Membrane Tyrosine Kinase Receptors Kit and FLT3 are an Important Targets for the Therapy of Acute Myeloid Leukemia
Affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanita, Viale Regina Elena 299, 00161 Rome, Italy.
KIT and FLT3 are class III trans membrane tyrosine kinases playing key roles in the control of hematopoietic
stem cell survival and proliferation. KIT is mutated in about 2.5-3% of acute myeloid leukemia (AML) patients mainly by
point mutations occurring at the level of tyrosine kinase domains. FLT3 is mutated in about 30% of AML patients, either
by internal tandem duplication of the juxtamembrane domain or by point mutations occurring at the level of tyrosine
kinase domains. All these types of mutations lead to the constitutive activation of KIT and FLT3 receptors, respectively.
In some AML subsets, the occurrence of FLT3/ITD mutation is associated with a poor prognosis.
These observations have represented the basis for the development of a large number of Tyrosine Kinase Inhibitors (TKIs)
with activity against KIT and FLT3. Some of these inhibitors are still in the preclinical phase, but many have been tested
in phase I/II/III clinical studies. Although these inhibitors when used as single agents have lead to a significant reduction
of the number of leukemic blasts, they have produced only transient and limited clinical responses. This efficacy may be
related to the limited inhibitory caefficacy of these inhibitors, occurrence of resistance and to the complexity of the genetic
abnormalities occurring in AMLs. However, recently Quizartinib, a potent FLT3 inhibitor, showed an impressive
rate of remission induction in patients with chemotherapy-refractory FLT3-ITD-positive AMLs, but most remissions do
not meet classical criteria of complete remissions and instead represent clearance of bone marrow blasts with incomplete
recovery of blood cell counts. However, the majority of these patients after an initial sustained response exhibit a leukemic
relapse due to the rare pre-exisisting or new FLT3-ITD-TKD mutants surviving to the treatment with this drug and
becaming driver leukemic clones. The combination of various types of FLT3 TKIs, including a type II TKI like Quizartinib
with a type I FLT3 inhibitor efficiently targeting TKD mutants, such as Crenolanib, or the combination of FLT3 inhibitors
with other molecularly targeted agents inhibiting other pathways activated in leukemic cells would determine a
major progress in leukemia therapy. The efficacy of FLT3 TKIs in combination with standard anti-leukemic chemotherapeutics
is also under evaluation in several combination clinical trials. It is expected that these trials could determine an
improvement in the negative prognosis of AML patients with FLT3/ITD mutations.
Keywords: Membrane tyrosine kinase receptors, leukemia, cytogenetic.
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