gilteritinib and Mycoses

Mutation within the FMS-like tyrosine kinase 3 (FLT3) gene are one of the most frequent genetic alterations in acute myeloid leukemia. A high mutation fraction of FLT3-ITD molecules on the surface of leukemia cells is associated with short remissions and overall adverse outcomes in AML. In this article we summarize the clinical trial data of midostaurin - one of the FLT3 inhibitors. We review its use in various combinations both in relapsed/refractory acute myeloid leukemia as well as in the newly diagnosed patients and recollect the evidence of its use as maintenance therapy post allogenic stem cell transplantation. We enumerate the practical issues faced in the use of midostaurin like antifungal prophylaxis, dosage of concomitant chemotherapy agents as well as available data on sequencing of the FLT3 inhibitors. Lastly, we provide our perspective of the future directions for FLT3 inhibition especially midostaurin, the underlying resistance mechanisms and the need for standardization of the FLT3 tests.

Topics: Aniline Compounds; Anthracyclines; Antifungal Agents; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Cytarabine; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Echinocandins; fms-Like Tyrosine Kinase 3; Forecasting; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Maintenance Chemotherapy; Mutation; Mycoses; Protein Kinase Inhibitors; Pyrazines; Randomized Controlled Trials as Topic; Recurrence; Staurosporine; Triazoles

Gilteritinib is primarily metabolized via cytochrome P450 (CYP). Therefore, concomitant administration of strong CYP3A4 inducers or inhibitors is not recommended. We evaluated the incidence of gilteritinib-related adverse events (AEs) in 47 patients who received gilteritinib with or without antifungal triazoles which are known inhibitors of CYP3A4. Reasons for coadministration were antifungal prophylaxis or treatment of suspected or confirmed fungal diseases. Gilteritinib-related AEs were similar in the gilteritinib-triazole group compared to the gilteritinib without triazole group (75 % vs. 55.5 %, P = 0.23). Additionally, severity of AEs, gilteritinib dose reductions (15 % vs. 14.8 %) or discontinuation due to AEs (10 % vs. 22.2 %), and 90-day mortality (35 % vs. 11.1 %) were similar in both groups. Thus, concomitant gilteritinib and triazole therapy is feasible and is not associated with clinically meaningful increase in gilteritinib-related AEs.

Topics: Adult; Aged; Aged, 80 and over; Aniline Compounds; Antifungal Agents; Female; Follow-Up Studies; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Mycoses; Prognosis; Pyrazines; Retrospective Studies; Survival Rate; Triazoles; Young Adult