FLT3 D835E

Ten pts were R/R following previous treatment with other FLT3 inhibitors (gilteritinib, quizartinib, midostaurin, or HM43239). In dose-escalating phase Ia clinical trials, PHI-101 was well tolerated at all dose levels with no DLTs. Phase Ib dose-expansion trials with 160 mg daily dosing are currently ongoing. PHI-101 has delivered CRcs at 120 mg and 160 mg.

While the variant clones in mature populations may be the temporal salvages of AML-MRD clones (functional MRD) to survive against treatment, the variant clones in LSC-like populations might be the AML-MRDs practically contributing to AML recurrence and treatment-refractory.This approach suggests the methodology for specifying AML-MRD and pursuing its clonal evolution according to the treatment progress. This will help to improve AML risk stratification and the diagnostic methodology, enabling the preemptive detection of AML MRD at the initial diagnosis/treatment.

No engraftment was observed in mice injected with FLT3mut TCR-treated cells at 26 weeks, while all mock-TCR T cell-treated mice showed leukemic engraftment. In conclusion, we have identified a TCR specific for a peptide encoded by the recurrent FLT3 D835Y mutation presented on HLA-A2 that mediates efficient and specific in vivo rejection of AML harboring this mutation.

Sorafenib has limited activity against tyrosine kinase domain mutations...Treatment: Crenolanib was given with curative intent to three patients, one in combination with Vyxeos (liposomal cytarabine/daunorubicin), one with high-dose cytarabine, and one as maintenance therapy after her second HSCT... This series of five children with multiply relapsed FLT3-mutant AML shows that treatment with full doses of crenolanib can be safely combined with salvage chemotherapy. Rapid remissions could be obtained even in patients with co-occurring KMT2A, 3q, and p53 mutations. Crenolanib, which is novel type-I pan FLT3 inhibitor, was able to inhibit variant FLT3 mutations (D835H, D835E and D848P).