嶋田 明

BACKGROUND: Relapsed or refractory cases of pediatric acute myeloid leukemia (AML) have poor outcomes despite advancements in chemotherapy and hematopoietic stem cell transplantation (HSCT). While a second HSCT is often a salvage option, its outcomes vary widely, and prognostic factors remain unclear. OBJECTIVES: This study aimed to evaluate outcomes and identify prognostic factors in pediatric patients with AML who underwent multiple HSCTs. METHODS: We conducted a retrospective, multicenter study of 49 pediatric patients with AML who underwent two or more HSCTs at 18 Japan Association of Childhood Leukemia Study institutions during 2000-2019. Clinical data on patient demographics, disease status, transplant characteristics, and complications were collected. The primary endpoint was 5-year overall survival (OS) after the second HSCT. Kaplan-Meier and multivariate Cox regression analyses were performed. RESULTS: Of the 49 patients, three and 46 underwent three and two HSCTs, respectively. Among these 46 patients, 5-year OS after the second HSCT was 28.3%. Achieving hematological complete remission (CR) before the second HSCT was associated with significantly better outcomes (5-year OS: 45.0% vs. 0%, p < 0.01). Severe sinusoidal obstruction syndrome (SOS) after the second HSCT was a strong predictor of transplant-related mortality (5-year OS: 0% in severe SOS cases, p < 0.01). Patient age, donor type, conditioning regimen, and acute/chronic graft-versus-host disease were not significantly associated with survival in multivariate analysis. CONCLUSIONS: Achieving CR before the second HSCT is critical for long-term survival, while severe SOS significantly worsens prognosis. Optimized pre-transplant strategies to reduce SOS risk are essential to improve outcomes of pediatric patients with AML who undergo multiple HSCTs.

Arsenic trioxide (ATO) in combination with all-trans retinoic acid (ATRA) has been shown to be effective in both adult and pediatric patients with acute promyelocytic leukemia (APL). Addition of ATO to conventional chemotherapy could lead to a reduction in the doses of cytotoxic agents, but the long-term safety of ATO is not fully understood, especially in children. The Japan Children's Cancer Group conducted a risk-stratified prospective study to investigate safety and efficacy of ATO in children with newly diagnosed APL by replacing all three intensification phases with ATO. The 3-year event-free survival and overall survival rates in 27 children were 96.3% (95% CI 76.5%-99.5%) and 100% (95% CI 87.2%-100%), respectively. Prolonged QTc interval or other cardiac conduction disorders of any grade were observed in 20 out of the 63 intensification cycles. The durations of leukocytopenia, neutropenia, and G-CSF treatment were significantly shorter in this study than in a previous Japanese study that used conventional cytotoxic chemotherapy. Furthermore, no cardiac, metabolic, renal, cutaneous, or neurological symptoms were reported for up to 5 years after completion of the protocol therapy. The JPLSG AML-P13 study demonstrated excellent outcomes and safety of ATO in children with APL.

Transient abnormal myelopoiesis (TAM) occurs in 10% of neonates with Down syndrome (DS). Although most patients show spontaneous resolution of TAM, early death occurs in approximately 20% of cases. Therefore, new biomarkers are needed to predict early death and determine therapeutic interventions. This study aimed to determine the association between clinical characteristics and cytokine levels in patients with TAM. A total of 128 patients with DS with TAM enrolled in the TAM-10 study conducted by the Japanese Pediatric Leukemia/Lymphoma Study Group were included in this study. Five cytokine levels [interleukin (IL)-1b, IL-1 receptor agonist, IL-6, IL-8, and IL-13] were significantly higher in patients with early death than in those with non-early death. Cumulative incidence rates (CIR) of early death were significantly associated with high levels of the five cytokines. Based on unsupervised consensus clustering, patients were classified into three cytokine groups: hot-1 (n = 37), hot-2 (n = 42), and cold (n = 49). The CIR of early death was significantly different between the cytokine groups [hot-1/2 (n = 79); cold (n = 49); CIR (95% confidence interval [CI]) = 16.5% (7.9%-24.2%); 2.0% (0.0%-5.9%), P = 0.013]. Furthermore, cytokine groups (hot-1/2 vs. cold) were independent poor prognostic factors in the multivariable analysis for early death [hazard ratio (95% CI) = 19.25 (2.056-180.3), P = 0.010]. These results provide valuable information that cytokine level measurement was useful in predicting early death in patients with TAM and might help to determine the need for therapeutic interventions.

CD25 is an aberrant marker expressed on the leukemic stem cell (LSC) surface and an immunotherapy target in acute myeloid leukemia (AML). However, the clinical prevalence and significance of CD25 expression in pediatric AML are unknown. High IL2RA/CD25 expression in pediatric AML showed a stem cell-like phenotype, and elevated CD25 expression was associated with lower overall survival (p < .001) and event-free survival (p < .001) in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 study. This finding was reproduced in AML without a core-binding factor in the Children's Oncology Group study cohort. High CD25 expression has prognostic significance in pediatric AML.