FLT3 mutations: biology and treatment.
FLT3 is a receptor tyrosine kinase with important roles in hematopoietic stem/progenitor cell survival and proliferation. It is mutated in about 1/3 of acute myeloid leukemia (AML) patients, either by internal tandem duplications (ITD) of the juxtamembrane domain or by point mutations usually involving the kinase domain (KD). Both types of mutation constitutively activate FLT3. Many studies have shown that AML patients with FLT3/ITD mutations have poor cure rates due to relapse. This has led to the development of a number of small molecule tyrosine kinase inhibitors (TKI) with activity against FLT3. Many of these are still in preclinical development, but several have entered clinical phase I and II trials as monotherapy in patients with relapsed AML. Patients with FLT3 mutations in these trials have shown clinical responses, most often a clearing of peripheral blasts, but rarely major reductions of bone marrow blasts. Several studies have shown that FLT3 was successfully inhibited in most patients. However, complete remissions have rarely been achieved in these trials. The difference in responses of chronic myeloid leukemia (CML) patients to BCR-ABL inhibitors compared to FLT3 mutant AML patients to FLT3 inhibitors may be reflective of treating a single gene disease in CML versus multiply altered gene disease in AML. This has led to clinical testing of FLT3 TKI in combination with conventional chemotherapy, with trial designs based on preclinical testing showing synergistic effects between these agents in inducing cytotoxic responses. Several combination trials are ongoing or planned in both relapsed and newly diagnosed FLT3-mutant AML patients.
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Donald
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Johns Hopkins Hospital, 1650 Orleans Street, Baltimore MD 21231, USA. donsmall@jhmi.edu
D000208:Acute Disease; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3