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Acute myeloid leukemia (AML), a malignant clonal disorder of the hematopoietic system, is characterized by an enormous heterogeneity of acquired genetic and epigenetic changes in hematopoietic precursor cells and by impaired mechanisms of proliferation, differentiation, and self-renewal. So far, over 200 structural and numerical cytogenetic abnormalities have been described in this disease, with incidences ranging from<0.1% to 10%. Standard therapy, such as intensive chemotherapy with or without allogeneic hematopoietic stem cell transplantation (HSCT), has limited efficacy in AML, with only 30% to 40% cure rate. The prognosis of the patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-ALL) or acute promyelocytic leukemia (APL), has been significantly improved by the application of molecular-targeting agents, suggesting that development of other targeting agents is necessary for improving the prognosis of AML patients. Many genetic alterations, which are closely associated with the progression of AML, have been identified, and some of them are expected to be therapeutic targets. The FLT3 (FMS-like tyrosine kinase 3) mutation is the most frequently identified genetic alteration in AML and induces the constitutive activation of FLT3 kinase. Thus, the FLT3 inhibitor serves as a promising molecular target in the treatment of leukemia. Up to now, several FLT3 kinase inhibitors were developed and their safety and efficacy were evaluated in phase I/II studies.
FLT3 belongs to a type III receptor tyrosine kinase. It dimerizes on binding its cognate ligand, the cytokine FLT3 ligand (FL), goes through autophosphorylation, and transduces signals promoting proliferation and survival by proteins such as AKT, STAT5, and ERK. In hematopoietic tissues, FLT3 is expressed in a progenitor/stem population that is not pluripotent but rather one that is already lineage-restricted, and it plays crucial roles in the function of early T-cell precursors and dendritic cells. FLT3 is expressed in AML cells of most patients and is mutated in AML cells of about 30%. Mutations include internal tandem duplications (ITD), present in AML cells of about 25% of patients, and point mutations in the tyrosine kinase domain (TKD), present in about 5%. Both ITD and TKD mutations are activating, leading to ligand-independent, or constitutive, FLT3 receptor signaling, and thereby promote cytokine-independent AML cell survival and proliferation.
Figure 1. Signaling pathways in cells with FLT3-ITD. (Larrosa-Garcia M, et al. 2017)
AML with FLT3-ITD usually presents with high blood blast counts, and has poor treatment outcomes, with initial treatment response, but high relapse rate and short relapse-free survival and overall survival. New structural cytogenetic abnormalities are often present at relapse of AML with FLT3-ITD, consistent with genomic instability. Hematopoietic stem cell transplantation (HSCT) is the preferred treatment for FLT3-ITD AML patients in remission, but outcomes are inferior to those of patients without FLT3-ITD owing to a high rate of early relapses, indicating the potential utility of treatments targeting FLT3 signaling after transplant. Compared with FLT3-ITD, FLT3 TKD mutations are not associated with leukocytosis and only modestly negatively impact treatment outcomes. These clinical differences may be because of the difference in downstream signaling between FLT3-ITD and TKD mutations.
FLT3 Inhibition for AML Therapy
Given the high frequency with which FLT3 mutations occur in AML, many TKIs are under development that disrupts the oncogenic signaling initiated by FLT3. Apart from a variety of improved treatment strategies in AML, the recognition that FLT3-ITD is an adverse prognostic marker, the integration of FLT3 inhibitors into the treatment algorithm, and the increased use of alloHSCT have resulted in improvements in clinical outcomes in patients with FLT3-ITD-mutated AML. FLT‐ITD AML patients receiving the FLT3 inhibitor quizartinib form characteristic mutations in the tyrosine kinase domain of the FLT3 gene, and these mutations confer resistance to quizartinib therapy. The finding that FLT3 inhibitors can contribute to the evolution of a resistant clone confirms the status of the ITD as a driver mutation in AML. Initial trials of FLT3 inhibitors used TKIs originally developed to treat solid tumors. These agents were devised to impede signaling by other receptors and were found also to have inhibitory action against the FLT3 RTK. It has been observed that, because these drugs are relatively non‐specific, they can have significant off‐target effects, leading to noteworthy toxicity. The efficacy signal seen with the first wave of FLT3 inhibitors prompted the design of a newer group of TKIs, devised specifically as FLT3 inhibitors. These drugs are more specific for the FLT3 receptor and appear to have less toxicity than the older agents.
Figure 2. FLT3 inhibitors. (Daver N, et al. 2019)
Earlier agents tested as FLT3 inhibitors include tandutinib, sunitinib, sorafenib, lestaurtinib, and midostaurin. KW‐2449 was the first FLT3 inhibitor tested in the clinical trial that was designed specifically to inhibit the FLT3 receptor. Newer FLT3 inhibitors currently in clinical trials include crenolanib, quizartinib, PLX‐3397, and gilteritinib. Overall, the use of FLT3 inhibitors, compared with historical outcomes before their emergence, has demonstrated a significant clinical benefit in the relapsed/refractory AML setting and provides promising treatment strategies for patients with few options.
An important strategy to overcome resistance to chemotherapy in a variety of tumor types has been the use of combination regimens. Therefore, several ongoing studies are evaluating the utility of combining different agents that inhibit key signaling pathways by different modes of action or using two or more agents that target different leukemic cell survival signaling pathways. Planned and ongoing studies investigating this clinical strategy include combinations of FLT3 inhibitors with approved antileukemic therapies, such as low-dose cytarabine, hypomethylating agents, CPX-351, and investigational agents (e.g., BCL-2, MDM2, IDH1/IDH2, MEK, bromodomain, and CYP3A4 inhibitors). Combination therapies not only may improve response rates but also produce more durable remissions in patients with FLT3-mutated AML.