FLT3 Inhibitor Highly Active in Newly Diagnosed Acute Myeloid Leukemia

Patients with newly diagnosed FLT3-mutated acute myeloid leukemia (AML) had a high response rate and prolonged event-free survival (EFS) following treatment with an investigational FLT3 inhibitor and chemotherapy, a preliminary study showed.

The combination of crenolanib and cytarabine/anthracycline chemotherapy led to complete responses (CRs) in 86% of patients and a median EFS of 44.5 months in 44 evaluable patients. After a median follow-up of 45 months, median overall survival (OS) had yet to be reached.

Almost 90% of patients had negative measurable residual status, reported Eunice S. Wang, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, New York, and co-authors in the Journal of Clinical Oncology. Crenolanib differs from the currently approved FLT3 inhibitors, midostaurin (Rydapt) and quizartinib (Vanflyta), in ways that could be advantageous, she told MedPage Today.

“Quizartinib, like crenolanib, is a newer-generation inhibitor, but quizartinib is only effective for a subset of patients that have FLT3 mutation,” said Wang. “FLT3 mutations include an ITD, or internal tandem duplication mutation, and there is also a tyrosine kinase domain [TKD] mutation. Quizartinib is only active in patients who have the ITD mutation. Crenolanib is active against all FLT3 mutations. Some mutations confer resistance to other FLT 3 inhibitors, and crenolanib has a very potent in vitro panel and sensitivity across many of the FLT3 mutations that confer resistance.”

“Number two, crenolanib has a unique side-effect profile,” she continued. “It does cause nausea, vomiting, and GI [gastrointestinal] toxicity, but it does not cause QTc prolongation and cardiac issues. Quizartinib has a REMS [risk evaluation and mitigation strategies] program that all prescribers must enroll in to recognize that they understand and will monitor patients for cardiac toxicity on that particular agent. That is not part of the crenolanib toxicity profile.”

Another new-generation FLT3 inhibitor, gilteritinib (Xospata), is approved for use in the relapsed/refractory setting, Wang noted.

As many as 30% of newly diagnosed cases of AML are associated with FLT3 mutations, about 75% of which are the ITD mutation, which is linked with high relapse rates and poor OS. The current standard of care for newly diagnosed FLT3-mutated AML in younger adults is cytarabine/daunorubicin chemotherapy induction and high-dose cytarabine consolidation, followed by FLT3 inhibition.

Midostaurin received FDA approval on the basis of a phase III trial that showed a 7.2% absolute improvement in 4-year survival with the addition of the FLT3 inhibitor to chemotherapy. However, allogeneic stem-cell transplant (ASCT) played an important role in treatment. Additionally, the 2-year relapse rate approached 40%.

Quizartinib received FDA approval for FLT3-mutated AML in 2023 on the basis of a phase III trial that showed significant improvement in OS when added to chemotherapy. However, the magnitude of benefit appeared similar to that of midostaurin, Wang and co-authors noted.

Crenolanib demonstrated single-agent activity and tolerability in patients with heavily pretreated FLT3-mutated AML. More than half of the patients obtained clinical benefit from the treatment, which produced complete responses in 20% of patients, including a third of patients with no prior exposure to a tyrosine kinase inhibitor.

Wang and colleagues reported findings from a phase II trial of newly diagnosed FLT3-mutated AML. Data analysis included 33 patients with FLT3-ITD, eight with FLT3 point mutations, with three with both FLT3-TKD and point mutations. All patients received standard 7+3 cytarabine/daunorubicin (or idarubicin) induction followed by high-dose cytarabine consolidation and/or ASCT. Crenolanib was administered between chemotherapy cycles and for up to 12 months after consolidation/ASCT.

The primary objective was safety/tolerability. Secondary endpoints included objective response rate (ORR), EFS, and OS.

The most common all-grade treatment-emergent adverse events (TEAEs) were diarrhea (65.9%), nausea (56.8%), febrile neutropenia (52.3%), vomiting (45.5%), peripheral edema (40.9%), decreased appetite (38.6%), and maculopapular rash (38.6%). The most frequent grade 3 TEAE was febrile neutropenia (22 of 44), followed by diarrhea (eight patients), nausea, decreased appetite, maculopapular rash, and acute kidney injury (three each). Grade 4 TEAEs consisted of two cases of hypokalemia.

The CR rate included 77% with complete count recovery and 9% without incomplete recovery. CR rates were 90% in patients ages 60 or younger and 80% in older patients. The minimal residual disease (MRD)-negative CR rate included 45% with incomplete recovery. Younger patients had an estimated 3-year OS of 71.4% with a 15% cumulative incidence of relapse. Median time to platelet recovery was 29 days and time to neutrophil recovery was 32 days. No new FLT3-mutant clones were detected at relapse among patients who completed consolidation therapy.

If crenolanib were to receive FDA approval, the availability of multiple FLT3 inhibitors would offer opportunities to sequence the drugs.

“I think it would make sense and might be useful to sequence them,” said Wang. “We already have multiple BCR-ABL inhibitors for CML [chronic myeloid leukemia] and multiple JAK inhibitors for myelofibrosis. A lot of times, the particular inhibitor that we select for our patients may be individualized on the basis of a patient’s underlying disease status, their presentation, as well as the biology of their disease.”

“Having a multitude of inhibitors does allow for the ability to offer other therapies,” she added. “We know that none of these FLT3 inhibitors is 100% effective, even in combination. The ability to utilize them throughout the course of a patient’s disease also is very attractive. However, we need to wait for additional data, as these move into the upfront setting, about what would be the best sequence. It may be driven a little bit by continued mutation testing.”

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