Abstract

Abstract 2085

Introduction:

Atypical hemolytic uremic syndrome (aHUS) is a rare chronic disorder characterized by persistent uncontrolled complement activation that results in life-threatening systemic thrombotic microangiopathy (TMA). In an estimated 50%–70% of patients (pts) with aHUS, uncontrolled complement activation can be attributed to identified genetic mutation(s) in complement regulatory factors and/or the presence of complement factor H auto-antibodies (CFH auto-Abs); newly identified complement mutations continue to be reported in the medical literature. For the 30%–50% of pts who currently have no identified genetic mutation/CFH auto-Abs, the overall risk of end-stage renal disease or death is high and similar to that observed in pts with known genetic mutation(s)/CFH auto-Abs, supporting the need for immediate management of disease in all aHUS pts regardless of mutation/CFH auto-Ab status. Eculizumab, an anti-C5 monoclonal antibody that inhibits terminal complement activation, is the only approved treatment for aHUS. Chronic eculizumab treatment has been proven to inhibit systemic TMA via terminal complement inhibition, improve renal function, and reduce or eliminate the need for plasma exchange/infusion (PE/PI) and dialysis. Furthermore, earlier eculizumab treatment has been associated with greater clinical improvement. The purpose of this analysis was to evaluate the relative efficacy of eculizumab in aHUS pts with or without identified genetic complement mutation(s)/CFH auto-Abs based on data from 3 clinical studies.

Methods:

This report summarizes a subgroup analysis of efficacy outcomes based on the presence or absence of identified genetic mutation(s)/CFH auto-Abs in 3 aHUS studies: 2 controlled, prospective studies (pts aged ≥12 y), and 1 retrospective study (pts aged <18 y).

Results:

Across the 3 studies, 24%–41% of pts had no identified genetic complement mutation or detectable CFH auto-Abs. The efficacy of eculizumab was similar regardless of mutation/CFH auto-Ab status (Table ).

Conclusions:

Across 3 studies investigating the efficacy of eculizumab treatment in aHUS pts, our analysis shows that improvements in hematologic, renal, and supportive care interventions (PE/PI, dialysis) outcomes were similar in pts with or without identified genetic complement mutation(s)/CFH auto-Abs. Given that (1) genetic testing often requires several months to complete, (2) uncontrolled complement activation places aHUS pts at risk of life-threatening systemic TMA events and organ damage, and (3) earlier intervention with eculizumab is associated with greater clinical improvement, we conclude that the results of this analysis provide a rationale for initiating eculizumab as first-line therapy at the time of clinical diagnosis of aHUS, without the availability of genetic testing results

Table.

Efficacy of eculizumab in pts with or without an identified genetic complement mutation and/or CFH auto-Abs

ParameterPts with Long Duration of Disease (Median Eculizumab Duration 114 Weeks) (N=20)Pts with Progressing TMA (Median Eculizumab Duration 100 Weeks) (N=17)Pediatric Pts (Retrospective Study)a (N=17)
Identified mutationb n=13No identified mutationc n=7Identified mutationb n=13No identified mutation n=4I entified mutation n=10No identified mutation n=7
TMA event-free status,d n (%) 13 (100) 6 (86) 12 (92) 3 (75) 7 (70) 5 (71) 
Platelet count ≥150×109/L, n (%) 12 (92) 6 (86) 12 (92) 3 (75) 10 (100) 6 (86) 
Hematological normalization,f n (%) 12 (92) 6 (86) 12 (92) 3 (75) 4 (40) 3 (43) 
Serum creatinine decrease ≥25%, n (%) 7 (54) 4 (57) 11 (85) 2 (50) 4 (40) 4 (57) 
eGFR increase ≥15 mL/min/1.73 m2, n (%) 5 (38) 3 (43) 8 (62) 2 (50) 5 (50) 3 (43) 
eGFR increase, mL/min/1.73 m2, mean (SE) 8.0 (2.1)g 2.0 (9.5) 37.7 (10.0) 35.7 (20.0)e NA NA 
ParameterPts with Long Duration of Disease (Median Eculizumab Duration 114 Weeks) (N=20)Pts with Progressing TMA (Median Eculizumab Duration 100 Weeks) (N=17)Pediatric Pts (Retrospective Study)a (N=17)
Identified mutationb n=13No identified mutationc n=7Identified mutationb n=13No identified mutation n=4I entified mutation n=10No identified mutation n=7
TMA event-free status,d n (%) 13 (100) 6 (86) 12 (92) 3 (75) 7 (70) 5 (71) 
Platelet count ≥150×109/L, n (%) 12 (92) 6 (86) 12 (92) 3 (75) 10 (100) 6 (86) 
Hematological normalization,f n (%) 12 (92) 6 (86) 12 (92) 3 (75) 4 (40) 3 (43) 
Serum creatinine decrease ≥25%, n (%) 7 (54) 4 (57) 11 (85) 2 (50) 4 (40) 4 (57) 
eGFR increase ≥15 mL/min/1.73 m2, n (%) 5 (38) 3 (43) 8 (62) 2 (50) 5 (50) 3 (43) 
eGFR increase, mL/min/1.73 m2, mean (SE) 8.0 (2.1)g 2.0 (9.5) 37.7 (10.0) 35.7 (20.0)e NA NA 

eGFR, estimated glomerular filtration rate; NA, not available; SE, standard error.

a

Variable follow-up duration.

b

Identified genetic mutations includes CFH auto-Abs.

c

A pt with a CFHR1-3 deletion has been included under no identified mutation for this analysis.

d

No decrease in platelet count of >25%, no PE/PI, and no new dialysis ≥12 consecutive weeks.

e

Data from pt who discontinued after 1 dose due to an exclusion criteria is not included.

f

Platelet count ≥150×109/L and lactate dehydrogenase ≤ upper limit of normal for ≥4 weeks.

g

For the 1 pt receiving transplant during study, post-transplant data are excluded.

Disclosures:

Goodship:Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Legendre:Alexion Pharmaceuticals: Speakers Bureau. Licht:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding. Muus:Alexion Pharmaceuticals.: Sat on advisory board of Alexion Pharmaceuticals. Other. Bedrosian:Alexion Pharmaceuticals: Employment, Equity Ownership. Loirat:Alexion Pharmaceuticals: Coordinator of Alexion trials of eculizumab in atypical HUS for France. Honoraria for conferences. Other.

Author notes

*

Asterisk with author names denotes non-ASH members.