Haematopoietic Stem Cell Transplantation for CTLA-4 Insufficiency Across Europe: an EBMT Inborn Errors Working Party Study

Background Cytotoxic T-lymphocyte antigen-4 (CTLA-4) insufficiency causes a primary immune regulatory disorder characterised by lymphoproliferation, dysgammaglobulinaemia, and multi-organ autoimmunity including cytopenias and colitis. Objective To examine the outcome of HSCT for CTLA-4 insufficiency and study the impact of pre-HSCT CTLA-4-Ig therapy and pre-HSCT immune dysregulation on survival and immunological outcome. Methods Retrospective study of HSCT for CTLA-4 insufficiency and 2q33.2-3 deletion from the Inborn Errors Working Party of EBMT. Primary endpoints were overall survival (OS) and disease- and chronic GvHD-free survival (DFS). Secondary endpoint was immunological outcome assessed by Immune Dysregulation Disease Activity (IDDA) score. Results Forty patients were included over a 25-year period. Pre-HSCT, 60% received CTLA-4-Ig and IDDA was 23.3 (3.9–84.0). Median age at HSCT was 14.2 (1.3–56.0) years. Patients received PBSC (58%) or marrow (43%) from MUD (75%), MMUD (12.5%) or MFD (12.5%).Median follow-up was 3 years (0.6–15 years) and 3-year OS was 76.7% (58–87%) and DFS was 74.4% (54.9-86.0%). At latest follow-up, 28/30 surviving patients are in disease-free remission with median IDDA reduction of 16.Probability of OS and DFS was greater in patients with lower disease activity pre-HSCT (IDDA<23, p=0.002 and p=0.006, respectively). CTLA-4-Ig receipt did not influence OS or DFS. Cause of death was transplant-related in 7/8 patients. Conclusion This is the largest retrospective study of HSCT for CTLA-4 insufficiency to date. HSCT is an effective therapy to prevent ongoing disease progression and morbidity, with improving survival rates over time and in patients with lower pre-HSCT disease activity.