Abstract 4682

Background.

aHUS is a rare and life-threatening genetic disease characterized by systemic thrombotic microangiopathy (TMA) due to chronic, uncontrolled complement activation. Genetic mutation can be identified in only 50–70% of aHUS patients. Systemic TMA manifests as endothelial injury, hemolytic anemia, and platelet consumption, leading to multiorgan damage/failure. Despite chronic plasma exchange/infusion (PE/PI), >50% of aHUS patients die, require dialysis, or have permanent renal damage within 1 yr of diagnosis. Off-label use of eculizumab, a humanized high-affinity monoclonal antibody against complement protein C5, was previously reported to produce clinical remission of TMA in an 18-mo-old boy with a fourth relapse of aHUS (Gruppo et al, NEJM 2009). Results of more recent 26-wk, controlled, prospective, open-label, single-arm trials have demonstrated that eculizumab is effective in aHUS patients resistant to PE/PI or patients undergoing chronic PE/PI in inducing hematologic and TMA remission, restoring renal function, and improving QoL. No difference in response to eculizumab is seen in patients with or without an identified mutation. Long-term efficacy and safety outcomes for sustained eculizumab treatment of aHUS have not yet been reported.

Aim.

To provide a 3-yr follow-up of our previously-reported pediatric patient regarding the long-term efficacy and safety of eculizumab treatment for aHUS.

Methods.

Retrospective data collection analysis.

Results.

A 4-yr-old boy born at 34-wk gestation, initially presented with TMA at 4 d of age: Hg 8.5 g/dL, plt 18×109/L, BUN 34 mg/dL, Cr 1.0 mg/dL, LDH 6077 U/L (normal <920 U/L), and schistocytes on blood smear. Levels of ADAMTS13 activity and complement proteins C3–C9, factor H, factor I, and factor B were normal. Analysis of complement factor H, factor I, factor B, C3, MCP, and THBD genes did not identify any mutations; factor H autoantibody was not detected. PE/PI resulted in clinical improvement after 13 d. Relapses occurred at 3, 9, and 11 mo of age with remission occurring with re-institution of PE/PI. A fourth relapse occurred at 18 mo of age after discontinuation of plasma infusions. Despite daily plasmapheresis, severe TMA persisted with worsening renal function (BUN 62, Cr 3.2) and platelet count <25×109/L, requiring institution of hemodialysis.

Following initiation of eculizumab therapy in this 12-kg infant, hematologic and renal improvement began within 48 hr and remission occurred within 10 d, allowing permanent discontinuation of dialysis and PE/PI. Eculizumab 600mg was administered every 2 wk and continued for 4 mo with sustained clinical remission, then reduced to the currently recommended weight-based dose of 300mg every 2 wk, with 36 mo of ongoing therapy; PK/PD blood sampling has confirmed sustained terminal complement blockade at both eculizumab dosages. Renal function has improved over time and been maintained to 36 mo (data cut-off). Despite normal growth, neurocognitive development is delayed likely secondary to germinal matrix hemorrhage during initial hospitalization. Bilateral sensorineural hearing loss possibly secondary to aminoglycoside antibiotic therapy during his initial hospitalization required bilateral cochlear implants. Eculizumab infusions have been well tolerated without adverse events. Despite 2 surgical procedures and minor upper respiratory infections, he has maintained normal hematologic and renal parameters with ongoing long-term eculizumab treatment, with no serious infections. Current Hg 12.2 gm/dL, HCT 34.5%, plt 211×109/L, Retic 0.8%, no schistocytes on blood smear, LDH 695 U/L, haptoglob 22 mg/dL (normal 16–200 mg/dL), BUN 20 mg/dL, Cr 0.4 mg/dL, and cystatin C GFR 108 mL/min. Urinalysis is negative for blood. Modest proteinuria (urine protein/Cr ratio 0.4 mg/dL) and hypertension (related to previous renal injury) is controlled with enalapril. The patient continues to receive penicillin prophylaxis.

Conclusion:

Long-term treatment with eculizumab has maintained complete continuous suppression of TMA and maintained normal renal function, with no adverse events or serious infections for 36 months of ongoing treatment for aHUS.

Disclosures:

Gruppo: Alexion Pharmaceuticals: Honoraria. Off Label Use: Eculizumab for treatment of atypical hemolytic uremic syndrome. Dixon:Regeneron Pharmaceuticals: Equity Ownership.

Author notes

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Asterisk with author names denotes non-ASH members.