Complement blockade for TA-TMA: lessons learned from a large pediatric cohort treated with eculizumab.
Blood
; 135(13): 1049-1057, 2020 03 26.
Article
en En
| MEDLINE
| ID: mdl-31932840
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.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Proteínas del Sistema Complemento
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Trasplante de Células Madre Hematopoyéticas
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Inactivadores del Complemento
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Microangiopatías Trombóticas
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Anticuerpos Monoclonales Humanizados
Tipo de estudio:
Diagnostic_studies
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Etiology_studies
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Incidence_studies
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Prognostic_studies
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Risk_factors_studies
Límite:
Adolescent
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Child
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Child, preschool
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Female
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Humans
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Male
Idioma:
En
Revista:
Blood
Año:
2020
Tipo del documento:
Article