Immune Reconstitution and Long-Term Outcomes Following Allo-HCT with TLI-ATG and Post-Transplant Rituximab

Abstract

Post-transplant, prophylactic rituximab has been associated with low incidence of chronic graft-versus host disease (cGVHD) by significantly reducing B-cell allogeneic immunity. However, the long-term effects of B-cell depletion on immune reconstitution and the long-term overall survival (OS) and incidence of cGVHD remain unknown. We describe 35 patients with mantle cell lymphoma (MCL; n = 13) or high-risk chronic lymphocytic leukemia (CLL; n = 22) treated with allogeneic hematopoietic cell transplantation (HCT) with total lymphocyte irradiation/anti-thymocyte globumin (TLI-ATG) conditioning and prophylactic rituximab. The median follow up time was 9.9 years. As a comparison group, we analyzed 43 patients of various histologies transplanted during the same time period who received TLI-ATG conditioning but no prophylactic rituximab. Overall survival and progression-free survival (PFS) at 8 years for CLL were 54.5% and 22.7%, respectively; for MCL patients 8-year OS and PFS were 53.8% and 23.1%, respectively. The 8-year cumulative incidence of cGHVD and freedom from immunosuppression for all patients treated with prophylactic rituximab were 22.8% and 65.7%, respectively, compared to 34.9% and 48.8% for the comparison group. To assess B-cell alloimmunity, we examined formation of antibodies targeting Y-chromosome encoded protein (HY Abs) in male patients receiving grafts from female donors (F à M). At 3 years post-HCT, 20% of F à M patients receiving rituximab had formed HY Abs compared to 78% of F à M patients in the comparison group (p = 0.04). At 10 year follow up, only 33% of F à M patients who received rituximab had formed HY Abs. B-cell alloimmunity was also assessed by development of antibodies to common infectious antigens. At 3 years post-HCT, patients who received rituximab had significantly lower tetanus (3.29 vs 3.74 fold, p = .017) and EBV (3.36 vs 3.76 fold; p = 0.045) titers than patients who did not. At 10-year follow up, tetanus and EBV titers patients who received rituximab had not significantly changed. Importantly, patients who received prophylactic rituximab had significantly lower IgG levels at both 3 years (498 vs 843 mg/dL, p = 0.009) and 5 years (357 vs 724 mg/dL, p = 0.041) post-HCT. For patients receiving prophylactic rituximab, at 10 years post-transplant, the median IgG was 603, and 20% of patients had IgG < 400 mg/dL. More patients receiving rituximab required intravenous immunoglobulin (IVIG) supplementation than patients not receiving rituximab (62.9% vs 32.6%, p = 0.01). Of the patients who required IVIG, patients receiving rituximab did so for a longer amount of time (median duration of use 3.9 vs 0.6 years, p = 0.002). Despite decreased IgG levels, use of rituximab was not associated with a significant increase in hospitalizations for infectious etiologies or febrile neutropenia. Rituximab treatment after allogeneic transplantation provides significantly decreased incidence of chronic GVHD and reduction in B cell alloimmunity, but associates with prolonged hypogammaglobulinemia without increased infection risk. Figure Disclosures Miklos: Kite-Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; AlloGene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Precision Bioscience: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotech: Membership on an entity's Board of Directors or advisory committees; Becton Dickinson: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees.