Predictors of More Rapid Lymphoid Reconstitution after Allogeneic Transplantation.

Introduction: Aberrant post-transplant immune reconstitution contributes to the major risks of graft versus host disease (GVHD), infection, and relapse following allogeneic hematopoietic progenitor cell transplantation. Faster lymphocyte engraftment has been found to predict better clinical outcomes in patients after autologous and allogeneic bone marrow transplantation. The purpose of our study was to investigate factors that may contribute to more rapid lymphocyte engraftment in patients who underwent transplantation using grafts procured from HLA-matched volunteer unrelated donors.

Methods:We analyzed 47 recipients of BM (n=13) and G-CSF mobilized blood hematopoietic progenitor cell grafts (n=34) for post-transplant lymphoid reconstitution, and constituents of the graft that predicted early lymphoid recovery. Diagnoses included 28 patients with AML/MDS/MPD, 6 with lymphoma/CLL, 6 with ALL, 3 with CML, 2 with MM and 2 with AA, with a median age of 43 years (range 17–68). 34 patients received TBI or busulfan-based myeloablative regimens; 13 patients received fludarabine and low-dose TBI. Numbers of T-cell, NK, B-cell, and dendritic cell subsets in the grafts were enumerated by flow cytometry. Our primary end point was lymphocyte engraftment at day+30 (ALC > 500 x 2 days). Secondary analyses included: univariate and multivariate models exploring the relationship between graft constituents and early lymphoid recovery.

Results: With a median follow-up of 1 year (range 1–32 months), 11 (23%) patients died prior to lymphocyte engraftment; 2 patients failed to achieve ALC > 500; and 20 (43%) patients were alive with stable lymphocyte engraftment. The median dose of CD34+ cells administered was 5.35 x 10E6 cells/kg; and the median dose of CD3+ cells was 211 x 10E6 cells/kg.The mean absolute lymphocyte count (ALC) on day +30 for the entire group was 714 ± 125 cells per mcL, with a median time to achieve an ALC > 500/mcL for 2 consecutive days of 23 days (range 0–111 days). In univariate analyses, higher doses of the following T-cell subsets in the graft were predictive of faster lymphocyte engraftment (all x 10E6 cells/kg): CD3+ > 296 (p=0.01), CD4+ > 172 (p=0.04), CD123+11c- (DC2) > 3.38 (p=0.03), and gamma-delta T- cells > 5.50 (p=0.01). The graft content of CD34+ cells and other graft constituents were not significantly associated with faster lymphoid engraftment. Stepwise multivariate Cox regression models including all graft constituents, conditioning regimen and patient characteristics determined that gamma-delta T-cell dose in the graft was the only factor associated with faster lymphocyte engraftment (p < 0.01). Faster lymphocyte engraftment was not significantly associated with CMV reactivation, or the incidence of either acute or chronic GVHD.

Conclusions: The kinetics of lymhoid reconstitution following allogeneic volunteer unrelated donor transplantation are associated with the content of donor T-cells and DC2 in the graft. Faster lymphoid reconstitution was not associated with less CMV infection nor improved survival in this relatively small population. Ongoing studies are examining the role of lymphoid reconstitution in post-transplant outcomes in a larger data base of allogeneic transplant recipients.