Key Points• Although the risk of ALL relapse is significantly higher in children with DS, goodprognosis subgroups have been identified. • Patients with DS-ALL have higher treatment-related mortality throughout the treatment period independent of the therapeutic regimen.Children with Down syndrome (DS) have an increased risk of B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). The prognostic factors and outcome of DS-ALL patients treated in contemporary protocols are uncertain. We studied 653 DS-ALL patients enrolled in 16 international trials from 1995 to 2004. Non-DS BCP-ALL patients from the Dutch Child Oncology Group and Berlin-Frankfurt-Münster were reference cohorts. DS-ALL patients had a higher 8-year cumulative incidence of relapse (26% 6 2% vs 15% 6 1%, P < .001) and 2-year treatment-related mortality (TRM) (7% 6 1% vs 2.0% 6 <1%, P < .0001) than non-DS patients, resulting in lower 8-year event-free survival (EFS) (64% 6 2% vs 81% 6 2%, P < .0001) and overall survival (74% 6 2% vs 89% 6 1%, P < .0001). Independent favorable prognostic factors include age <6 years (hazard ratio [HR] 5 0.58, P 5 .002), white blood cell (WBC) count <10 3 10 9 /L (HR 5 0.60, P 5 .005), and ETV6-RUNX1 (HR 5 0.14, P 5 .006) for EFS and age (HR 5 0.48, P < .001), ETV6-RUNX1 (HR 5 0.1, P 5 .016) and high hyperdiploidy (HeH) (HR 5 0.29, P 5 .04) for relapse-free survival. TRM was the major cause of death in ETV6-RUNX1 and HeH DSALLs. Thus, while relapse is the main contributor to poorer survival in DS-ALL, infection-associated TRM was increased in all protocol elements, unrelated to treatment phase or regimen. Future strategies to improve outcome in DS-ALL should include improved supportive care throughout therapy and reduction of therapy in newly identified good-prognosis subgroups. (Blood. 2014; 123(1):70-77)

The ALL IC-BFM 2002 trial is a good example of international collaboration in pediatric oncology. A wide platform of countries able to run randomized studies in ALL has been established. Although the alternative DI did not improve outcome compared with standard treatment and the overall results are worse than those achieved by longer established leukemia groups, the national results have generally improved.