Therapeutic Research

Abstract

Fms‒like tyrosine kinase 3（FLT3）mutation is found in about 30％ of newly diagnosed acute myeloid leukemia（AML）patients. Two different types of the mutation are internal‒tandem duplication（ITD）and point mutations in the tyrosine kinase domain （TKD）. AML with FLT3 mutations is associated with lower remission rates, higher relapse rates, and consequently shorter survivals than AML without them using conventional chemotherapy. Quizartinib is the second‒generation type 2 FLT3 inhibitor, which is specifically cytotoxic to FLT3‒ITD mutated AML. In phase Ⅰ/Ⅱ trials, the maximum tolerated dose of quizartinib was determined to be 200 mg/day, and the major adverse reactions included cytopenias, infections, and QT elongation. The dose was eventually adjusted to 60 mg/day due to the side effect of QT elongation. As the pivotal phase Ⅲ trial, QuANTUM‒R was conducted to compare quizartinib and conventional chemotherapies（low‒dose cytarabine, MEC, FLAG‒IDA）in 367 relapsed/refractory FLT‒ITD mutated AML patients. The starting dose of quizartinib was 30 mg/day and the dose was increased to 60 mg/day. The overall survival as the primary endpoint was 6.2 months for quizartinib and 4.7 months for chemotherapies, with the 24.2％ reduction of the risk of death in quizartinib. The composite complete remission rates were 48.2％ for quizartinib and 27.0％ for chemotherapies. The major adverse events（Grade≧3）were anemia, thrombocytopenia, and infections. QT elongation was seen in only 3％ of the patients taking 60 mg. Quizartinib was approved in June 2019 and is now used as a single agent for treating relapsed or refractory AML in Japan.