REVEAL Biomarkers of Engraftment After Alternative Donor HSCT

Study Overview
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Brief Summary
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The purpose of this study is to find new tests that could help determine if the newly infused bone marrow cells are growing well after bone marrow transplantation or if new bone marrow cells are needed. In this study we will use FLT imaging which is an investigational imaging test, and collect blood samples to investigate if the cells are growing well.

Detailed Description
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This is a prospective pilot study whose primary aim is to determine whether investigational FLT imaging can detect and distinguish non-engraftment from delayed engraftment after hematopoietic stem cell transplantation (HSCT) in populations at highest risk for graft failure. The investigators will enroll 50 patients undergoing myeloblative transplantation on this trial (15 pediatric and adult recipients of cord blood stem cells, 15 pediatric and adult recipients of haplo-identical HSCT, and 20 recipients of these two stem cell sources who have not engrafted by day 28). Should a patient be unable to undergo FLT evaluation after enrollment or relapse in the first 30 days, the patient will be replaced. The planned length of this trial is 5 years and it will be conducted at 3 centers enrolling pediatric and adult participants: Emory/Children's Healthcare of Atlanta, University of Oklahoma, and University of Michigan. For all pediatric and adult patients undergoing cord blood HSCT, three FLT images will be taken: first, one day prior to HSCT and second and third, on days 9 and 28 after HSCT. For recipients of haplo-HSCT, the FLT images will be taken one day prior to HSCT and then on days 5 and 28 after HSCT. Pediatric and adult patients who have not engrafted by day 24 after cord or haplo-identical HSCT will undergo a single FLT PET/CT image within one week, to determine if this scan can identify graft failure versus delayed engraftment. Blood samples will also be collected from all patients for blood biomarker analysis, including thymidine kinase-1 (TK1). Each patient will be in this study for one year.

Official Title
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Multi-institutional Prospective Pilot Research of Imaging and Blood Biomarker EValuation of Engraftment After ALlogeneic Hematopoietic Stem Cell Transplantation

Conditions
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Primary Graft Failure

Intervention / Treatment
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* Drug: FLT imaging and TK1 blood measurements


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: General Ability to undergo 18F FLT imaging without sedation Patients > 4 years of age and less than 70 years of age at highest risk for graft failure: cord blood HSCT, haplo HSCT, or lack of engraftment by day 28. Diagnosed with a condition for which hematopoietic stem cell transplant (HSCT) is standard of care and HSCT is planned (Arm A) or occurred (Arm B) Able to perform FLT imaging without anesthesia In morphologic remission prior to HSCT Patient or guardian able to give informed consent No investigational therapies within past 28 days Karnofsky or Lansky performance status > 60% Arm A Cord blood recipients: Absence of donor specific antibodies to cord HLA Haplo-identical recipients: ≥ 5/10 and < 7/8 allele mismatch donor Diagnosed with a condition for which myeloablative hematopoietic stem cell transplant (HSCT) is standard of care and HSCT is planned Total bilirubin < 2.5 mg/dL (unless documented Gilbert's syndrome) and transaminases (ALT and AST) < 5 x the upper limit of normal Creatinine clearance or GFR > 60 ml/min/1.73 m2. (performed pre-HSCT) FEV1 > 80% pre or post-bronchiolator whichever is higher and DLCO Adj > 70% (performed pre-HSCT if age appropriate) and Sa02 > 94% on room air Ejection fraction > 50% (performed pre-HSCT) Arm B • Non-engraftment recipients of HCT with any donor source (related or unrelated): primary graft failure as defined by ANC not > 500 for 3 consecutive days and at least 24 days after HSCT. Inclusion Criteria - Donors 2 cords and >.4/6 match to recipient for each (as per current National Marrow Donor guidelines), with a dose >2 x 10e6 CD34 cells/kg for each cord OR > 5/10 and <7/8 allele mismatch related donor Institutional guidelines met for donor suitability Exclusion Criteria: History of psychiatric disorder which may compromise compliance with transplant protocol, or which does not allow for appropriate informed consent Clinically significant systemic illness with manifestations of significant organ dysfunction which, in the judgment of the PI, or Co-I, would render the patient unlikely to tolerate the protocol therapy or complete the study Presence of active malignancy from an organ system other than hematopoietic Pregnant or lactating females Patients who are unable or unwilling to use effective form (s) of contraception during the course of the study Prior history of fluorothymidine allergy or intolerance Decline enrolment on CIBMTR research protocol

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 70 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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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cord and haplo imaging cohort<br>For all pediatric and adult patients undergoing cord blood HSCT, FLT PET/CT imaging will occur one day prior to HSCT and on days 9 and 28 after HSCT. For recipients of haplo-HSCT, FLT PET/CT imaging will occur one day prior to HSCT and on days 5 and 28 after HSCT. | Drug: FLT imaging and TK1 blood measurements<br>* F18 labeled thymidine PET/CT scans will be performed. Serum measurements of TK1 will be obtained.<br>|
| Experimental: Nonengrafted cohort<br>Pediatric and adult patients who have not engrafted by day 24 after cord or haplo-identical HSCT will undergo a single FLT PET/CT image within one week to determine if this scan can identify graft failure versus delayed engraftment. | Drug: FLT imaging and TK1 blood measurements<br>* F18 labeled thymidine PET/CT scans will be performed. Serum measurements of TK1 will be obtained.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FLT SUV identifies graft failure | To calculate if SUV > 1.2 identifies subclinical engraftment using FLT PET/CT imaging for recipients of cord and haplo-HSCT who have not engrafted within 24 days of HSCT. | 24-28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Map subclinical engraftment in alternative donor HSCT | Use SUV increase in particular medullary spaces to identify the first site of marrow settling after HSCT in alternative donor HSCT | Day -1 to Day 28 after HSCT | 
| TK1 serum levels identify graft failure | Calculate if TK1 level increases correlate with clinical engraftment | 24-28 days | 
| Number of patients with CTCAE version 5 events exceeding grade 3 that are possibly, probably, or definitely attributed to the FLT imaging | Safety of FLT in alternative donor HSCT - Calculate the number of patients with CTCAE version 5 events exceeding grade 3 that are possibly, probably, or definitely attributed to the FLT imaging | Day -1 to Day 28 after HSCT | 
| Other cytokine and chemokine markers of graft failure | Explore other cellular, cytokine, and chemokine markers of subclinical engraftment | 24-28 days |