Abstract：
Nonmyeloablative, matched sibling donor hematopoietic stem cell transplantation with alemtuzumab/total body irradiation (TBI) conditioning is a curative therapy with low toxicity for adults with sickle cell disease (SCD). However, relatively low donor chimerism levels and graft rejection remain important challenges. We hypothesized that adding azathioprine/hydroxyurea preconditioning will improve donor chimerism levels and reduce graft failure rate. In this prospective cohort study, we enrolled consecutive adult patients with SCD undergoing matched sibling donor transplantation at the Amsterdam UMC. Patients received azathioprine 150 mg/day and hydroxyurea 25 mg/kg/day for 3 months prior to alemtuzumab 1 mg/kg and 300 cGy TBI conditioning. Twenty patients with SCD (median age 26 years [range 19-49], 13 females) were transplanted. Median follow-up was 46.0 months (IQR 21.8-57.9). One-year overall survival and event-free survival (graft failure or death) were both 95% (95% confidence interval 86-100). Mean donor myeloid and T-cell chimerism 1-year post-transplant were 95.2% (SD ±10.6) and 67.3% (±15.3), respectively. One patient (5%) experienced graft failure without autologous regeneration, resulting in infections and death. All other patients had a corrected SCD phenotype and were able to discontinue sirolimus. Three patients were successfully treated with alemtuzumab (1 mg/kg) after the transplant because of declining donor chimerism and cytopenias to revert impending graft rejection. Toxicity was mostly related to sirolimus and alemtuzumab. One patient developed steroid-responsive grade II intestinal acute graft-versus-host disease. Collectively, preconditioning with azathioprine/hydroxyurea prior to nonmyeloablative matched sibling donor transplantation resulted in excellent event-free survival and robust donor T-cell chimerism, enabling the successful withdrawal of sirolimus. ClinicalTrials.gov: NCT05249452.
摘要：
非清髓性,配对同胞供者造血干细胞移植联合阿仑单抗/全身照射(TBI)预处理是治疗镰状细胞病(SCD)成人的低毒性治疗.然而,相对较低的供体嵌合水平和移植物排斥仍然是重要的挑战.我们假设添加硫唑嘌呤/羟基脲预处理将改善供体嵌合水平并降低移植物失败率。在这项前瞻性队列研究中，我们招募了在阿姆斯特丹UMC接受配对同胞移植的SCD连续成年患者.患者接受硫唑嘌呤150mg/天和羟基脲25mg/kg/天，持续3个月，然后接受阿仑珠单抗1mg/kg和300cGyTBI预处理。20例SCD患者（中位年龄26岁[范围19-49]，13只雌性）被移植。中位随访时间为46.0个月(IQR21.8-57.9)。一年总生存率和无事件生存率（移植失败或死亡）均为95％（95％置信区间86-100）。移植后1年平均供体髓样和T细胞嵌合率分别为95.2％（SD±10.6）和67.3％（±15.3），分别。一名患者（5％）经历了无自体再生的移植失败，导致感染和死亡。所有其他患者均具有校正的SCD表型，并且能够停止西罗莫司。移植后，三名患者成功接受了阿仑珠单抗（1mg/kg）治疗，因为供体嵌合体和血细胞减少减少以恢复即将发生的移植物排斥。毒性主要与西罗莫司和阿仑单抗有关。一名患者发展为类固醇反应性II级肠道急性移植物抗宿主病。总的来说，在非清髓性匹配的同胞供体移植之前用硫唑嘌呤/羟基脲进行预处理可导致出色的无事件存活率和强大的供体T细胞嵌合状态，使西罗莫司成功退出。ClinicalTrials.gov：NCT05249452。
