Prognosis and treatment-related toxicities in Down syndrome acute lymphoblastic leukemia in JCCG ALL-B12

Children with Down syndrome (DS) have an increased risk of acute lymphoblastic leukemia (ALL). Although recent reports describe some improvement, survival in DS-ALL remains inferior to that of non-DS-ALL. This study evaluated the prognosis, relapse patterns, and treatment-related toxicities of DS-ALL in the Japan Children's Cancer Group ALL-B12 trial, a nationwide prospective study using risk-adapted therapy. A total of 1,804 patients, including 44 DS-ALL, were analyzed. Risk classification used standardized criteria. The 5-year event-free survival and overall survival in DS-ALL were 70.5% and 81.8%, respectively, lower than 85.6% and 94.6% in non-DS-ALL (P < 0.001). Survival differences were most pronounced in standard-risk patients. DS-ALL showed fewer favorable genetics and relapse patterns dominated by isolated bone marrow events, with no CNS relapse. CRLF2 rearrangement was assessable in 43 of 44 DS-ALL cases; 15 of 43 (34.9%) were positive. In an exploratory analysis excluding canonical favorable or unfavorable subtypes (n = 36), the 5-year EFS in DS-ALL with and without CRLF2 rearrangement were 57.1% and 81.8%, respectively (P = 0.300), and the corresponding 5-year OS were 78.6% and 86.4%, respectively (P = 0.331). Treatment-related toxicities were more frequent in DS-ALL, including mucositis (27.3% vs. 7.1%), hyperglycemia (25.0% vs. 6.9%), and pulmonary infections (20.5% vs. 7.4%). Among DS-ALL patients with TP2 MRD ≥ 10-4 (n = 3), all relapsed and died within three years. No treatment-related death was recorded after induction, but one death of undetermined cause occurred. These findings highlight the continuing need to optimize DS-ALL therapy to reduce relapse and toxicity. UMIN CT Registry (UMIN000009339) and JCT (jRCTs041180101).