexpressed on most AML blasts. FLT3 mutations are the most common genetic alteration in AML, consisting of internal tandem duplication (ITD) and point mutations in the tyrosine kinase domain (TKD). Both mutations result in downstream signaling of the mammalian target of rapamycin (mTOR). The majority of AML patients who are FLT3+ eventually relapse when treated solely with FLT3 inhibitors(i). While allogenic hematopoietic stem cell transplantation (allo-HCT) decreases the relapse rate in FLT3+ AML patients, the natural killer (NK) cells reconstituting immediately following allo-HCT have reduced effector function. Thus, NK cell cytotoxicity following allo-HCT is pivotal in preventing AML relapse. We show the effects of gilteritinib (a FLT3i) alone or in combination with mTORi’s on their ability to induce cell death on an FLT3+ITD+AML cell line and increase NK cell function. We show that gilteritinib alone significantly increased NK cell degranulation and cell death of FLT3+ AML cells. Also, a significant synergistic effect was observed when gilteritinib was used in combination with mTORi’s. This study provides new insight into NK cell activation by gilteritinib and mTORi’s and aims to improve AML treatment by introducing novel combination therapy.