Acute Lymphoblastic Leukemia in Children with Down Syndrome: A Report From the Ponte Di Legno Study Group,

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.

Outcomes of treatment for relapsed acute lymphoblastic leukaemia in children with Down syndrome

“…Higher frequency and severity of adverse events, such as infection, mucositis following the use of methotrexate and glucocorticoid-associated hyperglycaemia, have been widely reported for children with DS undergoing primary therapy for ALL (Garre et al, 1987;Bassal et al, 2005;Whitlock, 2006;Buitenkamp et al, 2010;Maloney, 2011). Excessive ID/TRM, mainly due to infection, was observed among children with DS undergoing first-line chemotherapy for standard and high risk ALL on protocols developed by North American and UK study groups (Maloney, 2011;Maloney et al, 2011) and was not limited to early phases of primary treatment in a retrospective multinational study (Buitenkamp et al, 2011). We found a similar pattern during ALL relapse therapy for children with DS both during and after the induction phase.…”

“…Acute lymphoblastic leukaemia (ALL) occurs with 24-fold greater incidence (Hasle et al, 2000) in children with Down syndrome (DS) (Online Mendelian Inheritance in Man [OMIM] number 190685) and poses specific challenges during treatment (Whitlock, 2006;Maloney, 2011). Survival of ALL in children with DS (DS-ALL) is lower than in the general paediatric population (Bassal et al, 2005;Whitlock, 2006;Buitenkamp et al, 2011). This inferior success rate of primary ALL therapy in children with DS has not been attributable to a specific disease mechanism, such as increased expression of the cytokine receptor CRLF2 (Mullighan et al, 2009;Russell et al, 2009;Harvey et al, 2010;Hertzberg et al, 2010) and activating mutations of the gene encoding the signal transducer JAK2 (Gaikwad et al, 2009;Kearney et al, 2009;Harvey et al, 2010;Hertzberg et al, 2010) in the blasts of DS-ALL.…”