Eculizumab exposure in children and young adults: indications, practice patterns, and outcomes-a Pediatric Nephrology Research Consortium study

Abstract

Background: Eculizumab is approved for the treatment of atypical hemolytic uremic syndrome (aHUS). Its use off-label is frequently reported. The aim of this study was to describe the broader use and outcomes of a cohort of pediatric patients exposed to eculizumab.

Methods: A retrospective, cohort analysis was performed on the clinical and biomarker characteristics of eculizumab-exposed patients < 25 years of age seen across 21 centers of the Pediatric Nephrology Research Consortium. Patients were included if they received at least one dose of eculizumab between 2008 and 2015. Traditional summary statistics were applied to demographic and clinical data.

Results: A total of 152 patients were identified, mean age 9.1 (+/-6.8) years. Eculizumab was used "off-label" in 44% of cases. The most common diagnoses were aHUS (47.4%), Shiga toxin-producing Escherichia coli HUS (12%), unspecified thrombotic microangiopathies (9%), and glomerulonephritis (9%). Genetic testing was available for 60% of patients; 20% had gene variants. Dosing regimens were variable. Kidney outcomes tended to vary according to diagnosis. Infectious adverse events were the most common adverse event (33.5%). No cases of meningitis were reported. Nine patients died of noninfectious causes while on therapy.

Conclusions: This multi-center retrospective cohort analysis indicates that a significant number of children and young adults are being exposed to C5 blockade for off-label indications. Dosing schedules were highly variable, limiting outcome conclusions. Attributable adverse events appeared to be low. Cohort mortality (6.6%) was not insignificant. Prospective studies in homogenous disease cohorts are needed to support the role of C5 blockade in kidney outcomes.

Trial registration: ClinicalTrials.gov NCT02205541.

Keywords: Atypical hemolytic uremic syndrome; Eculizumab; Hemolytic uremic syndrome; Pediatric.

Figures

Fig. 1

Overall schematic of the disease classification, genetic testing, treatment duration, and renal outcomes in the 152 children from 21 different centers within the Pediatric Nephrology Research Consortium study who had received eculizumab therapy from 2008 to 2015

Fig. 2

Disease characteristics of patients treated with eculizumab within the Pediatric Nephrology Research Consortium from 2008 to 2015. a Provider reported diagnoses in children treated with terminal complement blockade. *The glomerulonephritis category includes patients with C3 GN, dense deposit disease, and membranoproliferative GN. **The other TMA category includes patients with hematopoietic stem cell transplant TMA, thrombotic thrombocytopenic purpura (TTP), TMA secondary to systemic lupus erythematosus, and TMA from an unknown etiology. ***The other category captures all remaining indications. b DNA variants reported in those patients diagnosed with atypical hemolytic uremic syndrome. Sixty-two atypical hemolytic uremic syndrome patients underwent genetic testing. Twenty-five DNA variants were identified, across 6 different genes and 37 patients did not have a reported abnormality in these gene variants. The authors made no attempt to confirm the relative pathogenicity of reported DNA variants

Fig. 3

Median estimated glomerular filtration (eGFR) at initiation and at follow-up by diagnosis for pediatric patients receiving eculizumab from 2008 to 2015. *Median with interquartile range. #p values were calculated using signed rank test. aHUS: atypical hemolytic uremic syndrome, STEC HUS: Shiga toxin-producing Escherichia coli hemolytic uremic syndrome, non-STEC Inf: non-Shiga toxin-producing Escherichia coli infection-related thrombotic microangiopathy, TMA: other thrombotic microangiopathy, GN: glomerulonephritis, AMR: antibody-mediated rejection, PNH: paroxysmal nocturnal hemoglobinuria, other

Fig. 4

Median urine protein-to-creatinine (UPC) at initiation of eculizumab and at follow-up by diagnosis for pediatric patients receiving eculizumab from 2008 to 2015. *Median with interquartile range. #p values were calculated using signed rank test. aHUS: atypical hemolytic uremic syndrome, STEC HUS: Shiga toxin-producing Escherichia coli hemolytic uremic syndrome, non-STEC Inf: non-Shiga toxin-producing Escherichia coli infection-related thrombotic microangiopathy, TMA: other thrombotic microangiopathy, GN: glomerulonephritis, AMR: antibody-mediated rejection, PNH: paroxysmal nocturnal hemoglobinuria, other