Research progress of novel tyrosine kinase inhibitor AC220 in the treatment of acute myeloid leukemia / 白血病·淋巴瘤

Acute myeloid leukemia (AML) is a highly heterogenous disease with multiple signaling pathways contributing to its pathogenesis.A key driver of AML is the mutation of FMS-like tyrosine kinase receptor-3 (FLT3) gene.Mutations in FLT3,primarily the FLT3-internal tandem duplication (FLT3-ITD),are associated with decreased progression-free and overall survival.Due to the importance of FLT3-ITD and its pathway in the prognosis of patients with AML,it has stimulated efforts to develop therapeutic inhibitors of FLT3.Although the FLT3 inhibitors show a certain degree of antileukemia activity,their clinical effect has some limitations as a single drug.Now,Quizartinib (AC220) is the potent second generation FLT3 selective inhibitors.Based on the resistance mechanism for FLT3 inhibitom,more and more scholars has been studying the inhibition of FLT3-ITD+ cell lines and primary leukemia cells by AC220 alone and in combination with cytotoxic chemotherapies/protein kinase inhibitors as well.However,the clinical effects of a variety of combination plan remain to be further investigated.

Low Frequency and Variability of FLT3 Mutations in Korean Patients with Acute Myeloid Leukemia

FLT3 mutations are common genetic changes, and are reported to have prognostic significance in acute myeloid leukemia (AML). The FLT3 internal tandem duplication (ITD) and the D835 activating mutation in the tyrosine kinase domain (TKD) were analyzed by polymerase chain reaction (PCR) in the genomic DNA of Korean patients with AML at diagnosis and during follow-up. There were 226 patients with AML enrolled between March 1996 and August 2005. The incidence of ITD and TKD at diagnosis was 13% (29/226) and 3% (6/226). When compared to Western and other Asian patients with AML, Korean patients had a lower frequency by about two-thirds of ITD and TKD. Among the non-M3 cases (N=203), the patients with an ITD had a significantly shorter event-free survival when compared with those without an ITD (p=0.0079). Among 54 relapsed patients, 9 patients had the FLT3 ITD at diagnosis. Six patients demonstrated a reappearance of the ITD and 3 patients remained negative at relapse. One patient, among 45 patients who relapsed, had a negative baseline ITD but acquired a de novo ITD at relapse. There were 101 samples from 93 patients in remission; they were all negative for an ITD. Among 34 patients who failed to achieve a remission, five patients had a persistent ITD and one patient had a de novo ITD. These results support the concept of resistance of FLT3 ITD leukemic clones to chemotherapy. Therefore, effective therapy with FLT3 targeting agents may improve the prognosis of non-M3 AML patients with the FLT3 mutation.