A Multicenter Nonrandom Clinical Study of Induction Regimen of FLAG-ID and Dae in the Treatment of Childhood De Novo Acute Myeloid Leukemia in South of China:the Early Report of Efficacy and Safety

Objective: Complete remission (CR) after induction chemotherapy was one of the important prognostic factors in the treatment of acute myeloid leukemia(AML). Intensive induction regimen have potential of increasing the CR rate, but also followed high risk of treatment related mortality (TRM). This multicenter nonrandom clinical study is to evaluate the early efficacy and safety of induction regimen of FLAG-IDA and DAE in the treatment of childhood de novo acute myeloid leukemia in south of China.

Methods: Total of 135 newly diagnosed childhood AML patients come from 8 centers of south of China involved in the clinical study from November 2014 to January 2017.Eighty-three boys and 52 girls, median age 6 (1-14) year old were included. Patients with Down syndrome and acute promyelocytic leukemia were excluded. The median follow-up period was 12 (4 to 33) months till to June 2017.Thirty-seven patients (27.4%)had favorable cytogenetic karyotypes including t(8;21) and inv(16) but without FLT3-ITD, and c-KIT mutations. Sixty-one patients had unfavorable cytogenetic karyotypes including 11q23/MLL(non MLL-MLLT3) , FLT3-ITD, ASXL1 and c-KIT. Double FLAG-IDA courses(n=77) or DAE(3+5+10) followed DAE(3+5+8) course(n=58) by non random scheme admitted to patients for induction chemotherapy. The similarity of clinical data between two groups was analyzed by the chi square test. Complete remission (CR) rate, serious adverse event(SAE) and treatment related mortality (TRM) were studied by Log-Rank chi square test.

Results:The FLAG-IDA and DAE group in gender, age, initial WBC count, morphological classification, risk classification,cytogenetics and molecular genes(favorable and unfavorable ) had no significant difference.The overall CR rates was 80.0% and 91.1% after 1st course and 2^nd course respectively. CR rates of FLAG-IDA group is 83.1% and 96.1% after 1^st and 2^nd course.CR rates of DAE group is 75.8% and 84.5% after 1^st course of DAE(3+5+10) and 2^nd course of DAE(3+5+8).The remission rates of FLAG-IDA group was significantly superior than that of DAE group after 2 courses of induction treatment(P=0.03).The CR rates of patients with favorable cytogenetic karyotypes was significantly higher than patients with unfavorable cytogenetic karyotypes (100% vs 84.3%,P=0.012) after the first course. The SAE during induction chemotherapy included : 44 cases of sepsis (32.59%), 34 cases of invasive fungal disease (25.18%), 32 cases of abdominal infection (23.70%), 22 cases of severe pneumonia (16.30%),4 cases of heart failure (2.96%). Nine cases died (6.67% ) during induction chemotherapy.Moreover, the TRM in FLAG-IDA group were not different from DAE group in induction treatment.

FLAG-IDA is an effective induction regimen with high CR rates after 2 courses of treatment and can be used as first line induction chemotherapy in childhood de novo acute myeloid leukemia in south of China. Severe infection and drug toxicity will be needed more strategies of prophylaxis and treatment.