In April 2017, the FDA approved midostaurin (Rydapt) as the first tyrosine kinase inhibitor (TKI) for acute myeloid leukemia (AML) with a specific biomarker, FLT3 mutation, marking the introduction of targeted therapy for this notoriously difficult-to-treat type of leukemia.
Since then, FLT3 inhibitors have shown promising efficacy in clinical trials, which could dramatically change the treatment of patients with AML and FLT3 mutation, according to Amanda Seddon, PharmD, BCOP, BCPS, Assistant Professor, Chicago College of Pharmacy, Midwestern University, IL.
At the 2018 Hematology/Oncology Pharmacy Association meeting, Dr Seddon reviewed the treatment of AML with FLT3 mutation.
FLT3 Mutations in AML
FLT3 mutations are common in AML, and can occur with other molecular mutations, including NPM1, CEBPA, and other cytogenetic defects. It is recommended that patients with AML should always be tested for FLT3 mutations. According to Dr Seddon, test results should be available within 48 to 72 hours, at least for patients eligible for intensive induction chemotherapy.
The more common FLT3 mutation, the internal tandem duplication (ITD) mutation, has no impact on the ability to achieve a complete remission but is associated with an increased risk for relapse and reduced disease-free survival and overall survival. The other FLT3 mutation, the tyrosine kinase domain (TKD) mutation, is less common, with a 6% to 10% incidence in AML, and has no known prognostic value. Very rarely, a small percentage of patients have the ITD and TKD mutations together, which carry a worse outcome than having a single mutation.
Clinical Benefit of Midostaurin
The first-generation FLT3 inhibitors include sunitinib (Sutent), sorafenib (Nexavar), as well as the most recently approved midostaurin, which is so far the only FDA-approved FLT3 inhibitor for AML.
The FDA approval of midostaurin for patients with newly diagnosed AML with FLT3 mutation, in combination with standard chemotherapy induction and consolidation, was based on results showing median overall survival of 74.7 months with midostaurin and chemotherapy compared with 25.6 months with placebo. Median event-free survival and disease-free survival also improved, with minimal added toxicities.
As a result, the National Comprehensive Cancer Network guidelines now include midostaurin as a treatment option for patients with AML and FLT3-ITD or TKD mutations.
Several clinical trials of midostaurin in AML are currently recruiting. Midostaurin is also being evaluated in adenocarcinoma of the rectum.
Second-Generation FLT3 Inhibitors
According to Dr Seddon, much of the promising data will come from second-generation FLT3 inhibition in AML.
“The second-generation FLT3 inhibitors, namely quizartinib, crenolanib, and gilteritinib are much more selective,” she said. “So, although they may target a couple of other receptors, they’re very specific and potent for FLT3.”
The investigational drug quizartinib is a type II inhibitor, and the most potent FLT3 inhibitor, based on in vitro data. Quizartinib is being investigated in 4 clinical trials that are recruiting patients and 2 clinical trials that are not yet recruiting.
Crenolanib, an orally available TKI, is also being investigated in clinical trials that are recruiting patients.
Gilteritinib, another investigational second-generation oral TKI, has shown potent activity against FLT3-ITD and TKD mutations. It also inhibits AXL, an oncogenic tyrosine kinase that facilitates FLT3 activation and has been implicated in some FLT3 inhibitor resistance.
“AXL is also overexpressed in AML, so gilteritinib has a couple of different targets that seem to be promising for AML therapy,” Dr Seddon said.
Gilteritinib is also involved in several clinical trials that are recruiting patients, including studies in the post–stem-cell transplant setting, in newly diagnosed patients, in the refractory setting, and in comparison with chemotherapy.
According to Dr Seddon, a few types of resistance have been identified with these TKIs. The first is acquisition of a secondary TKD point mutation.
“So, we do see some additional acquired mutations occurring in the ATP-binding domain that ultimately alter the conformational state and weaken its binding affinity for FLT3 inhibitors,” she said.
Acquired resistance is also seen in the “gatekeeper” residue of F691L, as well as in the activation loop residues, specifically D835 and Y842.
“The D835 mutation favors the active kinase conformation, so those drugs that bind to that active conformation state would have better efficacy, or would likely be able to overcome this particular resistance mechanism,” Dr Seddon said.
Resistance to FLT3 inhibitors also occurs through increased ligand expression and upregulation of downstream signaling pathways, such as ERK/MAPK.
“Going forward, ensuring that FLT3 is being tested in all of our patients with AML, especially those cytogenetically normal patients, is very important,” Dr Seddon said.
Providers should also strongly encourage clinical trial participation, she added. Because midostaurin is currently the only FDA-approved FLT3 inhibitor, helping patients obtain access to and coverage for this particular drug will play an important role in the future, as will educating providers and patients on drug interactions in the treatment of this disease.