REVEAL Biomarkers of Engraftment After Alternative Donor HSCT

This is a prospective pilot study whose primary aim is to determine whether investigational
FLT imaging can detect and distinguish nonengraftment from delayed engraftment after 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). The planned
length of this trial is 5 years and it will be conducted at 3 centers: Children's National
Medical Center (pediatric), University of Oklahoma (pediatric and adult), and University of
Michigan (pediatric and adult). For all pediatric and adult patients undergoing cord blood
HSCT, FLT 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. 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. All patients will undergo
serial peripheral blood evaluation for blood biomarker analysis, including thymidine kinase-1
(TK1). Study endpoints include: 1) detection of nonengraftment with FLT and TK1, 2)
development of a model that predicts nonengraftment versus delayed engraftment using FLT and
TK1, 3) sensitivity of individual biomarkers to distinguish between graft failure and delayed
engraftment, and 4) biology of cord blood and haplo-HSCT engraftment.

Inclusion Criteria:

- General

- 4 to 60 years of age

- Able to perform FLT imaging without anesthesia

- Diagnosed with a condition for which myeloablative hematopoietic stem cell
transplantation (HSCT) is standard of care and HSCT is planned

- 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 (DSA) to cord HLA

- Haplo-identical recipients: > 5/10 and < 7/8 allele mismatch related donor

- Total bilirubin < 2.5 mg/dL (unless documented Gilbert's syndrome) and transaminases <
5 x the upper limit of normal

- Creatinine clearance > 60 ml/min/1.73 m2 or GFR

- FEV1 > 80% post-bronchodilator 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 cord or haplo-identical HSCT: Primary graft failure as
defined by ANC not > 500 for 3 consecutive days and at least 24 days after HSCT

Inclusion Criteria - Donors

Arms A and B

- 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