Internal Tandem Duplication and Kinase Domain Mutation of FLT3 in Pediatric Acute Myeloid Leukemia Treated on Japan Cooperative AML 99 Protocol.

FLT3 is a type III receptor tyrosine kinase and this kinase mutation is most frequently observed in cases of acute myeloid leukemia (AML). Approximately 30% of adult AML patients have internal tandem duplication (ITD) of the juxtamembrane domain or point mutation of kinase domain (D835Mt) leading to the constitutive activation of downstream signaling pathways and aberrant cell growth. We examined FLT3-ITD and D835Mt in 160 pediatric AML patients treated on Japan pediatric AML cooperative treatment protocol, AML 99. This protocol is consisted of intensification of multi-drug chemotherapy and early application of stem cell transplantation (SCT) for the high risk patients (monosomy 7, Ph1, or delayed remission etc.). FLT3-ITD was found in 22 of 160 (13.8%) patients, including 5 of 15 (33.3%) patients with FAB-M3, 5 of 25 (20.0%) with M5, and 4 of 24 (16.7%) with M1. No specific chromosomal abnormalities were associated with ITD; 9 of 17 (52.9%) patients with ITD showed normal karyotype except for t(15;17). The D835Mt was found in 12 of 160 (7.5%) patients, including 4 of 15 (26.7%) patients with M3. The initial WBC count and the age at diagnosis in ITD or D835Mt patients were significantly higher than those in patients with wild type (WT) of FLT3 (p< 0.05). Except for M3, 12 of 17 (70.6%) patients with ITD received SCT (3 patients in 1^st CR, 1 patient in 2^nd CR, 3 patients in 1^st relapse, although 4 patients in non-CR). Eight patients showed early relapse after SCT and died. No patients with D835Mt showed the induction failure or relapse. In M3, only one patient with FLT3-WT died in early induction phase. The overall survivals (OS) for patients with ITD, D835Mt and WT by Kaplan-Meier method were 33%, 100% and 80%, respectively (p<0.05). These results suggest that patients with ITD are associated with poor outcome despite of receiving SCT, while those with D835Mt are associated with good outcome.