Acute Lymphoblastic Leukemia in Children with Down Syndrome: A Report From the Ponte Di Legno Study Group,
Authors: Buitenkamp Trudy , Izraeli Shai , Zimmermann Martin , Forestier Erik , Heerema Nyla A. , van den Heuvel Marry M. , Pieters Rob , de Haas Válerie , Silverman Lewis B. , Schmiegelow Kjeld , Liang Der-Cherng , Horibe Keizo , Arico Maurizio , Cazzaniga Giovanni , Basso Giuseppe , Rabin Karen R. , Schrappe Martin , Cario Gunnar , Mann Georg , Mondelaers Veerle , Lammens Tim , Cavé Hélène , Stark Batia , Moorman Anthony V. , Vora Ajay J , Hunger Stephen , Pui Ching-Hon , Mullighan Charles G , Manabe Atsushi , Escherich Gabriele , Kowalczyk Jerzy , Whitlock James A. , Zwaan Christian M. 
Published: October 2019

Abstract
Abstract 3579
Children with Down syndrome (DS) have an increased risk of developing B-cell precursor acute lymphoblastic leukemia (BCP-ALL), characterized by a low frequency of the common genetic aberrations, and a high frequency of CRLF2 and JAK aberrations. Because this disease is relatively rare, the clinical outcome, treatment-related mortality (TRM) and prognostic factors of DS-ALL patients treated in contemporary protocols are uncertain. Previous studies demonstrated poorer survival and a high rate of treatment related mortality (TRM), but most studies are small since DS ALL patients comprise only 1–2% of all protocol patients. We therefore conducted a large retrospective study of 653 children with DS-ALL treated in clinical trials of 16 collaborative study groups between 1995 and 2005. All genotypes obtained from conventional karyotyping, FISH or RT-PCR were centrally reviewed and assigned to specific cytogenetic groups. The 310 girls and 343 boys have a median age of 5.0 years (range, 1.2 – 17.9) and a median white blood-cell count (WBC) of 10.2 × 109/L (range, 0.2 – 459). The 827 non-DS BCP-ALL control patients from the Dutch Childhood Oncology Group treated in the same era had similar WBC (8.8 × 109/L; p=0.25) but were younger (4.6 years; p< 0.001). The median follow-up time was 6.8 years for DS-ALL survivors and 7.3 years for non-DS-ALL survivors. DS patients have a higher 8-year cumulative incidence of relapse (CIR) (26±2% vs. 18±1%; p=0.001) and higher 2-year TRM (7±1% vs. 1.0±<0.1%; p<0.0001) than controls, resulting in lower 8-year event free survival (EFS) (64±2% vs. 78±1%; p<0.0001) and lower 8-year overall survival (OS) (74±2% vs. 86±1%; p<0.0001). In the multivariate analysis, age ≥ 6 years and WBC ≥ 10 × 109/L were independent predictors for poor EFS (HR = 1.68, p = 0.003; WBC = 1.79, p = 0.001, respectively), and poor relapse-free survival (HR = 1.99; p = 0.001; HR = 1.55; p = 0.04, respectively). DS patients with age <6 years and WBC <10 × 109/L constituted a favourable risk-group when compared to the remaining DS patients but still had a relatively high relapse rate (EFS, 78±3% vs. 58±3%; p <0.001, TRM, 3±1% vs. 9±1%; p =0.002, CIR, 17±3% vs. 30±2%; p = 0.003). This criterion was a better predictor of outcome than that in classic NCI-criteria, even after exclusion of patients with TEL-AML1 rearrangement or trisomies 4 and 10. Of the 444 (68%) patients with available cytogenetic data, 40.3% had normal cytogenetics, 9.0% was high hyperdiploid (HeH) (34% in non-DS ALL; p<0.001), 8.3% had TEL-AML1 rearrangements (21.7% in non-DS ALL; p <0.001), and 2% had t(8;14)(q11.2)(q32). Remarkably, the 8-year EFS was nearly identical between TEL-AML1- rearranged DS and non-DS patients (95±4% vs.92±3%; p=0.77). HeH DS patients showed a trend towards lower EFS when compared to HeH non-DS patients (77±7% vs. 86±2%; p=0.06). Within HeH DS ALL patients, the number of patients with trisomy 4+10 was only 45%. The OS of these patients was 88±8%, and there were no relapses. Data on CRLF2 aberrations and JAK2 R683 mutations was available for 134 and 141 patients, respectively. Neither CRLF2 aberrations (OS 74±5%; p=0.29, CIR 29±6%; p=0.23) nor JAK2 mutations predict prognosis in DS ALL (OS 71±8%; p=0.21, CIR 25±9%; p=0.55). In total, 32% (n=16) of TRM's in DS patients occurred during remission induction, most (n=10) were caused by infection. The inclusion of anthracyclines in induction had no impact on TRM. When comparing NCI-SR patients of the CCG/POG studies (3-drug induction) with patients treated on AIEOP/BFM-studies (4-drug-induction) the incidence of TRM was 1.5±1% vs. 1.7±1%; p= 0.46). Also the EFS was similar (64±6% vs. 69±5%; p= 0.39). There was no distinct decrease of TRM after induction, it was not related to a specific treatment-phase or treatment-regimen and also occurred 2 years after diagnosis (∼1%), suggesting better supportive care throughout the treatment is needed. In conclusion, DS patients enrolled in contemporary protocols with curative intent continued to have a poor survival due to both high rates of relapse and TRM. Within DS ALL, patients age < 6 year, WBC <10 × 109/L and the presence of TEL-AML1 or trisomies 4 and 10 are favourable prognostic factors, which may be used to guide risk-directed treatment.

Disclosures:
No relevant conflicts of interest to declare.