Freeman Alexandra F, Gonzalez Corina E, Yates Bonnie, Cole Kristen, Little Lauren, Flannelly Erin, Steinberg Seth M, Mo George, Piette Nicole, Hughes Thomas E, Cuellar-Rodriguez Jennifer, Gea-Banacloche Juan, Heller Theo, Hammoud Dima A, Holland Steve M, Kong Heidi H, Young Fernanda D, Jing Huie, Kayaoglu Basak, Su Helen C, Pai Sung-Yun, Hickstein Dennis D, Shah Nirali N
Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.
Immune-Deficiency Cellular Therapy Program, National Cancer Institute, Bethesda, Md.
J Allergy Clin Immunol. 2025 Jan;155(1):176-187. doi: 10.1016/j.jaci.2024.08.021. Epub 2024 Sep 2.
DOCK8 deficiency is a primary immunodeficiency in which allogeneic hematopoietic cell transplantation (HCT) represents the only known cure. We tested the ability of a busulfan-based regimen to achieve reliable engraftment and high levels of donor chimerism with acceptable toxicity in a prospective clinical trial in DOCK8 deficiency.
To both evaluate the ability of HCT to reverse the clinical phenotype and to correct the immunologic abnormalities by 1 year post HCT.
We conducted a prospective HCT trial for recipients with DOCK8 deficiency. Subjects were recruited from October 5, 2010, to December 30, 2022. Donor sources included fully matched related and unrelated donors and haploidentical donors. The reduced toxicity, myeloablative conditioning regimen contained no serotherapy. Graft-versus-host disease (GVHD) prophylaxis included either a calcineurin inhibitor with methotrexate or post-HCT cyclophosphamide (PT/Cy) followed by tacrolimus and mycophenolate mofetil. The trial was later amended to study PT/Cy in all patients. (Pilot Study of Reduced-Intensity Hematopoietic Stem Cell Transplant of DOCK8 [NCT01176006].) RESULTS: Thirty-six subjects, both children and adults (median age 16.4 years), underwent HCT for DOCK8 deficiency. Most patients, 33 of 36 (92%), achieved full (≥98%) donor chimerism in whole blood as early as day +30. With a median potential follow-up of 7.4 years, 29 (80.6%) were alive with no evidence of new DOCK8 deficiency-related complications. PT/Cy was effective in reducing the risk of acute GVHD in patients who had received matched unrelated donor and haploidentical transplants, but it was associated with transient delays in immune-reconstitution and hemorrhagic cystitis.
A busulfan-based HCT regimen using PT/Cy for GVHD prophylaxis and a broad range of donor types and hematopoietic cell sources were well tolerated, leading to the reversal of the clinical immunophenotype.
DOCK8缺陷是一种原发性免疫缺陷病，同种异体造血细胞移植（HCT）是目前已知的唯一治愈方法。在一项针对DOCK8缺陷的前瞻性临床试验中，我们测试了一种基于白消安的方案在可接受的毒性水平下实现可靠植入和高水平供体嵌合的能力。
评估HCT在移植后1年内逆转临床表型和纠正免疫异常的能力。
我们对DOCK8缺陷的受者进行了一项前瞻性HCT试验。研究对象于2010年10月5日至2022年12月30日招募。供体来源包括完全匹配的相关和无关供体以及单倍体相合供体。降低毒性的清髓预处理方案不包括血清疗法。移植物抗宿主病（GVHD）预防措施包括使用钙调神经磷酸酶抑制剂联合甲氨蝶呤或移植后环磷酰胺（PT/Cy），随后使用他克莫司和霉酚酸酯。该试验后来修订为在所有患者中研究PT/Cy。（DOCK8低强度造血干细胞移植的初步研究[NCT01176006]。）结果：36名受试者（包括儿童和成人，中位年龄16.4岁）因DOCK8缺陷接受了HCT。大多数患者，即36名中的33名（92%），早在+30天时全血中就实现了完全（≥98%）供体嵌合。中位潜在随访时间为7.4年，29名（80.6%）患者存活，没有新的DOCK8缺陷相关并发症的证据。PT/Cy在降低接受匹配无关供体和单倍体相合移植患者的急性GVHD风险方面有效，但与免疫重建的短暂延迟和出血性膀胱炎有关。
一种基于白消安的HCT方案，使用PT/Cy预防GVHD，以及广泛的供体类型和造血细胞来源耐受性良好，导致临床免疫表型逆转。
