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The protein product of the FLT3 gene, FMS-like tyrosine kinase 3, is a receptor normally expressed on committed lymphoid and myeloid progenitor cells. Mutations in the gene are detectable in 25–30% of acute myeloid leukemias. The mutations are of two main types. In about 75% of cases, the change is an internal tandem repeat insertion of 3 to >100 codons into the juxtamembrane portion of the enzyme; in about 25%, the change is an activating mutation in the kinase domain. Both types of mutation lead to ligand-independent activation of the kinase.

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The CALGB cooperative group undertook an evaluation of midostaurin, a multikinase inhibitor with some inhibitory activity against the flt3 kinase, as a component of induction chemotherapy in patients with acute myeloid leukemia containing FLT3 mutations (Stone et al, 2017). Among 3277 patients screened for the mutations, 717 patients (21%) had mutations; 357 were assigned to standard daunorubicin and cytarabine induction therapy plus placebo, and 360 received the same therapy plus midostaurin 50 mg bid on days 8–21.

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The complete response rates were similar on the two arms (54–59%). However, median overall survival for the midostaurin arm was about 75 months compared with 26 months for the standard therapy arm (hazard ratio, 0.78; one-sided p = 0.009). The toxicities were similar in the two groups. Thus, addition of a putative flt3 kinase inhibitor to acute leukemia induction therapy improves survival in patients with FLT3-mutated acute myeloid leukemia.

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Stone  RM  et al.: Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med 377:454, 2017
[PubMed: 28644114]