Tsilifis Christo, Speckmann Carsten, Lum Su Han, Fox Thomas A, Soler Adriana Margarit, Mozo Yasmina, Corral Dolores, Ewins Anna-Maria, Hague Rosie, Oikonomopoulou Christina, Kałwak Krzysztof, Drabko Katarzyna, Wynn Robert, Morris Emma C, Elcombe Suzanne, Bigley Venetia, Lougaris Vassilios, Malagola Michele, Hauck Fabian, Sedlacek Petr, Laberko Alexandra, Tjon Jennifer M L, Buddingh Emilie P, Wehr Claudia, Grimbacher Bodo, Gennery Andrew R, Lankester Arjan C, Albert Michael H, Neven Bénédicte, Slatter Mary A
Paediatric Haematopoietic Stem Cell Transplant Unit, Great North Children's Hospital, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom; Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
J Allergy Clin Immunol. 2024 Dec;154(6):1534-1544. doi: 10.1016/j.jaci.2024.08.020. Epub 2024 Aug 30.
Cytotoxic T-lymphocyte antigen 4 (CTLA-4) insufficiency causes a primary immune regulatory disorder characterized by lymphoproliferation, dysgammaglobulinemia, and multiorgan autoimmunity including cytopenias and colitis.
We examined the outcome of hematopoietic stem cell transplantation (HSCT) for CTLA-4 insufficiency and study the impact of pre-HSCT CTLA-4 fusion protein (CTLA-4-Ig) therapy and pre-HSCT immune dysregulation on survival and immunologic outcome.
This was a retrospective study of HSCT for CTLA-4 insufficiency and 2q33.2-3 deletion from the European Society for Blood and Marrow Transplantation Inborn Errors Working Party. Primary end points were overall survival (OS) and disease- and chronic graft-versus-host disease-free survival (DFS). Secondary end point was immunologic outcome assessed by immune dysregulation disease activity (IDDA) score.
Forty patients were included over a 25-year period. Before HSCT, 60% received CTLA-4-Ig, and median (range) IDDA score was 23.3 (3.9-84.0). Median (range) age at HSCT was 14.2 (1.3-56.0) years. Patients received peripheral blood stem cell (58%) or marrow (43%) from a matched unrelated donor (75%), mismatched unrelated donor (12.5%), or matched family donor (12.5%). Median (range) follow-up was 3 (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, disease of 28 of 30 surviving patients was in disease-free remission with median IDDA reduction of 16. Probability of OS and DFS was greater in patients with lower disease activity before HSCT (IDDA < 23, P = .002 and P = .006, respectively). CTLA-4-Ig receipt did not influence OS or DFS. Cause of death was transplant related in 7 of 8 patients.
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.
细胞毒性T淋巴细胞抗原4（CTLA-4）功能不全导致一种原发性免疫调节紊乱，其特征为淋巴细胞增殖、免疫球蛋白异常血症以及包括血细胞减少和结肠炎在内的多器官自身免疫。
我们研究了造血干细胞移植（HSCT）治疗CTLA-4功能不全的疗效，并探讨HSCT前CTLA-4融合蛋白（CTLA-4-Ig）治疗以及HSCT前免疫失调对生存和免疫结局的影响。
这是一项来自欧洲血液和骨髓移植学会先天性疾病工作组的关于CTLA-4功能不全和2q33.2 - 3缺失的HSCT回顾性研究。主要终点为总生存期（OS）以及无疾病和慢性移植物抗宿主病生存期（DFS）。次要终点是通过免疫失调疾病活动（IDDA）评分评估的免疫结局。
在25年期间共纳入40例患者。HSCT前，60%的患者接受了CTLA-4-Ig治疗，IDDA评分中位数（范围）为23.3（3.9 - 84.0）。HSCT时的年龄中位数（范围）为14.2（1.3 - 56.0）岁。患者接受了来自匹配无关供者（75%）、不匹配无关供者（12.5%）或匹配家族供者（12.5%）的外周血干细胞（58%）或骨髓（43%）。随访中位数（范围）为3（0.6 - 15）年，3年总生存率为76.7%（58 - 87%），无病生存率为74.4%（54.9 - 86.0%）。在最近一次随访时，30例存活患者中有28例疾病处于无病缓解状态，IDDA评分中位数降低了16。HSCT前疾病活动度较低的患者（IDDA < 23）的总生存和无病生存概率更高（分别为P = 0.002和P = 0.006）。接受CTLA-4-Ig治疗并不影响总生存或无病生存。8例患者中有7例的死亡原因与移植相关。
HSCT是预防疾病持续进展和发病的有效治疗方法，随着时间推移以及HSCT前疾病活动度较低的患者生存率有所提高。
