Biomarker Verification in Pediatric Chronic GvHD: ABLE 2.0 / PTCTC GVH 1901 Study

Study Overview
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Brief Summary
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This study will validate a previously developed pediatric prognostic biomarker algorithm aimed at improving prediction of risk for the later development of chronic graft-versus-host disease (cGvHD) in children and young adults undergoing allogeneic hematopoietic stem cell transplant. By developing an early risk stratification of patients into low-, intermediate-, and high-risk for future cGvHD development (based upon their biomarker profile, before the onset of cGvHD), pre-emptive therapies aimed at preventing the onset of cGvHD can be developed based upon an individual's biological risk profile. This study will also continue research into diagnostic biomarkers of cGvHD, and begin work into biomarker models that predict clinical response to cGvHD therapies.

Detailed Description
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Chronic graft-versus-host disease (cGvHD) occurs when the new donor immune system attacks tissues in the recipient following allogeneic hematopoietic stem cell transplantation (HSCT), leading to chronic inflammation, scarring and fibrosis, impaired immunity (including immune deficiency and immune dysregulation), and altered organ system functioning. Almost any organ or system has the potential to be affected by cGvHD, although eight organ systems are classically involved, including the skin, eyes, mouth, lungs, liver, gastrointestinal tract, genitourinary tract, and the musculoskeletal system. The investigators will be enrolling allogeneic HSCT recipients before conditioning, following these patients prospectively until 12-months (+/- 1 month) post-transplant for the development of all forms of GvHD (classical acute, late acute and chronic GvHD), collecting blood samples at day +60 (+/- 7 days), day +100 (+/- 14 days), and at the onset of either late acute or chronic GvHD. Two extra blood samples will be collected exclusively from HAPLO transplant recipients, who never developed any late-acute GvHD or chronic GVHD at the 6- and 12-month post-transplant time points. In addition, clinical data will be collected at different time points. Case report forms of standard transplant related data will be completed and entered into a REDCap database. Blood samples will be drawn and shipped to the Central Laboratory in Vancouver, BC, Canada, processed, analyzed, and the final biomarker risk algorithm completed. Selected clinicians will be offered to complete a short survey asking about their perception of the feasibility of altering their approach to cGvHD management based upon these results. If chronic GvHD develops at any time after transplant (day 0 to 1 year), or if any form of GvHD occurs at or after day +100 (whether late acute, chronic GvHD, or overlap syndrome), a blood sample will be drawn before escalating immune suppression, and the onset GvHD case report form will be completed following the protocol. If chronic GvHD is confirmed, an additional CRF will be submitted at 24-months (+/- 3 months) post-transplant to document new chronic GvHD manifestations, severity, and response to therapy. Study participants will have between 2 and 4 blood samples drawn over the course of 1-year post-transplant, depending upon their event and GvHD status.

Official Title
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Biomarker Verification in Pediatric Chronic Graft-Versus-Host Disease: Applied Biomarkers to Minimize Long Term Effects of Childhood/Adolescent Cancer Treatment (ABLE) / Pediatric Transplantation & Cellular Therapy Consortium (PTCTC)

Conditions
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Chronic Graft-versus-Host-Disease, Leukemia, Allogeneic Hematopoietic Stem Cell Transplantation, Blood Cancer, Non-Malignant Hematologic and Lymphocytic Disorder

Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Any indication for allogeneic hematopoietic stem cell transplant (malignant or non-malignant) Age 0 - 24.99 years at the time of transplant (on day 0) Any conditioning regimen (including myeloablative or reduced-toxicity/reduced-intensity) Any graft source (bone marrow, peripheral blood, cord blood) Any graft-versus-host disease prophylaxis strategy, including serotherapy such as ATG or alemtuzumab Haploidentical transplants, including post-transplant cyclophosphamide and alpha-beta TCR depletion, are allowed EXCLUSION CRITERIA: Second or greater allogeneic transplant Weight 7 kg or less Pure CD34+ selected haploidentical stem cell transplant (not including CD34 enrichment used in alpha-beta TCR depleted haploidentical transplants, which is allowed) Inability of a center to follow a patient for the development of late-acute and chronic GVHD until 1-year post-transplant (referral sites who transplant patients from outside institutions should not enroll participants if sending back to the referring site early, such that long-term follow up, blood, and data collection cannot be assured).

Ages Eligible for Study
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Minimum Age: 0 Years
Maximum Age: 24 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Allogeneic HSC Transplant recipients<br>Five possible patient scenarios are anticipated to occur in those who underwent allogeneic HSCT: Early event (e.g. death, non-engraftment) occurring before day 100. No late-acute or chronic GvHD ever develops at any time point in the first year post-transplant (regardless of whether or not classical acute GvHD develops in the first 100 days after transplant). Early-onset chronic GvHD (including overlap syndrome) occurred before day 60. Early-onset chronic GvHD (including overlap syndrome) occurred between day 60 and day 100. Chronic GvHD after Day 100, Late-acute GvHD (de-novo or recurrent) after day 100, or cases of overlap syndrome occurred after day 100. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Day 60 blood sample collection | Validation of prognostic and diagnostic power of cGvHD biomarkers and testing of the biomarker assay performance of Day 60 post-transplant blood sample. Using this algorithm-based assay the investigators will attempt to develop risk assignment for cGvHD and L-aGvHD at Day 60 and determine whether this time point has a similar (or improved) predictive value to the day +100 (+/-14 days). Flow Cytometry and ELISA assays will be used for biomarker measurement. | Day 60 (+/- 7 days) post-transplant | 
| Day 100 blood sample collection | Validation of prognostic and diagnostic power of cGvHD biomarkers and testing of the biomarker assay performance of Day 100 post-transplant blood sample (diagnostic biomarkers). Using this algorithm-based assay the investigators will attempt to develop risk assignment for cGvHD and L-aGvHD at Day 100. Flow Cytometry and ELISA assays will be used for biomarker measurement. | Day 100 (+/- 14 days) post-transplant | 
| Onset CvHD blood sample collection | Validation of prognostic and diagnostic power of cGvHD biomarkers and testing of the biomarker assay performance of the GvHD onset blood sample. The investigators will attempt to determine whether biomarkers present at the onset of new late-acte GvHD developing after day +100 (diagnostic biomarkers) or are similar to or different than at the onset of chronic GvHD. Flow Cytometry and ELISA assays will be used for biomarker measurement. | The day of initial diagnosis | 
| Baseline transplant clinical data collection at Day 0 | Baseline Transplant Data Case Report Form to be completed. Clinical data will be used in data analysis. | Between day 0 (day of transplant) and day +21 | 
| Clinical data collection at Day 60 | Day 60 Case Report Form to be completed. Clinical data will be used in data analysis. | Day 60 (+/- 7 days) post-transplant | 
| Clinical data collection at Day 100 | Case Report Form to be completed. Clinical data will be used in data analysis. | Day 100 (+/- 14 days) post-transplant | 
| Clinical data collection at 6 months | Case Report Form to be completed. Clinical data will be used in data analysis. | 6 Months (+/- 1 month) post-transplant | 
| Clinical data collection at 12 months | Case Report Form to be completed. Clinical data will be used in data analysis. | 12 Months (+/- 1 month) post-transplant | 
| Clinical data collection at 24 months | Case Report Form to be completed. Clinical data will be used in data analysis. | 24 Months (+/- 1 month) post-transplant | 
| Clinical data collection at onset of GvHD | Case Report Form to be completed. Clinical data will be used in data analysis. | At the time of diagnosis | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Demonstration of identifiable and reproducible differences in diagnostics of cGvHD and L-aGvHD | Metrics to measure this outcome will employ the difference in biomarkers (in combination with clinical manifestation) that can be used to discriminate between cGvHD and L-aGvHD and aid clinicians in establishing a more accurate diagnosis. Laboratory procedure and statistical data analysis will be used to achieve this. | At the end of the study by year 2025 | 
| Determination of patient's risk profile and prediction of treatment responses | Utilizing cGvHD specific biomarkers, clinicians will be able to predict patient's treatment responses and chose the more accurate and effective treatment options. | At the end of the study by year 2025 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cGvHD, HSCT, L-aGvHD, Biomarkers, Blood, Pediatric, Adolescent, Chronic Graft-versus-Host-Disease, Hematopoietic Stem Cell Transplant, Late acute Graft-versus-Host Disease