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Complement blockade for TA-TMA: lessons learned from a large pediatric cohort treated with eculizumab.

Abstract：

: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.

journal_name

Blood

journal_title

Blood

authors

Jodele S,Dandoy CE,Lane A,Laskin BL,Teusink-Cross A,Myers KC,Wallace G,Nelson A,Bleesing J,Chima RS,Hirsch R,Ryan TD,Benoit S,Mizuno K,Warren M,Davies SM

doi

10.1182/blood.2019004218

subject

Has Abstract

pub_date

2020-03-26 00:00:00

pages

1049-1057

issue

eissn

0006-4971

issn

1528-0020

pii

430258

journal_volume

135

pub_type

杂志文章

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Complement blockade for TA-TMA: lessons learned from a large pediatric cohort treated with eculizumab.