Immunologic Recovery after Nonmyeloablative (NM) Conditioning: A Comparison between Related Versus Unrelated Donor Hematopoietic Cell Transplantation (HCT).
Authors: Baron Frederic , Maris M. , Storek J. , Metcalf M. , White K. , Sandmaier B. , Maloney D. , Storb R. , Boeckh M. 
Published: April 2020

Abstract
Background. After NM conditioning, recipients of peripheral blood stem cells (PBSC) from HLA-identical siblings (MRD) have persistent recipient-derived immunity leading to lower incidence of early infectious complications in comparison with patients (pts) given myeloablative conditioning (Exp Hematol31: 941, 2003). Because of greater genetic disparities, intensity and duration of postgrafting immunosuppression (IS) have been increased in pts given PBSC from HLA-matched unrelated donors (URD), in order to both promote engraftment and decrease risk of GVHD. This study was done to determine how this increased/extended postgrafting IS affected immune recovery and infectious complications.
Methods. We compared immunologic recovery in 51 pts given PBSC from MRD (n=51) and 43 pts given grafts from URD after 2 Gy TBI +/− fludarabine. Postgrafting IS concisted of mycophenolate mofetil (MMF, given TID for 40 days followed by a 56 day taper in URD recipients, and BID for 28 days in MRD recipients) and cyclosporin. The counts of blood mononuclear cell subsets were assessed by flow cytometry; frequency of CMV-specific CD4 T-helper cells among CMV seropositive pts or CMV-seronegative pts with CMV-seropositive donors was determined by lymphoproliferation (LPR), limiting-dilution assays (LDA), and intracellular interferon-gamma (IF) production (ICC). Analyses were performed on days 30, 80, 180 and 365 after HCT.
Results. On day 30 after HCT, URD recipients had lower counts of total B-cells (P=.02), naive B-cells (P=.03), memory B-cells (P=.01), CD4 T-cells (P=.06), naive CD4 T-cells (P=.05), memory CD4 T-cells (P=.003), CD8 T-cells (P=.0004), naive CD8 T-cells (P=.08) and memory CD8 T-cells (P=.006) than MRD recipients. However, the counts of mononuclear cell subsets were similar in URD and MRD recipients from day 30 to day 365 after HCT. Similarly, the frequency of CMV-specific T-helper cells was significantly lower in URD than in MRD recipients on day 30 after HCT as determined by LPR (median CPM 17 versus 92 per 1000 CD4 T-cells, P=.02), LDA (median 22307 versus 73251 CMV-CD4 T-helper cells per L, P=.7) and ICC (median 0.26% versus 0.93% CD4 cells positive for IF, P=.02). This delay in CMV-specific immune reconstitution translated into increased frequency of CMV-reactivation (and increased use of preemptive antiviral therapy [PET]) among CMV-seropositive pts or CMV-seronegative pts with CMV seropositive donors given URD grafts (63%) compared with MRD (33%) recipients (P=.02) the first 100 days after HCT. This did not lead to increased CMV disease among URD recipients (1 episode) compared with MRD recipients (1 episode), demonstrating that PET was similarly effective in preventing CMV diseases in both groups. After day 100, there were no statistically significant differences in immune reconstitution parameters. Incidence figures for non-CMV viral infections, bacteremias, and invasive fungal infections were not significantly different between the 2 groups. A multivariate analysis assessing pre-transplant and post-transplant factors associated with immunologic recovery after NM conditioning will be presented.
Conclusions. Despite similar NM conditioning regimens, immunologic recovery was delayed among URD recipients in comparison to MRD recipients, probably because of increased/extended postgrafting IS. This led to increased incidence of CMV reactivation among URD recipients. CMV infection and immune reconstitution pattern appear similar to those seen after myeloablative PBSC transplantation.