Naive T Cell Depletion for Preventing Chronic Graft-versus-Host Disease in Children and Young Adults with Blood Cancers Undergoing Donor Stem Cell Transplant

Summary

Objectives

PRIMARY OBJECTIVES:
I. To confirm that selective depletion of naive T cell (TN) from peripheral blood stem cell (PBSC) grafts is feasible in a multi-institutional setting. (Feasibility phase)
II. To confirm that engraftment with neutrophils is achieved by day +28. (Feasibility phase)
III. To compare the ‘current-graft-versus-host disease (GVHD)-free, relapse-free survival’ at one year post-hematopoietic cell transplantation (HCT) between subjects who receive allogeneic HCT using TN-depleted PBSC and those who receive unmanipulated T cell-replete bone marrow (BM). (Randomized Controlled Trial [RCT])

SECONDARY OBJECTIVES:
I. To compare the probabilities/proportions of the following outcomes between subjects who receive allogeneic HCT using TN-depleted PBSC and those who receive unmanipulated T cell-replete BM:
* Chronic GVHD (cGVHD) (National Institutes of Health [NIH] criteria) requiring prednisone (or equivalent systemic corticosteroid).
* Proportion of subjects alive and off prednisone (or equivalent systemic corticosteroid) for treatment of GVHD at 3, 6, 9, 12, 15, 18, 21, 24 months post-HCT.
* Time-to-neutrophil engraftment.
* Time-to-platelet engraftment.
* Acute GVHD (aGVHD) grade III-IV.
* AGVHD grade II-IV.
* Overall survival (OS).
* Disease-free survival (DFS).
* Non-relapse mortality (NRM).
* Relapse.
* Days alive out of hospital in the first year post-HCT.
* Infection and viral reactivation.
* Peripheral blood (PB) chimerism (CD3+ and CD33+).
* Lymphocyte recovery.
* Immune dysregulation phenomenon (including: type 1 diabetes mellitus, Grave’s disease, immune-mediated cytopenias, other newly diagnosed immune dysregulation [other than GVHD]).
* Thrombotic microangiopathy (TMA).

OUTLINE: Patients are randomized to 1 of 2 arms. All patients receive 1 of 3 conditioning regimens.

CONDITIONING REGIMEN A: Patients undergo total body irradiation (TBI) twice daily (BID) on days -10 to -7, then receive thiotepa intravenously (IV) over 3 hours once daily (QD) on days -6 and -5, and fludarabine IV over 30 minutes once daily on days -6 to -2.

CONDITIONING REGIMEN B: Patients undergo TBI BID on days -8 to -5, then receive fludarabine IV over 30 minutes QD on days -4 to -2, and cyclophosphamide IV over 1 hour QD on days -3 and -2.

CONDITIONING REGIMEN C: Patients receive fludarabine IV over 30 minutes QD on days -6 to -2, busulfan IV over 180 minutes QD on days -5 to -2, and undergo total body irradiation BID on day -1.

ARM I: Patients receive naive T-cell depleted PBSCs on day 0.

ARM II: Patients receive unmanipulated T cell-replete BM on day 0.

GVHD PROPHYLAXIS: All patients receive tacrolimus IV on days -1 to +50 followed by a taper in the absence of grade II-IV aGVHD. Patients also receive methotrexate IV on days +1, +3, +6, and +11.

After completion of study treatment, patients are followed up periodically.