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

Blood. 2020 Mar 26;135(13):1049-1057. doi: 10.1182/blood.2019004218.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Antibodies, Monoclonal, Humanized / administration & dosage
  • Antibodies, Monoclonal, Humanized / adverse effects
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Child
  • Child, Preschool
  • Complement Inactivating Agents / administration & dosage
  • Complement Inactivating Agents / adverse effects
  • Complement Inactivating Agents / therapeutic use*
  • Complement System Proteins / immunology*
  • Disease Susceptibility
  • Female
  • Hematopoietic Stem Cell Transplantation / adverse effects*
  • Hematopoietic Stem Cell Transplantation / methods
  • Humans
  • Incidence
  • Male
  • Risk Assessment
  • Risk Factors
  • Sepsis / epidemiology
  • Sepsis / etiology
  • Thrombotic Microangiopathies / diagnosis
  • Thrombotic Microangiopathies / drug therapy*
  • Thrombotic Microangiopathies / etiology*
  • Treatment Outcome

Substances

  • Antibodies, Monoclonal, Humanized
  • Complement Inactivating Agents
  • Complement System Proteins
  • eculizumab