Coline Daulne

Immune Recovery after Allogeneic Hematopoietic Stem Cell Transplantation following Flu-TBI versus TLI-ATG Conditioning

Purpose: A conditioning regimen for allogeneic hematopoietic cell transplantation (HCT) combining total lymphoid irradiation (TLI) plus anti-thymocyte globulin (ATG) has been developed to induce graft-versus-tumor effects without graft-versus-host disease (GVHD). Experimental Design: We compared immune recovery in 53 patients included in a phase II randomized study comparing nonmyeloablative HCT following either fludarabine plus 2 Gy total body irradiation (TBI arm, n = 28) or 8 Gy TLI plus ATG (TLI arm, n = 25). Results: In comparison with TBI patients, TLI patients had a similarly low 6-month incidence of grade II-IV acute GVHD, a lower incidence of moderate/severe chronic GVHD (P = 0.02), a higher incidence of CMV reactivation (P < 0.001), and a higher incidence of relapse (P = 0.01). While recovery of total CD8+ T cells was similar in the two groups, with median CD8+ T-cell counts reaching the normal values 40 to 60 days after allo-HCT, TLI patients had lower percentages of naïve CD8 T cells. Median CD4+ T-cell counts did not reach the lower limit of normal values the first year after allo-HCT in the two groups. Furthermore, CD4+ T-cell counts were significantly lower in TLI than in TBI patients the first 6 months after transplantation. Interestingly, while median absolute regulatory T-cell (Treg) counts were comparable in TBI and TLI patients, Treg/naïve CD4+ T-cell ratios were significantly higher in TLI than in TBI patients the 2 first years after transplantation. Conclusions: Immune recovery differs substantially between these two conditioning regimens, possibly explaining the different clinical outcomes observed (NCT00603954). Clin Cancer Res; 21(14); 3131–9. ©2015 AACR.

Impact of Pre-Transplant Anti-T Cell Globulin (ATG) on Immune Recovery after Myeloablative Allogeneic Peripheral Blood Stem Cell Transplantation.

Background Pre-transplant infusion of rabbit anti-T cell globulin (ATG) is increasingly used as prevention of graft-versus-host disease (GVHD) after allogeneic peripheral blood stem cell transplantation (PBSCT). However, the precise impact of pre-transplant ATG on immune recovery after PBSCT is still poorly documented. Methods In the current study, we compared immune recovery after myeloablative PBSCT in 65 patients who either received (n = 37) or did not (n = 28) pre-transplant ATG-Fresenius (ATG-F). Detailed phenotypes of circulating T, B, natural killer (NK) and invariant NKT (iNKT) cells were analyzed by multicolor flow cytometry at serial time-points from day 40 to day 365 after transplantation. Thymic function was also assessed by sjTREC quantification. Serious infectious events were collected up to 2 years post-transplantation. Results Pre-transplant ATG-F had a prolonged (for at least up to 1-year) and selective negative impact on the T-cell pool, while it did not impair the recovery of B, NK nor iNKT cells. Among T cells, ATG-F selectively compromised the recovery of naïve CD4+, central memory CD4+ and naïve CD8+ cells, while it spared effector memory T and regulatory T cells. Levels of sjTRECs were similar in both cohorts at 1-year after PBSCT, suggesting that ATG-F unlikely impaired thymopoiesis at long-term after PBSCT. Finally, the incidence and rate of serious infections were similar in both groups, while ATG-F patients had a lower incidence of grade II-IV acute graft-versus-host disease. Conclusions Pre-transplant ATG-F induces long-lasting modulation of the circulating T-cell pool after myeloablative PBSCT, that may participate in preventing graft-versus-host disease without deeply compromising anti-pathogen defenses.