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Patients undergo an optional saliva/buccal swab in part 1 and clinical assessment in part 2 of the study. Patients may then undergo blood sample collection in part 3 of the study.

Patients undergo saliva/buccal and blood sample collection

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Karen S. Fernandez

Jennifer G. Michlitsch

Anya Levinson

Ramamoorthy Nagasubramanian

Emad K. Salman

Don E. Eslin

Karen E. Effinger

Joshua W. Goldman

Keith J. August

Robert J. Hayashi

Alan K. Ikeda

Lauren R. Weintraub

Alice Lee

Denise A. Rokitka

Thomas W. McLean

Samuel J. Milanovich

Mukund G. Dole

Rene Y. McNall-Knapp

Susan J. Lindemulder

Jean M. Tersak

Jennifer J. Welch

Aniket Saha

Kayelyn J. Wagner

Susan E. Spiller

Shannon M. Cohn

Ksenya Shliakhtsitsava

Donald T. Beam

Maria M. Gramatges

Najat C. Daw

Shafqat Shah

Judy L. Felgenhauer

Jon M. Brandt

Maria M Gramatges

This study attempts to learn more about the health of persons with Down syndrome after treatment for acute leukemia. Children with Down syndrome are at increased risk for side effects during treatment for acute leukemia, but it is unclear of their risk for long-term effects of cancer treatment. By learning more about the factors that may contribute to chronic health conditions and long-term effects after treatment for leukemia in persons with Down syndrome, clinical practice guidelines for survivorship care can be developed to help improve their quality-of-life.

PRIMARY OBJECTIVE:

I. To determine the prevalence, type, and severity of chronic health conditions (CHC) in survivors of Down syndrome-associated acute leukemia (DS-AL), and to compare CHC with frequency-matched DS individuals that have no cancer history.

SECONDARY OBJECTIVES:

I. To characterize post-treatment clinical outcomes of DS-AL by prospective, in-person assessment.

II. To determine the prevalence and severity of parent-reported neuropsychological (NP) in survivors of DS-AL, compared with frequency-matched DS individuals with no cancer history.

III. To determine health-related quality of life (HRQOL) in survivors of DS-AL, compared with frequency-matched DS individuals with no cancer history.

IV. To identify clinical risk determinants of CHC, NP, and clinical outcomes in survivors of DS-AL.

V. To establish a well-annotated cohort of survivors of DS-AL and associated biobank as a resource for future investigations.

EXPLORATORY OBJECTIVES:

I. For DS-acute lymphoblastic leukemia (DS-ALL), test if structural birth defects and genetic associations with etiology extend to CHC.

II. For DS-ALL, test if telomere length determined by polygenic risk score and telomere flow-fluorescence in situ hybridization (FISH) are associated with outcomes from in-person NP assessment.

OUTLINE:

Patients undergo an optional saliva/buccal swab in part 1 and clinical assessment in part 2 of the study. Patients may then undergo blood sample collection in part 3 of the study.

A Study to Learn More About the Health of Persons With Down Syndrome After Treatment for Acute Leukemia

Chronic Health Conditions in Down Syndrome-Associated Acute Leukemia: The Down Syndrome Phenotyping Acute Leukemia Study in Survivors (DS-PALS Survivors)

Will determine the association between structural birth defects and the number, organ system category, and severity of CHC in DS-PALS survivors. Will use Cox regression to estimate hazard ratio and 95% CI for number, severity, and type of CHC by number of birth defects. Will explore the role of DS-ALL susceptibility variants identified in our genome-wide assessment on DS-associated CHC in survivors. Will use Cox regression to estimate the association between four DS-ALL susceptibility loci (rs58923657 near IKZF1, rs3731249 in CDKN2A, rs7090445 in ARID5B, and rs3781093 in GATA3) and CHC.

Will determine genetically-estimated TL. Will use a multivariable Cox proportional hazard model to estimate hazard ratio, 95% CI for the association between each of nine variants and risk for NP deficit =\<1 standard deviation below the mean, and consider the weighted and unweighted risk score from the number of risk alleles present and previously-published beta estimates. For flow-FISH analyses, TL =\< 1st percentile is considered 'very short,' as previously defined. Will determine objective responses for NP deficits =\< 1.5 standard deviation below the mean for an age-normative sample in subjects with TL \> or =\< 1st percentile, adjusted for relevant covariates and treatment factors. Will report 95% CI, p values using a Chi square test (two-tailed p-value of 0.05 statistically significant).

Summary statistics will be used to characterize the study populations on CHC outcomes. Quantitative data (number of comorbidities) will be summarized using descriptive statistics and correlational techniques. Will use pooled logistic regression to estimate overall response, 95% confidence interval (CI), and p-values for association of acute leukemia (AL) diagnosis with medical record-verified CHC, agnostic of time to CHC. Will use stratified Cox models to refine associations of AL diagnosis with CHC based on time to CHC incidence. Within each age interval, we will estimate the hazard ratio, 95% CI, and p-values to report time-dependent effects of AL diagnosis on CHC.

Summary statistics will be used to characterize the study population on clinical outcomes, by AL subtype and, for each test, the proportion of normal, abnormal, and missing tests.

NP outcomes (measured by both parent proxy and direct assessment) will be reported by both raw and normalized scores, and quantitative data summarized using descriptive statistics and correlational techniques. The mean score for each test will be compared between the cohorts using a student t-test (2-sided significance level of 0.05 and equal variance).

HRQOL will be assessed using the Pediatric Quality of Life Inventory. Parents will be asked to scale 23 items comprising four dimensions (Physical, Emotional, Social, and School functioning) on a 5 point unweighted Likert scale. Will use a t-test (or Wilcoxon rank sum test if appropriate) to compare the mean (or median) HRQOL score.

Will use Cox regression to estimate the hazard ratio and 95% CI for (1) number, severity, and type of CHC, and (2) NP deficits dichotomized as clinically significant impairment yes/no (=\< 1.5 standard deviation outside of the mean for the age-normative sample) according to age at diagnosis, years off therapy, sex, race/ethnicity, diagnosis, and treatment exposures.

The number of patients who agree to be in the Biobanking part of the study and have leftover tumor tissue and some normal blood, bone marrow, or other tissue saved for future research.

Children's Oncology Group

Spots Global Cancer Trial Database for b acute lymphoblastic leukemia associated with down syndrome