Editorial theme | The value of FLT3 targeting in AML

FMS-like tyrosine kinase 3 (FLT3) is a transmembrane protein expressed by hematopoietic stem and progenitor cells and is involved in the early stages of lymphopoiesis and myelopoiesis.¹ FLT3 gene mutations are the most common genetic abnormalities in patients with acute myeloid leukemia (AML) and are found in 20–30% of cases.¹ Of those, the internal tandem duplication (ITD) on FLT3 (FLT3-ITD) represents the most commonly detected FLT3 alteration in AML (25%) and is associated with short remissions and poor prognosis.¹ The tyrosine kinase domain FLT3 mutation (FLT3-TKD) has also been identified in patients with AML, but has a lower prevalence (7–10%) and its prognostic role is unclear.¹

The importance of FLT3 mutations in AML risk stratification is evident in the updated guidelines from the National Comprehensive Cancer Network (NCCN) and the European LeukemiaNet (ELN), which classify FLT3 mutations into a single category that confers a negative prognostic risk.^2,3 According to ELN (2017), patients with FLT3-ITD of high allelic ratio (> 0.5) without concurrent mutation in the nucleophosmin (NPM1) gene are considered as high risk. Both NCCN and ELN guidelines highlight the necessity for FLT3 screening at diagnosis to establish prognostic risk and allow for the addition of an FLT3 inhibitor in the treatment strategy.

The prognostic role of FLT3-ITD mutations not only at diagnosis but also at relapse was recently examined. A retrospective study by Shouval et al. published in Bone Marrow Transplantation⁴ evaluated the role of FLT3 and NPM1 mutations in risk stratification of intermediate-risk patients with AML undergoing autologous stem cell transplantation. Intermediate-risk cytogenetics were defined according to the ELN 2017 guidelines,³ with either NPM1 and FLT3-ITD high allelic ratio, or wild-type NPM1 without FLT3-ITD or with FLT3-ITD of low allelic ratio.⁴ The study analyzed 405 patients with a median follow-up of 5.5 years, and concluded that patients with the NPM1 mutation but not FLT3-ITD have favorable outcomes when receiving autologous stem cell transplantation at first complete remission. The results of this study showed that the FLT3/NPM1 mutational status is a strong predictor of overall survival (OS), leukemia-free survival, and relapse also in patients receiving second-line treatment for AML.⁴

FLT3 therapeutic targeting options were thoroughly discussed by many experts at the European Hematology Association (EHA) Congress in 2019. A summary of all the expert interviews and the latest information from EHA 2019 regarding FLT3 can be found here. We hereby provide a summary of the most important investigational or approved FLT3 inhibitors in the frontline and relapsed/refractory (R/R) AML setting.

FLT3 inhibitors: Frontline setting

FLT3 inhibitors have gained a lot of interest following the approval of midostaurin by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of patients with FLT3-mutated AML in the frontline setting. The results for this approval came from the pivotal phase III RATIFY trial (NCT00651261), demonstrating improved OS when midostaurin was added to standard chemotherapy.⁵ Further details regarding the study design and outcomes can be found on the AML Hub here.

FLT3 inhibitors: Relapsed/refractory setting

In the R/R setting, quizartinib monotherapy was superior to salvage chemotherapy in patients with FLT3-ITD R/R AML. This was established in the phase III QuANTUM-R trial (NCT02039726), which evaluated patients who were R/R within 6 months from frontline therapy. Quizartinib led to prolonged OS compared to salvage chemotherapy and had a manageable safety profile.⁶ Further details regarding the study design and outcomes of the trial can be found on the AML Hub here.

Another FLT3 inhibitor that has shown great promise in the R/R AML setting is gilteritinib. Gilteritinib is an oral, type 1 FLT3 inhibitor that has been approved by the FDA and more recently by the EMA for the treatment of patients with FLT3-mutated R/R AML. Data leading to the approvals were collected by the pivotal phase III ADMIRAL trial (NCT02421939). In this trial, patients with either FLT3-ITD or -TKD mutations that had relapsed following frontline treatment or were refractory to induction chemotherapy were randomized to gilteritinib or various salvage chemotherapy regimens. Gilteritinib monotherapy led to superior OS, as well as more and deeper responses than salvage chemotherapy.⁷ Further details regarding the study design and outcomes can be found in the AML Hub here.

Despite the great promise of FLT3 inhibitors, emerging resistance to these agents is an important cause of relapse and treatment failure. The mechanisms behind this resistance are yet unclear, but might involve the emergence of FLT3 inhibitor-resistant leukemic clones or the adaptation of leukemic cells to such drugs via the bone marrow microenvironment.⁸ The gatekeeper FLT3 F691L mutation seems to confer resistance in R/R FLT3-ITD mutant AML. Currently there are very few therapeutic options for patients who develop resistance to FLT3 inhibitors. Recently, a phase I/II trial investigated the safety and efficacy of pexidartinib, a novel, second-generation FLT3 inhibitor in patients with R/R FLT3-mutated AML. Pexidartinib has the advantage of remaining active and bound to a FLT3 F619L-mutated protein in vitro. Pexidartinib was well tolerated by patients but showed lower response rates when compared to other FLT3 inhibitors. Nevertheless, further clinical investigation of pexidartinib may validate its use in patients who develop FLT3 inhibitor resistance and progress following other FLT3 therapy. Further details regarding the study design and outcomes of the trial can be found on the AML Hub here.

Conclusion

FLT3-ITD mutations alone or in combination with the NPM1 mutation status have a prognostic role for patients with naïve or R/R FLT3-mutated AML, making FLT3 testing essential both at diagnosis and relapse. There are multiple therapeutic inhibitors targeting FLT3 that have shown great efficacy. Midostaurin in combination with standard chemotherapy has been approved for the treatment of naïve FLT3-mutated AML, while gilteritinib can be used as monotherapy for the R/R setting. Despite the great promise of FLT3 inhibitors, the important issue of treatment resistance is emerging and unresolved. Preliminary data have shown that pexidartinib, which remains active in cases of FLT3 inhibitor resistance, might be a therapeutic option for patients who experience disease progression following other FLT3 inhibitor therapy. Further clinical studies are needed to validate the use of pexidartinib and to further examine how to reduce FLT3 inhibitor-mediated resistance.