Emerging FMS-like tyrosine kinase 3 inhibitors for the treatment of acute myelogenous leukemia

Abstract

Introduction The FMS-like tyrosine kinase 3 (FLT3) is highly expressed in acute leukemias. Mutations involving FLT3 are among the most common molecular abnormalities in acute myelogenous leukemia (AML). Available evidence suggests that these molecular lesions confer a shorter disease-free survival and overall survival in patients with intermediate-risk cytogenetics. Therefore, substantial interest in FLT3 as a therapeutic target has led to the development of several promising inhibitors that target this tyrosine kinase. Areas covered This review covers the molecular pathways associated with FLT3 activation in patients with AML, the biological rationale for inhibiting FLT3 and recent clinical progress with FLT3 inhibitors for the treatment of AML. Six FLT3 inhibitors undergoing clinical evaluation are discussed. A review of selected published manuscripts on the subject of FLT3 inhibition in AML and a search of the English language manuscripts in PubMed using the index words FLT3 and AML were conducted and articles of interest selected. Expert opinion Mutated forms of FLT3, specifically FLT3-internal tandem duplication, have a significant impact on the prognosis of AML patients, particularly those with a normal karyotype. Inhibiting FLT3 may lead to clinical benefit for patients with AML. Newly developed FLT3 inhibitors have shown encouraging activity as monotherapy and in combination with other therapeutic agents.

Mutations of FLT3/ITD confer resistance to multiple tyrosine kinase inhibitors

“…Several groups have employed various techniques to identify FLT3 resistance mutations. 17–21 In contrast to the wide array of BCR-ABL resistance mutations, relatively few FLT3 resistance mutations have been identified, which may partially reflect the failure to achieve sufficient levels of inhibition of FLT3 signaling in many trials, 22 In this study, we identified the F691L and Y842C mutations previously identified as well as two novel mutations, F621L and A627P, that cause resistance to select TKI. These results suggest that novel mutations arising in FLT3/ITD, perhaps by selection during the course of treatment with a TKI, may prove to be refractory to FLT3 mutant AML management using most TKIs and emphasize the need for development of FLT3 inhibitors that can overcome resistance due to mutations.…”

Relapsed acute myeloid leukemia: Why is there no standard of care?

“…A number of inhibitors of FLT3 kinase activity are in clinical development, including lestaurtinib, midostaurin, sorafenib, and quizartinib [25]. Lestaurtinib was evaluated in a randomized trial where patients with first relapse of FLT3-mutataed AML were treated with chemotherapy with or without the kinase inhibitor [26].…”

Sorafenib plus all‐trans retinoic acid for AML patients with FLT3‐ITD and NPM1 mutations

“…For instance, patients with normal karyotype and NPM1 or CEBPA mutations without FLT3‐ITD mutation are no longer referred to allogeneic stem‐cell transplantation (allo‐SCT) in first complete response because their outcome is fairly good with chemotherapy alone . Additionally, therapies targeting specific molecular defects are intensively investigated, such as small molecule inhibitors of FLT3 tyrosine kinase in patients harbouring the FLT3‐ITD mutation . Among these inhibitors, sorafenib has shown some efficacy as a monotherapy in patients with relapsed FLT3‐ITD AML .…”