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Background: Patients with Down syndrome and acute lymphocytic leukaemia are at an increased risk of treatment-related mortality and relapse, which is influenced by unfavourable genetic aberrations (eg, IKZF1 deletion). We aimed to investigate the potential underlying effect of Down syndrome versus the effects of adverse cancer genetics on clinical outcome., Method: Patients (aged 1-23 years) with Down syndrome and acute lymphocytic leukaemia and matched non-Down syndrome patients with acute lymphocytic leukaemia (matched controls) from eight trials (DCOG ALL10 and ALL11, ANZCHOG ALL8, AIEOP-BFM ALL2009, UKALL2003, NOPHO ALL2008, CoALL 07-03, and CoALL 08-09) done between 2002 and 2018 across various countries (the Netherlands, the UK, Australia, Denmark, Finland, Iceland, Norway, Sweden, and Germany) were included. Participants were matched (1:3) for clinical risk factors and genetics, including IKZF1 deletion. The primary endpoint was the comparison of MRD levels (absolute MRD levels were categorised into two groups, low [<0·0001] and high [≥0·0001]) between patients with Down syndrome and acute lymphocytic leukaemia and matched controls, and the secondary outcomes were comparison of long-term outcomes (event-free survival, overall survival, relapse, and treatment-related mortality [TRM]) between patients with Down syndrome and acute lymphocytic leukaemia and matched controls. Two matched cohorts were formed: for MRD analyses and for long-term outcome analyses. For both cohorts, matching was based on induction regimen; for the long-term outcome cohort, matching also included MRD-guided treatment group. We used mixed-effect models, Cox models, and competing risk for statistical analyses., Findings: Of 251 children and adolescents with Down syndrome and acute lymphocytic leukaemia, 136 were eligible for analyses and matched to 407 (of 8426) non-Down syndrome patients with acute lymphocytic leukaemia (matched controls). 113 patients with Down syndrome and acute lymphocytic leukaemia were excluded from matching in accordance with predefined rules, no match was available for two patients with Down syndrome and acute lymphocytic leukaemia. The proportion of patients with high MRD at the end of induction treatment was similar for patients with Down syndrome and acute lymphocytic leukaemia (52 [38%] of 136) and matched controls (157 [39%] of 403; OR 0·97 [95% CI 0·64-1·46]; p=0·88). Patients with Down syndrome and acute lymphocytic leukaemia had a higher relapse risk than did matched controls in the IKZF1 deleted group (relapse at 5 years 37·1% [17·1-57·2] vs 13·2% [6·1-23·1]; cause-specific hazard ratio [HR cs ] 4·3 [1·6-11·0]; p=0·0028), but not in the IKZF1 wild-type group (relapse at 5 years 5·8% [2·1-12·2] vs 8·1% [5·1-12·0]; HR cs 1·0 [0·5-2·1]; p=0·99). In addition to increased induction deaths (15 [6%] of 251 vs 69 [0·8%] of 8426), Down syndrome and acute lymphocytic leukaemia was associated with a higher risk of post-induction TRM compared with matched controls (TRM at 5 years 12·2% [7·0-18·9] vs 2·7% [1·3-4·9]; HR cs 5·0 [2·3-10·8]; p<0·0001)., Interpretation: Induction treatment is equivalently effective for patients with Down syndrome and acute lymphocytic leukaemia and for matched patients without Down syndrome. Down syndrome itself provides an additional risk in individuals with IKZF1 deletions, suggesting an interplay between the germline environment and this poor risk somatic aberration. Different treatment strategies are warranted considering both inherent risk of relapse and high risk of TRM., Funding: Stichting Kinder Oncologisch Centrum Rotterdam and the Princess Máxima Center Foundation, NHMRC Australia, The Cancer Council NSW, Tour de Cure, Blood Cancer UK, UK Medical Research Council, Children with Cancer, Swedish Society for Pediatric Cancer, Swedish Childhood Cancer Fund, Danish Cancer Society and the Danish Childhood Cancer Foundation., Competing Interests: Declaration of interests KS reports speaker or advisory board honoraria from Jazz Pharmaceuticals and Servier; speaker fees from Amgen and Medscape; and an educational grant from Servier. CMZ reports grants from Pfizer, Takeda, AbbVie, and Jazz Pharmaceuticals; consulting fees from Novartis, Incyte, Pfizer, Jazz Pharmaceuticals, Takeda, and Abbvie; speaker fees from Pfizer; travel expenses from Jazz Pharmaceuticals; participation on data safety monitoring committees or advisory boards for Novartis, and Incyte; and is co-chair of the Innovative Therapies for Children with Cancer heamatological malignancies committee. GB reports grants from Swedish Society Pediatric Cancer. TT reports foundation funding to Children's Cancer Institute; project funding from Tour de Cure; and ownership of stock or stock options in CSL, Cochlear, Medical Developments International, Osteopore, and Sonic Healthcare. RS reports grants paid to the University of New South Wales from National Health and Medical Research Council Australia, Cancer Counsel New South Wales, and Cancer Australia; and foundation funding to the Children's Cancer Institute from Tour de Cure and Australian Cancer Research Foundation. All other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: ABL-class fusion genes other than BCR-ABL1 have been identified in approximately 3% of children with newly diagnosed acute lymphocytic leukaemia, and studies suggest that leukaemic cells carrying ABL-class fusions can be targeted successfully by tyrosine-kinase inhibitors. We aimed to establish the baseline characteristics and outcomes of paediatric patients with ABL-class fusion B-cell acute lymphocytic leukaemia in the pre-tyrosine-kinase inhibitor era., Methods: This multicentre, retrospective, cohort study included paediatric patients (aged 1-18 years) with newly diagnosed ABL-class fusion (ABL1 fusion-positive, ABL2 fusion-positive, CSF1R fusion-positive, and PDGFRB fusion-positive) B-cell acute lymphocytic leukaemia enrolled in clinical trials of multidrug chemotherapy done between Oct 3, 2000, and Aug 28, 2018, in which tyrosine-kinase inhibitors had not been given as a first-line treatment. Patients from 14 European, North American, and Asia-Pacific study groups of the Ponte di Legno group were included. No patients were excluded, and patients were followed up by individual study groups. Through the Ponte di Legno group, we collected data on the baseline characteristics of patients, including IKZF1, PAX5, and CDKN2A/B deletion status, and whether haematopoietic stem cell transplantation (HSCT) had been done, as well as treatment outcomes, including complete remission, no response, relapse, early death, and treatment-related mortality, response to prednisone, and minimal residual disease (MRD) at end of induction therapy. 5-year event-free survival and 5-year overall survival were estimated by use of Kaplan-Meier methods, and the 5-year cumulative incidence of relapse was calculated by use of a competing risk model., Findings: We identified 122 paediatric patients with newly diagnosed ABL-class fusion B-cell acute lymphocytic leukaemia (77 from European study groups, 25 from North American study groups, and 20 from Asia-Pacific study groups). 64 (52%) of 122 patients were PDGFRB fusion-positive, 40 (33%) were ABL1 fusion-positive, ten (8%) were CSF1R fusion-positive, and eight (7%) were ABL2 fusion-positive. In all 122 patients, 5-year event-free survival was 59·1% (95% CI 50·5-69·1), 5-year overall survival was 76·1% (68·6-84·5), and the 5-year cumulative incidence of relapse was 31·0% (95% CI 22·4-40·1). MRD at the end of induction therapy was high (≥10 -2 cells) in 61 (66%) of 93 patients, and most prevalent in patients with ABL2 fusions (six [86%] of 7 patients) and PDGFRB fusion-positive B-cell acute lymphocytic leukaemia (43 [88%] of 49 patients). MRD at the end of induction therapy of 10 -2 cells or more was predictive of an unfavourable outcome (hazard ratio of event-free survival in patients with a MRD of ≥10 -2 vs those with a MRD of <10 -2 3·33 [95% CI 1·46-7·56], p=0·0039). Of the 36 (30%) of 119 patients who relapsed, 25 (69%) relapsed within 3 years of diagnosis. The 5-year cumulative incidence of relapse in 41 patients who underwent HSCT (17·8% [95% CI 7·7-31·3]) was lower than in the 43 patients who did not undergo HSCT (45·1% [28·4-60·5], p=0·013), but event-free survival and overall survival did not differ between these two groups., Interpretation: Children with ABL-class fusion B-cell acute lymphocytic leukaemia have poor outcomes when treated with regimens that do not contain a tyrosine-kinase inhibitor, despite the use of high-risk chemotherapy regimens and frequent HSCT upon first remission. Our findings provide a reference for evaluating the potential benefit of first-line tyrosine-kinase inhibitor treatment in patients with ABL-class fusion B-cell acute lymphocytic leukaemia., Funding: The Oncode Institute, Pediatric Cancer Foundation Rotterdam, Dutch Cancer Society, Kika Foundation, Deutsche Krebshilfe, Blood Cancer UK, Associazione Italiana per la Ricerca sul Cancro, Cancer Australia, National Cancer Institute, National Institute of Health, and St Baldrick's Foundation., (Copyright © 2021 Elsevier Ltd. All rights reserved.)