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Abstract：
BACKGROUND: Activated phosphoinositide 3-kinase delta syndrome (APDS) is a combined immunodeficiency with a heterogeneous phenotype considered reversible by allogeneic hematopoietic cell transplantation (HCT).
OBJECTIVE: This study sought to characterize HCT outcomes in APDS.
METHODS: Retrospective data were collected on 57 patients with APDS1/2 (median age, 13 years; range, 2-66 years) who underwent HCT.
RESULTS: Pre-HCT comorbidities such as lung, gastrointestinal, and liver pathology were common, with hematologic malignancy in 26%. With median follow-up of 2.3 years, 2-year overall and graft failure-free survival probabilities were 86% and 68%, respectively, and did not differ significantly by APDS1 versus APDS2, donor type, or conditioning intensity. The 2-year cumulative incidence of graft failure following first HCT was 17% overall but 42% if mammalian target of rapamycin inhibitor(s) (mTORi) were used in the first year post-HCT, compared with 9% without mTORi. Similarly, 2-year cumulative incidence of unplanned donor cell infusion was overall 28%, but 65% in the context of mTORi receipt and 23% without. Phenotype reversal occurred in 96% of evaluable patients, of whom 17% had mixed chimerism. Vulnerability to renal complications continued post-HCT, adding new insights into potential nonimmunologic roles of phosphoinositide 3-kinase not correctable through HCT.
CONCLUSIONS: Graft failure, graft instability, and poor graft function requiring unplanned donor cell infusion were major barriers to successful HCT. Post-HCT mTORi use may confer an advantage to residual host cells, promoting graft instability. Longer-term post-HCT follow-up of more patients is needed to elucidate the kinetics of immune reconstitution and donor chimerism, establish approaches that reduce graft instability, and assess the completeness of phenotype reversal over time.
OBJECTIVE: This study sought to characterize HCT outcomes in APDS.
METHODS: Retrospective data were collected on 57 patients with APDS1/2 (median age, 13 years; range, 2-66 years) who underwent HCT.
RESULTS: Pre-HCT comorbidities such as lung, gastrointestinal, and liver pathology were common, with hematologic malignancy in 26%. With median follow-up of 2.3 years, 2-year overall and graft failure-free survival probabilities were 86% and 68%, respectively, and did not differ significantly by APDS1 versus APDS2, donor type, or conditioning intensity. The 2-year cumulative incidence of graft failure following first HCT was 17% overall but 42% if mammalian target of rapamycin inhibitor(s) (mTORi) were used in the first year post-HCT, compared with 9% without mTORi. Similarly, 2-year cumulative incidence of unplanned donor cell infusion was overall 28%, but 65% in the context of mTORi receipt and 23% without. Phenotype reversal occurred in 96% of evaluable patients, of whom 17% had mixed chimerism. Vulnerability to renal complications continued post-HCT, adding new insights into potential nonimmunologic roles of phosphoinositide 3-kinase not correctable through HCT.
CONCLUSIONS: Graft failure, graft instability, and poor graft function requiring unplanned donor cell infusion were major barriers to successful HCT. Post-HCT mTORi use may confer an advantage to residual host cells, promoting graft instability. Longer-term post-HCT follow-up of more patients is needed to elucidate the kinetics of immune reconstitution and donor chimerism, establish approaches that reduce graft instability, and assess the completeness of phenotype reversal over time.
摘要：
背景：激活的磷酸肌醇3-激酶δ综合征（APDS）是一种联合免疫缺陷，具有异基因造血细胞移植（HCT）认为可逆的异质性表型。
目的：本研究旨在表征APDS的HCT结局。
方法：收集57例APDS1/2患者的回顾性资料（中位年龄，13年；范围，2-66岁）接受HCT。
结果：HCT前合并症，例如肺，胃肠,肝脏病理很常见，血液系统恶性肿瘤占26%。中位随访时间为2.3年，2年总体和无移植物失败的生存概率分别为86％和68％，分别,APDS1与APDS2，供体类型没有显着差异，或调理强度。首次HCT后移植失败的2年累积发生率为17％，但如果在HCT后的第一年使用哺乳动物雷帕霉素抑制剂（mTORi），则为42％。与没有mTOri的9%相比。同样，非计划供体细胞输注的2年累计发生率为28％，但65%在mTOri收据的情况下，23%没有。表型逆转发生在96%的可评估患者中，其中17%有混合嵌合体。HCT后肾脏并发症的脆弱性持续存在，增加了对不能通过HCT纠正的磷酸肌醇3激酶的潜在非免疫作用的新见解。
结论：移植失败，移植物不稳定性，移植物功能差需要非计划的供体细胞输注是HCT成功的主要障碍。HCT后mTORi的使用可能会给残留的宿主细胞带来优势，促进移植物不稳定性。需要对更多患者进行更长期的HCT后随访，以阐明免疫重建和供体嵌合体的动力学，建立减少移植物不稳定性的方法，并评估表型逆转随时间的完整性。
目的：本研究旨在表征APDS的HCT结局。
方法：收集57例APDS1/2患者的回顾性资料（中位年龄，13年；范围，2-66岁）接受HCT。
结果：HCT前合并症，例如肺，胃肠,肝脏病理很常见，血液系统恶性肿瘤占26%。中位随访时间为2.3年，2年总体和无移植物失败的生存概率分别为86％和68％，分别,APDS1与APDS2，供体类型没有显着差异，或调理强度。首次HCT后移植失败的2年累积发生率为17％，但如果在HCT后的第一年使用哺乳动物雷帕霉素抑制剂（mTORi），则为42％。与没有mTOri的9%相比。同样，非计划供体细胞输注的2年累计发生率为28％，但65%在mTOri收据的情况下，23%没有。表型逆转发生在96%的可评估患者中，其中17%有混合嵌合体。HCT后肾脏并发症的脆弱性持续存在，增加了对不能通过HCT纠正的磷酸肌醇3激酶的潜在非免疫作用的新见解。
结论：移植失败，移植物不稳定性，移植物功能差需要非计划的供体细胞输注是HCT成功的主要障碍。HCT后mTORi的使用可能会给残留的宿主细胞带来优势，促进移植物不稳定性。需要对更多患者进行更长期的HCT后随访，以阐明免疫重建和供体嵌合体的动力学，建立减少移植物不稳定性的方法，并评估表型逆转随时间的完整性。
