Alternative Donor Transplantation with High-Dose Post-Transplantation Cyclophosphamide for Refractory Severe Aplastic Anemia.
Alternative Donor Transplantation with High-Dose Post-Transplantation Cyclophosphamide for Refractory Severe Aplastic Anemia.
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DOI：
10.1016/j.bbmt.2016.12.628
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发表时间：
2017-03
期刊：
影响因子：
--
通讯作者：
Brodsky RA
中科院分区：
文献类型：
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作者：
DeZern AE;Zahurak M;Symons H;Cooke K;Jones RJ;Brodsky RA
严重再生障碍性贫血 (SAA) 是一种危及生命的造血干细胞疾病，可通过骨髓移植 (BMT) 或免疫抑制疗法 (IST) 进行治疗。 IST 后难治性 SAA 患者的管理是一个重大挑战。替代供体 BMT 是治愈难治性 SAA 的最佳机会，但移植失败和移植物抗宿主病 (GVHD) 并发症导致的发病率和死亡率限制了人们对这种方法的热情。在这里，我们采用移植后高剂量环磷酰胺，以安全地扩大 16 名连续难治性 SAA 患者的供体库，这些患者没有匹配的同胞供体。 2011 年 7 月至 2016 年 8 月期间，16 名患者因难治性 SAA 接受了同种异体 (allo) BMT，这些患者来自 13 名半相合供体和 3 名无关供体。非清髓性预处理方案包括抗胸腺细胞球蛋白、氟达拉滨、低剂量环磷酰胺和全身照射。移植后环磷酰胺 50 mg/kg/天，静脉注射在+3和+4天施用用于GVHD预防。此外，患者在第+5天至第35天接受霉酚酸酯，并在第+5天至第1年接受他克莫司。移植时患者的中位年龄为 30 岁（范围为 11 至 69 岁）。中性粒细胞连续3天恢复超过1000×103/mm3的中位时间为19天（范围，16至27）天，红细胞植入为25天（范围，2至58）天，最后一次血小板输注以保持血小板计数超过50×103/mm3的中位时间为27.5天（范围，22至108）天。在所有患者中均未发现原发性或继发性移植失败。所有 16 名患者均存活，不依赖输血，且没有克隆性证据。中位随访时间为 21（范围：3 至 64）个月。两名患者出现 1 级或 2 级仅皮肤急性 GVHD。这两人还患有轻度慢性皮肤/口腔移植物抗宿主病（GVHD），需要全身类固醇。其中一名 GVHD 患者能够在 15 个月时摆脱所有 IST，另一名患者则在 17 个月时摆脱所有 IST。所有其他患者在 1 年时停止 IST。使用移植后环磷酰胺的非清髓性同种异体骨髓移植可以安全地扩大供体库，以包括 HLA 单倍体供体。这种方法对于难治性 SAA 患者似乎很有希望。重要的是，植入率为 100%，根除了预先存在的克隆性疾病，并且 GVHD 的风险很低。
Severe aplastic anemia (SAA) is a life-threatening hematopoietic stem cell disorder that is treated with bone marrow transplantation (BMT) or immunosuppressive therapy (IST). The management of patients with refractory SAA after IST is a major challenge. Alternative donor BMT is the best chance for cure in refractory SAA, but morbidity and mortality from graft failure and complications of graft-versus-host disease (GVHD) have limited enthusiasm for this approach. Here, we employed post-transplantation high-dose cyclophosphamide in an effort to safely expand the donor pool in 16 consecutive patients with refractory SAA who did not have a matched sibling donor. Between July 2011 and August 2016, 16 patients underwent allogeneic (allo) BMT for refractory SAA from 13 haploidentical donors and 3 unrelated donors. The nonmyeloablative conditioning regimen consisted of antithymocyte globulin, fludarabine, low-dose cyclophosphamide, and total body irradiation. Post-transplantation cyclophosphamide 50 mg/kg/day i.v. on days +3 and +4 was administered for GVHD prophylaxis. Additionally, patients received mycophenolate mofetil on days +5 through 35 and tacrolimus from day +5 through 1 year. The median age of the patients at the time of transplantation was 30 (range, 11 to 69) years. The median time to neutrophil recovery over 1000 × 103/mm3 for 3 consecutive days was 19 (range, 16 to 27) days, to red cell engraftment was 25 (range, 2 to 58) days, and to last platelet transfusion to keep platelets counts over 50 × 103/mm3 was 27.5 (range, 22 to 108) days. Graft failure, primary or secondary, was not seen in any of the patients. All 16 patients are alive, transfusion independent, and without evidence of clonality. The median follow-up is 21 (range, 3 to 64) months. Two patients had grade 1 or 2 skin-only acute GVHD. These same 2 also had mild chronic GVHD of the skin/mouth requiring systemic steroids. One of these GVHD patients was able to come off all IST by 15 months and the other by 17 months. All other patients stopped IST at 1 year. Nonmyeloablative alloBMT using post-transplantation cyclophosphamide allowed for safe expansion of the donor pool to include HLA-haploidentical donors. This approach appears promising in refractory SAA patients. Importantly, engraftment was 100%, pre-existing clonal disease was eradicated, and the risk of GVHD was low.