Insights, Future Considerations in FLT3 Inhibitors Following Allo-HCT in Patients With AML

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During a presentation at the National Comprehensive Cancer Network (NCCN) Annual 2024 Conference in Orlando, Florida, speaker James M. Foran, MD, of the Mayo Clinic Comprehensive Cancer Center, shared clinical data on the treatment of acute myeloid leukemia (AML) with FMS-like tyrosine kinase 3 (FLT3) inhibitors following allogeneic hematopoietic cell transplant (allo-HCT). In this NCCN session, Foran described the different FLT3 inhibitors that are available for FLT3-mutated AML, as well as considerations for the future.

Foran explained patients with AML are a high-risk population who can benefit from targeted therapy. In several small, randomized trials, the results demonstrated that sorafenib (Nexavar; Bayer HealthCare Pharmaceuticals) and midostaurin (Rydapt; Novartis)—which are multi-targeted kinase inhibitors with single-agent anti-leukemia activity and a poorer tolerability when used as single-agent therapies—were generally well-tolerated and effective, though adverse effects (AEs) were present. In addition, he suggested that quizartinib (Vanflyta; Daiichi Sankyo Co) may be a feasible option for patients with AML following allo-HCT; however, there is currently limited prospective data on the drug.

The RATIFY study, which led to the FDA approval of midostaurin, evaluated transplant outcomes for patients, which Foran noted were very encouraging. According to the findings, patients who received midostaurin with chemotherapy prior to allo-HCT with a FLT3 mutation had long-term survival that approached 70%, compared with those without allo-HCT (15%) and those with allo-HCT (45%).

“Currently in the NCCN guidelines, we recommend the therapy is not started until you know there's a FLT3 mutation or not—whenever possible—to hold the initiation of therapy, and [to use it] for patients who are fit for intensive therapy who are over the age of 18. It’s recommended to give standard intensive therapy either with midostaurin or with quizartinib; currently, we're not sure which is better in that situation,” said Foran during the session. “For patients who achieve a complete remission who have a FLT3 mutation, it's recommended to add the FLT3 inhibitor they [received] with induction therapy to their consolidation, and to consider trying to transplant in first remission, so that is now the current standard of care.”

Further, Foran described one of the most notable problems following allo-HCT is relapse, with relapse replacing transplant-related mortality as the primary treatment failure; according to Foran, relapse occurs in over 30% of patients who receive AML transplants. In this case, the 2-year overall survival rate for those with recurrent AML is consistently less than 15%. He also referenced a prior study that demonstrated a higher relapse rate in patients with a FLT3 mutation following transplant (30%) compared with those without the mutation (16%). Further, this study resulted in a much lower leukemia-free survival as a result of relapse, with the 2 groups demonstrating rates of 58% and 71%, respectively.

When looking at FLT3 inhibitor maintenance, Foran described a trial that examined sorafenib in 26 patients following allo-HCT and found an improved 2-year progression-free survival, which decreased 2-year relapse from approximately 37% to 8%; however, not every patient was able to tolerate the drug, with approximately 42% of patients needing to stop treatment due to AEs. In later studies, maintenance therapy with sorafenib following transplant resulted in a 60% reduction risk of relapse and 85% rate of 2-year relapse-free survival—compared with 53% for placebo—and was considered statistically significant.

“FLT3 mutations are common in AML and this represents a high-risk population. There's a clear benefit of targeted therapy in the first line and we believe [there is] a benefit of targeted therapy after transplant,” said Foran during the session. “Small randomized, prospective studies of sorafenib—particularly midostaurin—with a relapse-free survival hazard ratio dropped by about 50%, but [was] generally well-tolerated. [Further], quizartinib is feasible, but there's no prospective data, [there is only] retrospective [data].”

Further, Foran acknowledged that there is very little information that focuses on patients with AML who are aged 60 years and older. He noted that 75 years of age is typically the upper age limit for considering whether patients with AML would be candidates for allo-HCT—taking comorbidities into consideration—but this age group can still be candidates for FLT3 inhibitors. He also emphasized that it is important to consider cardiovascular comorbidities prior to initiating treatment with FLT3 inhibitors.

“[In regard to] how [FLT3 inhibitors] impact cardiotoxicity…we know that these agents can affect electrolytes, we know they can have GI toxicity, so it matters in these patients that you're monitoring those things we do closely anyway. I think comorbidity is a big issue there…[patients may be] more likely to get a recurrence or congestive heart failure,” said Foran in the session. “There’s more specific guidance with the selective inhibitors—gilteritinib (Xospata; Astellas Pharma US) and quizartinib—[but] we don't have prospective data on quizartinib after allo-HCT, but we are doing an EKG after 1 week and 2 weeks to make sure we're not seeing EKG changes [in order to] maintain normal electrolytes [in this population].”

Finally, Foran expressed his interest in seeing randomized trials comparing selective vs non-selective FLT3 inhibitors in AML populations. Further, he concluded the session by raising the question of maintenance therapy being adopted more regularly.

“I don't want to say we're moving towards the myeloma model of continuous therapy for everybody forever, which works in myeloma. Continuing people on treatment has changed the world for multiple myeloma—they're now managing AEs rather than stopping therapy,” said Foran during the session. “But in AML…we are thinking maintenance may be more and more important, and maybe the limited exposure in the first line setting is missing the opportunity to capitalize on it—which we're doing because we have to at the moment; we presume it's the right thing to do—but we'll find out [with further research].”

REFERENCE

Foran, JM. Acute Myeloid Leukemia: Role of FLT3 Inhibitors After Allogeneic Hematopoietic Cell Transplant. Presented at: National Comprehensive Cancer Network Annual 2024 Conference; Orlando, Florida; April 5-7, 2024.