Safety and Efficacy of Donor Leukocyte Infusion for Single Unit Umbilical Cord Blood Transplantation to Accelerate Immune Reconstitution Prior to Thymopoiesis

Abstract

Success of reduced intensity umbilical cord blood transplantation (UCBT) in chemotherapy naive patients is limited by an increased risk of mixed chimerism, infection, and delayed immune reconstitution (IR). In a prospective clinical trial, we utilized risk-adapted alemtuzumab dosing, tested the safety of donor leukocyte infusion (cDLI) from a fraction of the thawed graft and evaluated it's efficacy in impacting IR, viral infection, and/or donor chimerism. Patients with inborn errors of metabolism, immunity, or hematopoiesis underwent a single unit UCBT following a reduced-intensity conditioning regimen of alemtuzumab, hydroxyurea, fludarabine, melphalan, and thiotepa (ClinicalTrials.gov: NCT00744692). Up to 5% of the graft was re-cryopreserved for potential cDLI and administered in cases of declining donor Tcell chimerism, viral infection, or delayed IR. Alemtuzumab levels were obtained on the day of UCBT. Chimerism and IR were measured at standard time points. 33 patients had cDLI stored and 18 patients received cDLI at a median of 65 days post-UCBT. Indications included mixed whole blood or CD3 chimerism, viral infection, or delayed IR. All patients engrafted with neutrophils at a median of 15 days post-UCBT, however, one patient experienced secondary graft failure at day +38, despite cDLI 28 days post-UCBT. Improvement in chimerism was seen in 5 of 9 patients, viral load and/or symptoms of infection in 5 of 9 patients and absolute CD3 count in 5 of 5 patients. 15 patients developed acute grade I-III GVHD at a median of 69 days post-UCBT. In those who received cDLI, 8 developed grade I-II skin GVHD at a median of 19 days post-cDLI. 2 patients with a history of GVHD received subsequent cDLI without GVHD flare. No patients who received cDLI developed grade III or IV acute or extensive chronic GVHD, while 4 patients who did not receive cDLI developed grade III GVHD affecting skin and/or the gastrointestinal tract. There was no difference in the cumulative incidence of acute GVHD between those who received cDLI and those who did not (44% vs. 33%; p=0.81). The 3-year overall and event-free survival of all patients was 94% and 91% respectively, with treatment-related mortality (TRM) of 5% 1 year post-UCBT. We report outcomes on the largest prospective trial utilizing cord blood grafts for nonmalignant disease. cDLI is safe in patients undergoing single-unit UCBT as all engrafted. Greater than half of the patients had improvement in the primary indication for its use, without increased GVHD risk. Greatest benefit was seen in patients with delayed IR and TRM at 1 year was exceptionally low. In sum, cDLI may be a simple and effective way to address mixed chimerism, infection, and accelerate IR during the vulnerable time prior to the onset of thymopoiesis. Further characterization of the merits of cDLI should be explored in a larger clinical trial.