Chronic Health Conditions in Down Syndrome-Associated Acute Leukemia: The Down Syndrome Phenotyping Acute Leukemia Study in Survivors

Sponsor

Children's Oncology Group (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05702645

Collaborator

(none)

300

Enrollment

62.1

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

To address this critical knowledge gap, results from this study will be utilized to characterize late effects experienced by DS-AL childhood cancer survivors, by determining the prevalence and severity of CHC and clinical and NP outcomes in DS-AL survivors. This multi-site study will characterize cancer treatment outcomes in survivors of DS-AL, establishing an annotated and comprehensively-characterized contemporary survivor cohort and biospecimen bank.

Condition or Disease	Intervention/Treatment	Phase
Down Syndrome Acute Leukemia Thyroid Disease Osteopenia Seizure Disorder Visual Impairment Hearing Impairment Myeloid Leukemia	Other: Neurological Assessments Procedure: Saliva collection Procedure: Blood collection Other: Clinical Assessments

Detailed Description

PRIMARY OBJECTIVES:

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:

To characterize post-treatment clinical outcomes of DS-AL by prospective, in-person assessment.
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.
To determine health-related quality of life (HRQOL) in survivors of DS-AL, compared with frequency-matched DS individuals with no cancer history.
To identify clinical risk determinants of CHC, NP, and clinical outcomes in survivors of DS-AL.
To establish a well-annotated cohort of survivors of DS-AL and associated biobank as a resource for future investigations.

EXPLORATORY OBJECTIVES:

For DS-acute lymphoblastic leukemia (DS-ALL), test if structural birth defects and genetic associations with etiology extend to CHC.
For DS-ALL, test if telomere length determined by polygenic risk score and telomere flow-FISH are associated with outcomes from in-person NP assessment.

OUTLINE:

Study procedures are divided into Part 1, Part 2 and Part 3. The Coordinating Centers complete Part 1 assessments remotely by collecting surveys, neuropsychological measures, a saliva specimen, and medical records. Participating Sites conduct Part 2 and Part 3 activities in person. Part 2 includes a Clinical Assessment and Clinical Records Reporting. Part 3 will only be applicable to a limited subset of participants, and includes a Study Blood Draw and Direct Neurocognitive Assessment.

Study Design

Study Type:

Observational

Anticipated Enrollment :

300 participants

Observational Model:

Case-Only

Time Perspective:

Prospective

Official Title:

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

Anticipated Study Start Date :

Jul 30, 2023

Anticipated Primary Completion Date :

Sep 30, 2028

Anticipated Study Completion Date :

Sep 30, 2028

Arms and Interventions

Arm	Intervention/Treatment
Observational (Specimen Collection and Neurocognitive Assessments) Part 1 Activities: Medical Outcomes Survey, Medical Record Release form, and saliva kit will be collected. The Parent Proxy Neurocognitive Assessment and brief questionnaires will be administered to families Part 2 Activities: Clinical Assessment Part 3 Activities: Direct Neurocognitive Assessment and Study Blood Draw	Other: Neurological Assessments Ancillary studies Procedure: Saliva collection Saliva/buccal sample obtained via collection kit sent directly to the patient Procedure: Blood collection Blood specimen obtained at the time of Clinical Assessment Other: Clinical Assessments Laboratory testing and diagnostic tests

Arm

Intervention/Treatment

Observational (Specimen Collection and Neurocognitive Assessments)

Part 1 Activities: Medical Outcomes Survey, Medical Record Release form, and saliva kit will be collected. The Parent Proxy Neurocognitive Assessment and brief questionnaires will be administered to families Part 2 Activities: Clinical Assessment Part 3 Activities: Direct Neurocognitive Assessment and Study Blood Draw

Other: Neurological Assessments

Ancillary studies

Procedure: Saliva collection

Saliva/buccal sample obtained via collection kit sent directly to the patient

Procedure: Blood collection

Blood specimen obtained at the time of Clinical Assessment

Other: Clinical Assessments

Laboratory testing and diagnostic tests

Outcome Measures

Primary Outcome Measures

Determine the prevalence of CHC in DS-PALS Survivors [Up to 5 years]
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 (e.g., mean and SD). Variables with a p-value <0.05 are considered statistically significant for all comparisons.
Determine the type of CHC in DS-PALS Survivors [Up to 5 years]
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 (e.g., mean and SD). Variables with a p-value <0.05 are considered statistically significant for all comparisons.
Determine the severity of CHC in DS-PALS Survivors [Up to 5 years]
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 (e.g., mean and SD). Variables with a p-value <0.05 are considered statistically significant for all comparisons.
Comparison of CHC with frequency-matched DS individuals that have no cancer history [Up to 5 years]
Will construct longitudinal data to sufficiently power time-to-event analyses, using two modeling approaches to estimate the association between the time-varying independent variable (diagnosis with AL) and the dependent variable (CHC incidence and CHC-free survival). Within each age interval, an estimate of the hazard ratios (HR), 95% CI, and p-values to report time-dependent effects of ALL, AML, or AL diagnosis on CHC. All models will be adjusted for age, sex, race/ethnicity, and relevant cancer or DS characteristics.

Secondary Outcome Measures

Characterize post-treatment clinical outcomes in DS-PALS Survivors by prospective, in-person assessment. [Up to 5 years]
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.
Determine the prevalence of parent-proxy NP outcomes in DS-PALS Survivors, compared with frequency-matched DS individuals with no cancer history [Up to 5 years]
Mean scores for each NP assessment will be compared between DS-PALS Survivors (entire cohort) and DS Controls, as well as between DS-AML and DS Controls, and between DS-ALL and DS Controls. 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).
Determine the severity of parent-proxy NP outcomes in DS-PALS Survivors, compared with frequency-matched DS individuals with no cancer history [Up to 5 years]
Mean scores for each NP assessment will be compared between DS-PALS Survivors (entire cohort) and DS Controls, as well as between DS-AML and DS Controls, and between DS-ALL and DS Controls. 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).
Determine health-related quality of life (HRQOL) in DS-PALS Survivors, compared with frequency-matched DS individuals with no cancer history [Up to 5 years]
HRQOL will be assessed using the PedsQL A t-test (or Wilcoxon rank sum test if appropriate) will be used to compare the mean (or median) HRQOL score between DS-AL CCS, DS-AL subgroups, and DS Controls.
Identify clinical risk determinants of CHC, NP, and clinical outcomes in DS-PALS Survivors [Up to 5 years]
The Cox regression will be used to estimate the Hazard Ratio (HR).
Identify clinical risk determinants of CHC, NP, and clinical outcomes in DS-PALS Survivors [Up to 5 years]
The Cox regression will be used to estimate the 95% Confidence Interval (CI).

Other Outcome Measures

For DS-ALL, test if structural birth defects and genetic associations with etiology extend to CHC [Up to 5 years]
Will determine the association between structural birth defects and the number of CHC in DS-PALS Survivors. The Cox regression will be used to estimate 95% Confidence Interval (CI).
For DS-ALL, test if structural birth defects and genetic associations with etiology extend to CHC [Up to 5 years]
Will determine the association between structural birth defects and organ system category of CHC in DS-PALS Survivors. The Cox regression will be used to estimate Hazard Ratio (HR).
For DS-ALL, test if structural birth defects and genetic associations with etiology extend to CHC [Up to 5 years]
Will determine the association between structural birth defects and the severity of CHC in DS-PALS Survivors. The Cox regression will be used to estimate Hazard Ratio (HR).
For DS-ALL, test if telomere length determined by polygenic risk score are associated with outcomes from in-person NP assessment. [Up to 5 years]
A multivariable Cox proportional hazard model will be used to estimate Hazard Ratio (HR) for the association between each of nine variants.
For DS-ALL, test if telomere length determined by polygenic risk score are associated with outcomes from in-person NP assessment. [Up to 5 years]
A multivariable Cox proportional hazard model will be used to estimate 95% Confidence Interval (CI) for the association between each of nine variants.
For DS-ALL, test if telomere length determined by telomere flow-FISH are associated with outcomes from in-person NP assessment. [Up to 5 years]
A multivariable Cox proportional hazard model will be used to estimate Hazard Ratio (HR) for the association between each of nine variants.
For DS-ALL, test if telomere length determined by telomere flow-FISH are associated with outcomes from in-person NP assessment. [Up to 5 years]
A multivariable Cox proportional hazard model will be used to estimate 95% Confidence Interval (CI) for the association between each of nine variants.

Eligibility Criteria

Criteria

Ages Eligible for Study:

6 Years to 40 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

A diagnosis of Down syndrome is required, and may include any of the three recognized types: trisomy 21 resulting from chromosomal nondisjunction (most common), translocation (the patient has 46 chromosomes, but all or part of an additional copy of chromosome 21 is attached to another chromosome), or mosaicism (trisomy 21 that is present in only a fraction of cells).
All patients must be DS-AL survivors (ALL or AML). Note: Myeloid leukemia of Down syndrome (ML-DS) would be included under AML category above. Also note that Survivors of relapsed disease are eligible, so long as the patient otherwise meets eligibility criteria, i.e., treatment for relapse was completed at least 36 calendar months prior to enrollment (see 3.2.4) and did not include stem cell transplant (see 3.2.7).
Patients must have been treated for ALL or AML. Note: History of COG therapeutic trial participation is not required. As a reminder ML-DS would be included under the AML category here above.
All cancer treatment (oral or intravenous) must have been completed at least 36 calendar months prior to enrollment.
Patients must have a life expectancy of > 1 year.
Patient and parent of subject must be either English or Spanish speaking. At least one parent or guardian must be able to read and write in English or Spanish.

Note: Parents or guardians are responsible for completing all forms, even in the case of subjects that are ≥ 18 years old.

All patients and/or their parents or legal guardians must sign a written informed consent.
All institutional, FDA, and NCI requirements for human studies must be met

Exclusion Criteria:

Patients with a history of prior cancers other than ALL or AML are excluded. Note: Prior history of transient abnormal myelopoiesis is allowed, but is not sufficient for eligibility.
Female patients who are known to be pregnant are excluded. Note: A pregnancy test is not required for female patients of childbearing potential. Pregnancy status can be established by clinical history.
Patients with history of Hematopoietic Stem Cell Transplant (HSCT) are excluded.

Note: Patients with previous chimeric antigen receptor T-cell (CAR T-cell) therapy, and other cellular cancer therapies can participate, as long as all other eligibility criteria are satisfied.