Acute lymphoblastic leukemia in children with Down syndrome: a retrospective analysis from the Ponte di Legno study group

Abstract

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% ± 2% vs 15% ± 1%, P < .001) and 2-year treatment-related mortality (TRM) (7% ± 1% vs 2.0% ± <1%, P < .0001) than non-DS patients, resulting in lower 8-year event-free survival (EFS) (64% ± 2% vs 81% ± 2%, P < .0001) and overall survival (74% ± 2% vs 89% ± 1%, P < .0001). Independent favorable prognostic factors include age <6 years (hazard ratio [HR] = 0.58, P = .002), white blood cell (WBC) count <10 × 10(9)/L (HR = 0.60, P = .005), and ETV6-RUNX1 (HR = 0.14, P = .006) for EFS and age (HR = 0.48, P < .001), ETV6-RUNX1 (HR = 0.1, P = .016) and high hyperdiploidy (HeH) (HR = 0.29, P = .04) for relapse-free survival. TRM was the major cause of death in ETV6-RUNX1 and HeH DS-ALLs. 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.

Figure 1

Treatment outcome of the DS-ALL and non–DS-ALL patients. The continuous lines represent DS-ALL patients, and the dotted lines represent non–DS-ALL patients. The red line represents OS, the blue line EFS, the green line the cumulative incidence of TRM, and the light blue line CIR. SE, standard error.

Figure 2

Treatment outcome according to age and WBC in DS-ALL. The OS (A), EFS (B), cumulative incidence of TRM (C), and CIR (D) are depicted for patients aged <6 years with WBC <10 × 10⁹/L (blue line) vs all other DS-ALL patients (red line). The numbers on the curves for OS and EFS represent results at 8 years. The numbers on the curves for TRM are 2-year results (during treatment only) and those for relapse are results at 8 years. SE, standard error.