Utilizing FLT3 Inhibitors in Relapsed/Refractory AML

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Harry Erba, MD, PhD: The second-generation type 1 inhibitor, gilteritinib, has been evaluated as a single agent in relapsed/refractory AML and compared with chemotherapy in the ADMIRAL study, a phase III study in relapsed/refractory patients with FLT3-mutated AML, both ITD [internal tandem duplication] and TKD [tyrosine kinase domain] mutations. This study has completed accrual, and analysis is pending. In the study, patients were chosen to receive an intensive chemotherapy regimen such as mitoxantrone/etoposide/cytarabine; idarubicin with FLAG [fludarabine/cytarabine/G-CSF] chemotherapy; or a less intensive therapy, such as a hypomethylating agent or low dose cytarabine. The primary endpoint of the study is survival, very much like the QuANTUM-R study; however, the data are being analyzed now for response rates to see if there’s a difference in complete remission and complete remission with incomplete count recovery between gilteritinib as a single agent or chemotherapy in this group of patients.

Richard F. Schlenk, MD: In the relapsed/refractory setting, there have been early trial results presented at the European Hematology Association meeting on quizartinib and the QuANTUM-R study, a large, randomized trial where single-agent quizartinib was compared to the doctor’s choice, which can be intensive chemotherapy, low-intensity chemotherapy, or hypomethylating agents. Most patients in the control arm received intensive chemotherapy with a 2-to-1 randomization to quizartinib versus the control arm. The inclusion criteria were patients with an FLT3 internal tandem duplication, patients who were refractory to an intensive induction therapy, and patients who relapsed within 6 months after intensive induction and consolidation therapy once they achieved a complete remission.

Harry Erba, MD, PhD: Crenolanib as a monotherapy has a 40% to 50% response rate in patients with relapsed/refractory FLT3-mutated acute myeloid leukemia. Now, the further development of this drug is as follows: There are phase I/phase II studies being done where intensive chemotherapy is being combined with crenolanib followed by either allogeneic transplant or, in another study, followed by single agent consolidation and maintenance with gilteritinib. Both of these studies are being done in the relapsed/refractory setting. In distinction to the phase III development of gilteritinib and quizartinib, in these studies, crenolanib is being added to an intensive chemotherapy regimen that we typically use in this population. The third study is a phase III study in the relapsed refractory setting of chemotherapy, plus or minus crenolanib, and that is being performed by the German AML study group. There are many other agents that are in development. There are other second-generation type 2 inhibitors such as pacritinib and ponatinib that are being evaluated in the relapsed/refractory setting, and many other FLT3 inhibitors that are in preclinical and phase I development.

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