Minimal residual disease, long-term outcome, and IKZF1 deletions in children and adolescents with Down syndrome and acute lymphocytic leukaemia: a matched cohort study
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- Minimal residual disease, long-term outcome, and IKZF1 deletions in children and adolescents with Down syndrome and acute lymphocytic leukaemia: a matched cohort study
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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 [HRcs] 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]; HRcs 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]; HRcs 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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | The Lancet Haematology |
| Vol/bind | 8 |
| Udgave nummer | 10 |
| Sider (fra-til) | e700-e710 |
| ISSN | 2352-3026 |
| DOI | |
| Status | Udgivet - 2021 |
Bibliografisk note
Funding Information:
This study was a project of the Ponte di Legno group. The Dutch Childhood Oncology Group (DCOG), The Australian and New Zealand Children's Haematology and Oncology Group, The Children's Cancer and Leukemia Group, the Nordic Society of Pediatric Hematology-Oncology, and the co-operative study group for childhood acute lymphoblastic leukaemia contributed to this project. The DCOG collected and provided genetic and clinical information of Dutch patients enrolled in this study. The Immunology Department of the Erasmus Medical Center and Sanquin did the MRD monitoring of Dutch patients. This work is part of the nationwide research program Childhood Oncology Network Targeting Research, Organisation & Life expectancy (CONTROL) and is supported by the Danish Cancer Society (R-257-A14720) and the Danish Childhood Cancer Foundation (2019-5934 and 2020-5769). We thank the Stichting Kinder Oncologisch Centrum Rotterdam and the Princess Máxima Center Foundation for providing funds for research in children with leukaemia and funding the PhD position of NM. The MRD and IKZF1 testing for Australian participants was supported by several grants from NHMRC Australia, The Cancer Council NSW, and Tour de Cure. In the UK, this study was supported by Blood Cancer UK, UK Medical Research Council, and Children with Cancer and benefitted from data and patients samples from the UK Cancer Cytogenetics Group and Blood Cancer UK Childhood Leukaemia Cell Bank, respectively. GB is supported by funds from the Swedish Society for Pediatric Cancer. MH was supported by the Swedish Childhood Cancer Fund.
Funding Information:
This study was a project of the Ponte di Legno group. The Dutch Childhood Oncology Group (DCOG), The Australian and New Zealand Children's Haematology and Oncology Group, The Children's Cancer and Leukemia Group, the Nordic Society of Pediatric Hematology-Oncology, and the co-operative study group for childhood acute lymphoblastic leukaemia contributed to this project. The DCOG collected and provided genetic and clinical information of Dutch patients enrolled in this study. The Immunology Department of the Erasmus Medical Center and Sanquin did the MRD monitoring of Dutch patients. This work is part of the nationwide research program Childhood Oncology Network Targeting Research, Organisation & Life expectancy (CONTROL) and is supported by the Danish Cancer Society (R-257-A14720) and the Danish Childhood Cancer Foundation (2019-5934 and 2020-5769). We thank the Stichting Kinder Oncologisch Centrum Rotterdam and the Princess M?xima Center Foundation for providing funds for research in children with leukaemia and funding the PhD position of NM. The MRD and IKZF1 testing for Australian participants was supported by several grants from NHMRC Australia, The Cancer Council NSW, and Tour de Cure. In the UK, this study was supported by Blood Cancer UK, UK Medical Research Council, and Children with Cancer and benefitted from data and patients samples from the UK Cancer Cytogenetics Group and Blood Cancer UK Childhood Leukaemia Cell Bank, respectively. GB is supported by funds from the Swedish Society for Pediatric Cancer. MH was supported by the Swedish Childhood Cancer Fund.
Funding Information:
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.
Publisher Copyright:
© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license
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