FLT(3)-ing about: the search for the best inhibitor

In this issue of Blood, Loo et al report results from the fourth prospective randomized trial of a putative fms-like tyrosine kinase 3 (FLT3) inhibitor (in this case sorafenib) vs placebo plus chemotherapy in fit adults with newly diagnosed mutant FLT3 internal tandem duplication (ITD) acute myeloid leukemia (AML).¹ Unlike the CALGB 10603/RATIFY² and the QUANTUM-FIRST³ trials, which showed that midostaurin and quizartinib, respectively, produced superior survival compared with placebo plus chemotherapy, the current Australian trial was viewed as negative; neither survival nor event survival was better for patients randomized to sorafenib. The hope that sorafenib, a multikinase inhibitor approved in renal carcinoma because of its vascular endothelial growth factor–inhibiting activity, would be useful in the AML setting was based in part on its activity with chemotherapy in induction⁴ and superiority to placebo after allogenic transplant, each in the mutant FLT3 ITD context.⁵ Further trials of sorafenib plus chemotherapy in genetically unrestricted AML suggested some benefit,⁶ but toxicity was significant in older adults.⁷ 

Disappointment about the “negative” results in the current trial should be tempered by the small size as well as the trend toward superior outcome in those who received sorafenib compared with placebo and had an allogeneic transplant in first complete remission (CR1). The complete remission rate was high in the control arm, perhaps because of the use of intensive high-dose cytarabine-based induction in these relatively chemoresponsive FLT3 ITD patients, thus making it difficult to “beat” with the addition of sorafenib in this small trial. Furthermore, there was an imbalance in randomization such that favorable NPM1 mutant disease was more common in patients in the placebo (81%) than in the sorafenib arm (60%). The current trial was a phase 2 randomized trial powered to detect only relatively large differences between the 2 arms in the primary end point of event-free survival. Failure to meet the primary end point was not due to lack of bioavailability; sorafenib consistently lead to marked inhibition of FLT3 activity using the plasma in aqua assay, unlike the case with lestaurtinib, which failed to improve outcomes compared with placebo in a similar disease setting.⁸ Although the primary end point was not met, the concept of the superiority of FLT3 inhibitors plus chemotherapy compared with chemotherapy in newly diagnosed FLT3 ITD mutant AML should not be considered challenged in part due to the trend toward superior outcome among patients undergoing allogeneic stem cell transplant in CR1 who received sorafenib compared with placebo, suggesting that the tyrosine kinase inhibitor (TKI) led to remissions at a lower disease burden.

The relapse rate after transplant is markedly higher when a patient in apparent morphologic remission undergoes the procedure when the AML can be detected by sensitive molecular assay for the presence of FLT3 ITD compared with the situation where such disease is undetectable.⁹ Indeed, the FLT3 inhibitor gilteritinib is mainly effective (compared with no therapy in the so-called MORPHO trial) in the post-transplant setting in patients with FLT3 mutant AML who still had detectable FLT3 mutant DNA in this sensitive assay after initial chemotherapy.¹⁰ The assay is an important step forward in the measurable residual disease field as it was further shown to correlate with improved outcome in the QUANTUM-FIRST³ study (postinduction values were lower in the quizartinib than in the placebo arm), and a negative status in the Australasian Leukaemia & Lymphoma Group trial¹ was associated with a statistically higher 2-year overall survival compared with those in whom the DNA could be detected.

Although the standard of care for intensive chemotherapy-ineligible FLT3-ITD AML is a hypomethylating agent plus venetoclax, preliminary results in newly diagnosed patients using the so-called azacitidine/venetoclax/FLT3 inhibitor “triplet” are encouraging. Despite the top-line results in the ALLG trial, there is little doubt that an FLT3 inhibitor (now either quizartinib or midostauirn) should be combined with chemotherapy in adults with mutant FLT3-ITD AML who are candidates for intensive chemo. Despite 2 “positive” trials and 2 “negative” trials involving an FLT3 inhibitor or placebo plus intensive chemotherapy in younger adults with FLT3-ITD mutant AML (see table, 1 of each published in 2017 and 2023), given “valid excuses” available for the 2 “negative” trials (failure to inhibit FLT3 signaling and low power/randomization imbalance, respectively), the notion that an FLT3 inhibitor should accompany chemotherapy is widely accepted. But which of the 2 available drugs should be chosen? There are no randomized comparisons of chemotherapy plus midostaurin vs quizartinib; some have suggested that the adverse effect profiles (midostaurin with more serious rashes, whereas quizartinib may be more myelosuppressive) could guide the choice. A post hoc analysis of the CALGB 10603/RATIFY trial excluding the FLT3 tyrosine kinase domain mutant patients suggests that midostaurin did not meet an overall survival end point, which could prompt some to choose quizartinib in that setting. However, this debate may be moot if crenolanib (although accrual is currently on hold) or gilteritinib proves more effective than midostaurin in the ongoing prospective randomized trials. Gilteritinib is approved in refractory/relapsed mutant FLT3 AML, is generally well tolerated, is given daily (and like midostaurin, but not sorafenib), and is effective against the less common and less noxious FLT3 tyrosine kinase domain mutation. On the other hand, it may be challenging to outperform the ≈70% long-term relapse-free survival in patients with mutant FLT3-ITD AML who receive a TKI and a first remission allogenic stem cell transplant, a much better natural history than predicted in this subtype of AML 2 decades ago.

Conflict-of-interest disclosure: R.M.S. discloses ad hoc consulting for AbbVie,^∗ Actinium, Agios,^∗ Amgen, Argenix (data and safety monitoring board [DSMB]), Arog,^∗ Astellas, AztraZeneca, Biolinerx, BMS/Celgene (includes DSMB and steering committee), Elevate Bio, Fujifilm, Janssen, Jazz, Juno, Macrogenics, Novartis,^∗ Ono, Orsenix, Pfizer, Rigel, Roche, Stemline, Sumitomo, Syndax,^∗ Syntrix (DSMB only), Syros, Takeda (DSMB), and Trovagene (^∗ denotes support to his institution for clinical trials on which he was local principal investigator).