One hundred percent survival after transplantation of 34 patients with Wiskott-Aldrich syndrome over 20 years
One hundred percent survival after transplantation of 34 patients with Wiskott-Aldrich syndrome over 20 years
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DOI：
10.1016/j.jaci.2018.06.042
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发表时间：
2018-11-01
影响因子：
14.2
通讯作者：
Veys, Paul
中科院分区：
文献类型：
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作者：
Elfeky, Reem Ahmed;Furtado-Silva, Juliana M.;Veys, Paul
随着时间的推移，造血干细胞移植(HSCT)治疗Wiskott Aldrich综合征(Was)的结果有所改善。基于布舒芬(Bu)和环磷酰胺(Cyc)调节的标准清髓方案支持高水平的供体植入，尽管有频繁的并发症(1-3)。我们报告了在1996-2016年间，连续34名在单一中心接受各种移植手术的IS患者的总存活率为100%，包括替代移植物来源和减少的调理方案。34名男孩接受了36次移植，其中包括7名匹配的同胞捐赠者(MSD)和29名替代捐赠者来源。21名患者原有的IS评分为≥3，16名患者的评分为5，表明是自身免疫或恶性。33例男童中有25例检出致病基因突变，8例检出缺失；32例患者中有28例未见黄蜂基因表达。移植前有12例发生严重感染，包括巨细胞病毒肺炎(P13，P14)、EB病毒淋巴增生性疾病(P33)、隐孢子虫胆管病(P33)、真菌性肺炎(P2，P7，P13)。移植前自身免疫15例(44%)，包括细胞减少症(n=9)、血管炎和/或关节炎(n=2)和自身免疫性血小板减少性紫癜(n=4)。所有患者均接受全身激素治疗，9/15例患者同时接受了利妥昔单抗治疗，其中9例为自身免疫性溶血性贫血+自身免疫性血小板减少症(P2，P4，P24)或难治性血小板减少伴出血发作的患者(6例；P8，P19，P26，P29，P32，P33)行移植前脾切除术。1例患者(P13)为B-ALL前体，在接受HSCT前接受了UKALL2011方案B和C治疗。从诊断到移植的中位时间为27.1米(范围4-162米)(表1)。26例(76%)患者在2岁前接受了移植。P33在植入前遗传诊断(PGD)并选择了一个与人类白细胞抗原相合的“救世主”兄弟姐妹后接受了移植。减强度预适应(RIC)联合Treosulphan(Treo)42g/m~2(n=17)、Melphalan(MEL)140 mg/m~2(n=7)、减量Bu(AUC=55~65 mg/L/hr)(n=2)或Cyc120 mg/kg加甲基强的松龙12 mg/kg(n=1)。其余移植组包括Bu 16 mg/kg、Cyc 200 mg/kg(n=7)或Treo 42g/m~2/Flu 150 mg/m~2/Thiotepa(TT)10 mg/kg(n=2)。80%的手术采用血清疗法，包括阿伦图珠单抗(0.3-1 mg/kg，n=25)或兔抗胸腺细胞球蛋白(rATG，n=5，7.5-25 mg/kg)。3例不匹配的非亲缘供者脐带移植未进行血清治疗(4例)。患者接受的中位剂量为9.8x106/kg CD34+细胞(0.86-62x106细胞/kg)。34/36例移植后预防移植物抗移植物抗宿主病包括环孢素A单独或与甲基强的松龙、霉酚酸酯(MMF)或甲氨蝶呤(MTX)联合应用。两名单倍体相合移植的受者没有接受任何预防措施(P14，P28)。所有患者均接受静脉注射免疫球蛋白(IVIG)预防。
Outcomes following haematopoietic stem cell transplantation (HSCT) for Wiskott Aldrich syndrome (WAS) have improved over time. Standard myeloablative regimens based on Busulphan (Bu) and Cyclophosphamide (Cyc) conditioning support high levels of donor engraftment, albeit with frequent complications (1-3). We report 100% overall survival in 34 consecutive WAS patients who underwent a variety of transplant procedures at a single centre, including alternative graft sources and reduced conditioning regimens, between 1996-2016. 34 boys received 36 transplants comprising 7 matched sibling donor (MSD) and 29 alternative donor sources. Twenty-one patients had a pre-existing WAS score≥ 3, and 16 had a score of 5, indicating autoimmunity or malignancy. Pathogenic WAS gene mutations were confirmed in 25/33 boys and deletions were detected in 8/33; WASp expression was absent in 28/32 patients. Pre-transplant severe infections including CMV pneumonitis (P13, P14), EBV-lymphoproliferative disease (P33), cryptosporidium cholangiopathy (P33), fungal pneumonia (P2, P7, P13) were recorded in 12/34 patients. Pre-transplant autoimmunity was present in 15 patients (44%) and included cytopenias (n= 9), vasculitis and/or arthritis (n= 2) and autoimmune thrombocytopenic purpura (n= 4). All these patients required systemic steroid therapy and 9/15 also received Rituximab; pre-transplant splenectomy was performed in 9 patients for control of autoimmune hemolytic anemia±autoimmune thrombocytopenia (P2, P4, P24) or for refractory thrombocytopenia with uncontrolled bleeding episodes (n= 6; P8, P19, P26, P29, P32, P33). One patient (P13) had precursor B-ALL and was treated under UKALL 2011 regimen B and C before proceeding to HSCT. Median time from diagnosis to transplant was 27.1 m (range: 4-162m)(table 1).Twenty-six (76%) patients underwent transplantation before 2 years of age. P33 underwent transplantation after pre-implantation genetic diagnosis (PGD) and selection of a HLA-matched ‘savior’sibling. Reduced intensity conditioning (RIC) incorporated Treosulphan (Treo) 42g/m2 (n= 17), Melphalan (Mel) 140mg/m2 (n= 7), reduced dose Bu (AUC= 55-65 mg/l/hr)(n= 2) or Cyc 120 mg/Kg with Methylprednisolone 12mg/kg (n= 1) in 27 transplants. The remaining transplants included both Bu 16mg/kg and Cyc 200mg/kg (n= 7) or Treo 42g/m2/Flu 150mg/m2/Thiotepa (TT) 10mg/kg (n= 2). Serotherapy was used in 80% of the procedures comprising either Alemtuzumab (0.3-1mg/kg (n= 25) or rabbit anti-thymocyte globulin (rATG)(n= 5; 7.5-25mg/kg). No serotherapy was used in 3 mismatched unrelated donor cord transplants (4). Patients received a median dose of 9.8 x106/kg CD34+ cells (0.86-62x106cells/kg). Posttransplant prophylaxis against GvHD in 34/36 transplants comprised Cyclosporine A alone or in combination with Methylprednisolone, Mycophenolate mofetil (MMF) or Methotrexate (MTX). Two recipients of haploidentical transplants received no prophylaxis (P14, P28). All patients received prophylaxis with intravenous immunoglobulin (IVIG).