Potential Off-Target Effect of Gilteritinib With Venetoclax Decreases Tumor Burden for Patients With Relapsed/Refractory Wild-Type FLT3 Acute Myeloid Leukemia/Myelodysplastic Neoplasms.

Many tyrosine kinase inhibitors show nonspecific activity against multiple kinases, causing off-target effects when used in a broad patient population. This study evaluated the effectiveness of gilteritinib combined with venetoclax in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) or myelodysplastic neoplasms (MDS) with wild-type FLT3, who currently lack targeted therapy. After a 28-day cycle of venetoclax-gilteritinib therapy, one patient with R/R AML and other genetic alterations achieved minimal residual disease (MRD)-positive complete remission (CR) with incomplete hematologic recovery (CRi). Another patient with R/R ASXL1-mutated MDS/AML achieved morphologic leukemia-free state (MLFS) after one cycle, but cytopenias persisted across two cycles. A patient with R/R TP53-mutated AML related to myelodysplasia did not respond (NR) after two cycles, although the blast percentage in bone marrow (BM) and peripheral blood (PB) decreased by 50%. In a patient with R/R AML carrying an in-frame bZIP-mutated CEBPA, NR and disease progression occurred after one cycle, but elevated white blood cell (WBC) counts declined after treatment initiation and lasted for 2 weeks. These findings suggest that combining gilteritinib with venetoclax may reduce tumor burden in R/R AML/MDS patients with wild-type FLT3.