Complement blockade for TA-TMA: lessons learned from a large pediatric cohort treated with eculizumab
Complement blockade for TA-TMA: lessons learned from a large pediatric cohort treated with eculizumab
复制标题
DOI：
10.1182/blood.2019004218
复制
发表时间：
2020-03-26
期刊：
影响因子：
20.3
通讯作者：
Davies, Stella M.
中科院分区：
文献类型：
--
作者：
Jodele, Sonata;Dandoy, Christopher E.;Davies, Stella M.
补体过度激活是造血干细胞移植（HSCT）移植相关血栓性微血管病（TA-TMA）患者的高风险特征，未经治疗的患者预后不佳。我们介绍了64例儿童HSCT受者的经验，这些受者有高危TA-TMA （hrTA-TMA）和多器官损伤，使用补体阻滞剂eculizumab治疗。我们证明，在我们之前报道的未治疗队列中，具有相同hrTA-TMA特征的hsct后1年生存率为16.7%的患者中，接受治疗的患者在hsct后1年生存率显著提高至66%。响应的患者受益于使用药代动力学/药效学指导给药的eculizumab的短暂但强化疗程，中位数需要11剂eculizumab（四分位数范围[IQR] 7-20）。由于TA-TMA在中位66天（IQR 41-110）消退，停止治疗。在治疗开始时通过血液sC5b-9升高测量的补体活化较高的受试者不太可能有反应（优势比，0.15;P = 0.0014），并且需要更多剂量的eculizumab （r = 0.43; P = 0.004）。肠出血患者的eculizumab清除率最快，需要最多的eculizumab剂量（20 vs 9; P = 0.0015）， 1年生存率较低（44% vs 78%; P = 0.01）。在长期随访中，超过70%的幸存者有蛋白尿。幸存者的最佳肾小球滤过率（GFR）恢复中位数比hsct前的GFR低20% （IQR, 7.3%-40.3%）。综上所述，eculizumab补体阻断是hrTA-TMA的有效治疗策略，但一些严重疾病患者缺乏完全缓解，这促使我们提出早期干预并寻找其他可靶向的内皮损伤途径。
Overactivated complement is a high-risk feature in hematopoietic stem cell transplant (HSCT) recipients with transplant-associated thrombotic microangiopathy (TA-TMA), and untreated patients have dismal outcomes. We present our experience with 64 pediatric HSCT recipients who had high-risk TA-TMA (hrTA-TMA) and multiorgan injury treated with the complement blocker eculizumab. We demonstrate significant improvement to 66% in 1-year post-HSCT survival in treated patients from our previously reported untreated cohort with same hrTA-TMA features that had 1-year post-HSCT survival of 16.7%. Responding patients benefited from a brief but intensive course of eculizumab using pharmacokinetic/pharmacodynamic-guided dosing, requiring a median of 11 doses of eculizumab (interquartile range [IQR] 7-20). Treatment was discontinued because TA-TMA resolved at a median of 66 days (IQR 41-110). Subjects with higher complement activation measured by elevated blood sC5b-9 at the start of treatment were less likely to respond (odds ratio, 0.15; P = .0014) and required more doses of eculizumab (r = 0.43; P = .0004). Patients with intestinal bleeding had the fastest eculizumab clearance, required the highest number of eculizumab doses (20 vs 9; P = .0015), and had lower 1-year survival (44% vs 78%; P = .01). Over 70% of survivors had proteinuria on long-term follow-up. The best glomerular filtration rate (GFR) recovery in survivors was a median 20% lower (IQR, 7.3%-40.3%) than their pre-HSCT GFR. In summary, complement blockade with eculizumab is an effective therapeutic strategy for hrTA-TMA, but some patients with severe disease lacked a complete response, prompting us to propose early intervention and search for additional targetable endothelial injury pathways.