The Outcome of Relapsed Childhood Core Binding Factor Acute Myeloid Leukemia: A Report from the JPLSG AML-05R Study
Authors: Moritake Hiroshi , Tanaka Shiro , Nakayama Hideki , Miyamura Takako , Iwamoto Shotaro , Shimada Akira , Terui Kiminori , Saito Akiko M. , Shiba Norio , Hayashi Yasuhide , Tomizawa Daisuke , Taga Takashi , Goto Hiroaki , Manabe Atsushi , Horibe Keizo , Mizutani Shuki , Adachi Souichi 
Published: October 2019

Abstract
BACKGROUND: Core binding factor acute myeloid leukemia (CBF-AML), which is characterized by the chromosomal abnormalities of t(8;21) and inv(16), is the most frequent subtype of pediatric AML. Patients with CBF-AML have a better prognosis than patients with a normal karyotype when they receive chemotherapy of appropriate intensity; however, in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 study, the excessive treatment reduction was observed to induce a higher incidence of relapse in children with CBF-AML. We investigated the outcomes of patients with relapsed CBF-AML who were registered in the JPLSG AML-05.
PATIENTS & METHODS: We conducted a retrospective analysis of the JPLSG AML-05R study using a questionnaire. Furthermore, a mutation analysis was performed to identify NRAS, KRAS, KIT, WT1, NPM1, NUP98-NSD1, FLT3-ITD and MLL-PTD mutations using the available samples. We investigated the probability of overall survival (pOS) after relapse according to the patient's age, time from diagnosis to relapse, site of relapse, FAB classification, t(8;21) versus inv (16), reinduction chemotherapy regimen, obtaining a second complete remission before stem cell transplantation (SCT), the method of SCT and the presence of additional mutations.
RESULTS: Forty-one of the 154 children with CBF-AML who were registered in the JPLSG AML-05 study experienced a relapse. The information from 32 of these 41 patients was collected using a questionnaire. Twenty-seven had t(8;21), and 5 had inv (16). It was possible to perform molecular analyses for 28 of the patients. KIT mutations were identified in 16 of 28 patients (57.1%). The follwing mutations were also detected: NRAS (n=4), KRAS (n=1), and WT1 (n=1). There were no cases with FLT3 -ITD, NUP98-NSD1, MLL-PTD or NPM1 mutations. Twenty-five cases achieved a complete remission after the initial reinduction (78.1%). The pOS was 65.6% (21/32) after a mean observation period of 2.7 years. The significant prognostic factors influencing pOS included a failure to obtain complete remission prior to SCT (p=0.03), reinduction chemotherapy regimen [p=0.02, a FLAG-based or ECM (etoposide, cytarabine and mitoxantrone)-based regimen was better than other modalities], donor source (p<0.01, cord blood was better than bone marrow and peripheral blood) and HLA matching between the donor and recipient (p=0.03, a mismatch was better than a full-match). Additional mutations, including the presence of the KIT gene, did not have any effect on pOS (p=0.64).
CONCLUSIONS: Relapsed childhood CBF-AML in the JPLSG AML-05 study was still associated with a better prognosis, because almost two thirds of the patients were successfully treated with SCT. Obtaining complete remission prior to SCT was associated with a good prognosis. A FLAG- or ECM-based regimen is therefore recommended for reinduction chemotherapy. Unexpectedly, cord blood transplantation and HLA-mismatched SCT were associated with a better prognosis. Further investigations are necessary to clarify the genes that are associated with a poor prognosis in patients with CBF-AML.

Disclosures
No relevant conflicts of interest to declare.