Etoposide, Cytarabine and Mitoxantrone- or Fludarabine, Cytarabine and Granulocyte Colony-Stimulating Factor-Based Intensive Reinduction Chemotherapy Is Recommended for Children with Relapsed Acute Myeloid Leukemia: The Results from the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05R Study

Background:The current event-free survival rates of children with acute myeloid leukemia (AML) approach 60%, with hematopoietic cell transplantation (HCT) as an effective second-line therapy and improvements in supportive care; however, the overall survival rates of children with relapsed AML still remains 70%, which is an unsatisfactory situation that urgently needs to be solved.

Patients & Methods:In order to identify prognostic factors and improve their prognosis, we analyzed 111 patients with relapsed disease after treatment with the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 protocol, who were registered in the retrospective JPLSG AML-05R study. We collected the following data: age at relapse, time from the diagnosis to relapse, site of relapse, FAB classification, chromosomal analysis results, reinduction chemotherapy regimen, rate of achieving a second complete remission (CR2) after initial reinduction therapy, detailed information on HCT, outcome and cause of death. Moreover, ninety-three leukemic samples obtained from 111 patients at the time of their diagnosis were available for a genetic analysis. Mutational analyses ofFLT3-ITD,KIT, N-andK-RAS, NPM1,WT1,andKMT2A-partial tandem duplication were performed. Screening ofNUP98-NSD1was also performed. The high or low expression ofMECOMandPRDM16were determined based on theABL1ratio.

Results:The 5-year overall survival rate was 36.1%. t(8;21) was found in 27 patients and inv(16) was found in 5 patients.KMT2Arearrangement was found in 23 patients (24.7%).KITmutations were found in 17 patients (17.5%). The following mutations were also detected:FLT3-ITD (n=10),N-RAS(n=10),WT1(n=7),K-RAS(n=4),NUP98-NSD1(n=2),KMT2A-PTD (n=2), andNPM1(n=2). The high expression ofMECOMandPRDM16was found in 24 (25.8%) and 32 (34.4%) patients, respectively. A genetic analysis revealed the prognostic significance ofFLT3-ITD as a poor prognostic marker (p=0.04) and core binding factor-AML, t(8;21) and inv(16), as a good prognostic marker (p<0.01). The five-year overall survival rate in the AML-05 risk groups were as follows: high risk, 14.7%; intermediate risk, 32.3%; and low risk 61.7% (p<0.01). The major determinant of survival was duration from the diagnosis to relapse. The mean duration in the non-surviving group (10.1±4.1 months) was shorter than that in the surviving group (16.3±8.3 months) (p<0.01). Moreover, achieving CR2 prior to HCT was associated with a good prognosis (p<0.01). "Etoposide, cytarabine and mitoxantrone" (ECM)- or "fludarabine, cytarabine and granulocyte colony-stimulating factor" (FLAG)-based regimens were therefore recommended for reinduction therapy (p<0.01).

Conclusions:Achieving CR2 prior to HCT by intensive reinduction chemotherapy, ECM, or FLAG, is important for improving the prognosis of patients with relapsed pediatric AML. Liposomal daunorubicin or 3 fractionated doses of gemtuzumab ozogamicin is an attractive option which is under consideration for addition to FLAG. Moreover, recent molecular targeted therapeutics, such as FLT3 inhibitors, may contribute to improving the prognosis of these patients. Larger prospective investigations are needed in order to establish individualized treatment strategies for patients with relapsed childhood AML.