Down syndrome (DS), caused by an extra copy of material from chromosome 21, is one of the most common genetic conditions. The increased risk of acute leukemia in DS (DS-AL) has been recognized for decades, consisting of an approximately 150-fold higher risk of acute myeloid leukemia (AML) before age 4 years, and a 10- to 20-fold higher risk of acute lymphoblastic leukemia (ALL), compared with children without DS.
A recent National Institutes of Health-sponsored conference, ImpacT21, reviewed research and clinical trials in children, adolescents, and young adults (AYAs) with DS-AL and are presented herein, including presentation and treatment, clinical trial design, and ethical considerations for this unique population. Between 10% to 30% of infants with DS are diagnosed with transient abnormal myelopoiesis (TAM), which spontaneously regresses. After a latency period of up to 4 years, 20% to 30% develop myeloid leukemia associated with DS (ML-DS). Recent studies have characterized somatic mutations associated with progression from TAM to ML-DS, but predicting which patients will progress to ML-DS remains elusive. Clinical trials for DS-AL have aimed to reduce treatment-related mortality (TRM) and improve survival. Children with ML-DS have better outcomes compared with non-DS AML, but outcomes remain dismal in relapse. In contrast, patients with DS-ALL have inferior outcomes compared with those without DS, due to both higher TRM and relapse. Management of relapsed leukemia poses unique challenges owing to disease biology and increased vulnerability to toxic effects. Late effects in survivors of DS-AL are an important area in need of further study because they may demonstrate unique patterns in the setting of chronic medical conditions associated with DS.
Conclusions and Relevance
Optimal management of DS-AL requires specific molecular testing, meticulous supportive care, and tailored therapy to reduce TRM while optimizing survival. There is no standard approach to treatment of relapsed disease. Future work should include identification of biomarkers predictive of toxic effects; enhanced clinical and scientific collaborations; promotion of access to novel agents through innovative clinical trial design; and dedicated studies of late effects of treatment.
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Accepted for Publication: January 5, 2023.
Published Online: July 13, 2023. doi:10.1001/jamaoncol.2023.2163
Corresponding Authors: Anupam Verma, MD, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (email@example.com); Karen Rabin, MD, PhD, Department of Pediatrics, Division of Pediatric Hematology-Oncology, Baylor College of Medicine, Texas Children’s Cancer Center, 1102 Bates Ave, Ste 750.00, Houston, TX 77030 (firstname.lastname@example.org).
Author Contributions: Dr Verma had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: All authors.
Acquisition, analysis, or interpretation of data: Verma, Rabin.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important intellectual content: All authors.
Administrative, technical, or material support: Verma, Lupo, Shah, Rabin.
Supervision: All authors.
Conflict of Interest Disclosures: Dr Shah receives royalties from Syncopation Life Sciences and has participated in Advisory Boards for Sobi and VOR.
Funding/Support: This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research and the Warren Grant Magnuson Clinical Center (ZIA BC 011823, N. Shah). This work was in part supported by the National Institutes of Health (X01HL145686-01, R01CA249867, P30CA125123-14S4).
Role of the Funder/Sponsor: The funding agencies had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Disclaimer: The content of this publication does not necessarily reflect the views of policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.
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