Patients with severe sickle cell disease (SCD) experience organ damage, poor quality of life and premature mortality. Hematopoietic cell transplantation (HCT) is curative in SCD. Excellent outcomes have been achieved in young children with HLA matched related donors (MRD), with low rates of acute and chronic graft versus host disease (GVHD). Adolescent patients with SCD receiving MRD HCT and patients with SCD receiving matched unrelated donor (MUD) HCT, remain at highest risk for GVHD and resulting morbidity and mortality. Building on the encouraging experience with abatacept (CTLA-4Ig) for GVHD prophylaxis in URD HCT for hematologic malignancies, we launched an early phase, multicenter trial (n=25) through the Sickle Cell Transplant Advocacy and Research Alliance (STAR) of abatacept in pediatric SCD patients at high risk for GVHD. Patients with severe sickle cell disease were eligible if they were receiving a MRD HCT and either they or their donor were at least 10 years or if they were receiving a MUD HCT. Twenty-five patients have been enrolled to date with 23 patients completing conditioning and HCT. All patients received reduced intensity conditioning (RIC) with distal alemtuzumab, fludarabine, thiotepa and melphalan and marrow grafts. Four doses of abatacept (10 mg/kg/dose IV on days -1,+5,+14, +28) were added to standard GVHD prophylaxis using tacrolimus and methotrexate. Abatacept dosing was extended to eight doses for the last 11 patients (+60, +90, +120, +150). Tacrolimus was tapered at day 180 if no GHVD was present. The median age at HCT was 11 (3-21 years); 13 received a MRD HCT and 10 a MUD HCT. All patients engrafted with neutrophils at a median of 21 days (range 13-26) and platelets at a median of 23 days (13-55). As of 10/1/2019, median follow up is 804 days (range 46 – 1139). The mean myeloid and T-cell chimerisms at one (n=17) and two years (n=10) were 97.9 +/- 4.9 and 94.2 +/- 10.0 and 96.6 +/- 8.9 and 97.5 +/-4.3, respectively. Three evaluable patients at 2 years did not have chimerism studies sent. There have been 4 cases of EBV viremia (1 PTLD) and 6 cases of CMV viremia (1 disease). Grades 3-4 acute GVHD was seen in one patient and chronic/overlap in 5 patients with two patients currently receiving sytemic immune suppression. There has been no cerebral hemorrhages but one patient developed non-infectious encephalopathy of unclear etiology. The overall and sickle cell free survival at 2 years post HCT in evaluable patients (N=13) is 100% and 100%, respectively. The preliminary results in first 23 patients enrolled to date suggest that incorporating abatacept into GVHD prophylaxis is a safe and efficacious approach to improving outcomes in HCT for pediatric SCD.

患有严重镰状细胞疾病（SCD）的患者会遭受器官损伤，生活质量差和过早死亡。造血细胞移植（HCT）在SCD中可治愈。在HLA匹配相关供体（MRD）的幼儿中，急性和慢性移植物抗宿主病（GVHD）的发生率较低。接受MRD HCT的SCD青春期患者和接受匹配的无关供体（MUD）HCT的SCD患者仍处于发生GVHD的最高风险，从而导致发病和死亡。基于abatacept（CTLA-4Ig）在URD HCT中预防血液恶性肿瘤的GVHD的令人鼓舞的经验，我们通过abatacept的镰刀细胞移植倡导和研究联盟（STAR）开展了一项早期，多中心试验（n = 25）。 GVHD高危的小儿SCD患者。患有严重镰状细胞疾病的患者，如果他们接受MRD HCT，或者他们或他们的供体至少10年，或者接受MUD HCT，则符合资格。迄今为止，已有25例患者入组，其中23例患者完成了调理和HCT。所有患者均接受了远端阿仑单抗，氟达拉滨，噻替帕，美法仑和骨髓移植物的降低强度调节（RIC）。使用他克莫司和甲氨蝶呤将四剂阿巴西普（在第-1，+ 5，+ 14，+ 28天静脉注射10 mg / kg /剂量）添加到标准GVHD预防中。在最后11位患者中，Abatacept的剂量扩展到了8剂（+ 60，+ 90，+ 120，+ 150）。如果不存在GHVD，他克莫司在第180天逐渐减少。HCT的中位年龄为11岁（3-21岁）；13台收到了MRD HCT，10台收到了MUD HCT。所有患者的中位数为21天（范围13-26），中位数为23天（13-55）。截至2019年1月10日，中位随访时间为804天（范围46 – 1139）。一年（n = 17）和两年（n = 10）的平均髓样和T细胞嵌合率分别为97.9 +/- 4.9和94.2 +/- 10.0和96.6 +/- 8.9和97.5 +/- 4.3。3名2岁时可评估的患者未进行嵌合研究。有4例EBV病毒血症（1 PTLD）和6例CMV病毒血症（1种疾病）。一名患者出现3-4级急性GVHD，5名患者出现慢性/重叠，其中两名患者目前正在接受系统性免疫抑制。没有发生脑出血，但一名患者发展了病因不清楚的非感染性脑病。可评估的患者（N = 13）在HCT后2年的总生存率和镰刀无细胞生存率分别为100％和100％。迄今为止的前23名患者的初步结果表明，将abatacept纳入GVHD预防是改善小儿SCD HCT结局的安全有效方法。