A Children's Oncology Group Clinical Trial of Long-Term Outcomes in Survivors of Down Syndrome-Associated Acute Leukemia (ALTE22C1): Clinical Trial in Progress

Background and Significance: Children with Down syndrome (DS) have a 10-20 fold excess risk for developing acute leukemia (AL) compared with the general population and are at greater risk for acute cancer treatment-related toxicities. However, few studies have reported the late effects of treatment in DS-AL survivors. None has investigated if chronic health conditions (CHC) and neuropsychological (NP) outcomes in survivors differ from those experienced by the DS general population. The Children's Oncology Group (COG) study ALTE22C1 addresses this knowledge gap by characterizing CHC and NP outcomes in DS-AL survivors relative to outcomes seen in DS. Supporting pilot data demonstrated a) greater executive dysfunction, externalizing behavior, and inattention in 43 DS-AL vs. DS normative data and b) higher likelihood of multiple CHC in 25 survivors of DS-AL parallelling known late effects of chemotherapy (e.g., acquired cataracts, cardiovascular disease) vs. 53 age-matched individuals with DS and no cancer history (DS controls).

Study Design: COG ALTE22C1 (NCT05702645) is a multicenter observational cohort study collecting parent proxy-reported medical outcome (PPRO) data and NP outcomes from subjects with a history of DS-AL. A guidelines-directed in-person survivorship clinical assessment and in-person NP assessment and blood draw are optional. The primary aim is to determine and compare the prevalence, type, and severity of CHC in survivors of DS-AL vs. DS controls. Secondary aims will assess post-treatment clinical outcomes, prevalence and severity of NP outcomes, health-related quality of life, as well as clinical risk determinants of CHC and NP outcomes. Exploratory aims will determine if structural birth defects and genetic variants are associated with CHC and if leukocyte telomere length is associated with NP outcomes.

Eligible persons are ≥ 6 and < 40 years of age with DS and at least three years from end of treatment for acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). History of transplant or subsequent cancers are exclusionary. A national DS cohort study (DS360, PI: Rosser) that collects identical PPRO data will serve as the DS control comparison group.

The study design leverages centralized recruitment from COG registries and also allows site-based recruitment. This innovative design facilitates remote PPRO data collection to support the primary aim without requiring site activation. COG sites that open the study support recruitment of non-registry participants and provide key clinical survivorship outcome data. Active sites are incentivized to enroll subjects through an NCI Community Oncology Research Program (NCORP)-supported per-case reimbursement. A subset of participants will undergo an in-person NIH Toolbox Cognitive Battery to test associations between NP outcomes and leukocyte telomere length measured by polygenic risk score and telomere flow cytometry FISH (Repeat Diagnostics).

Statistical Methods: The primary outcome is PPRO-identified CHCs, verified by medical record abstraction (date of onset, category, severity grade). Secondary outcomes include clinical findings, laboratory/diagnostic tests, and both raw and standardized scores from NP measures. DS controls for primary and secondary objectives will be selected by frequency matched sex and age group at time of CHC or NP assessment. For the primary outcome, time-to-event analyses will estimate the association between the time-varying independent variable (AL diagnosis) and dependent variables (CHC incidence, CHC-free survival). Subjects without a CHC event will be censored at study enrollment (DS-AL) or update of CHC data (DS controls).

Progress: ALTE22C1 opened 6-12-2023 and will recruit through 2028. It is open at 38 COG sites with 32 subjects enrolled to date. Target accrual is 300 DS-AL survivors (200 ALL, 100 AML). In addition to elucidating DS-AL cancer treatment outcomes, the study will establish a comprehensively characterized, contemporary DS survivor cohort and biospecimen bank. Results are expected to inform clinical practice guidelines for DS-AL survivors and mitigate risk for outcome disparities in this vulnerable population.

This work is supported by grants to COG NCORP (UG1CA189955) and NCTN Operations Center (U10CA180886) and the Childhood Cancer Survivorship, Treatment, Access and Research (STAR) Act (R01CA263000 to Gramatges, Rabin, Lupo, Jacola).

Li:Novartis Pharmaceuticals Canada: Membership on an entity's Board of Directors or advisory committees. O'Brien:Pfizer: Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy; AbbVie, Amgen: Research Funding.