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Terminal Complement Inhibitor Eculizumab in Atypical Hemolytic-Uremic Syndrome

Legendre, C. M. ; Licht, C. ; Muus, P. ; Greenbaum, L. A. ; Babu, S. ; Bedrosian, C. ; Bingham, C. ; Cohen, D. J. ; Delmas, Y. and Douglas, K. , et al. (2013) In New England Journal of Medicine 368(23). p.2169-2181
Abstract
Background Atypical hemolytic-uremic syndrome is a genetic, life-threatening, chronic disease of complement-mediated thrombotic microangiopathy. Plasma exchange or infusion may transiently maintain normal levels of hematologic measures but does not treat the underlying systemic disease. Methods We conducted two prospective phase 2 trials in which patients with atypical hemolytic-uremic syndrome who were 12 years of age or older received eculizumab for 26 weeks and during long-term extension phases. Patients with low platelet counts and renal damage (in trial 1) and those with renal damage but no decrease in the platelet count of more than 25% for at least 8 weeks during plasma exchange or infusion (in trial 2) were recruited. The primary... (More)
Background Atypical hemolytic-uremic syndrome is a genetic, life-threatening, chronic disease of complement-mediated thrombotic microangiopathy. Plasma exchange or infusion may transiently maintain normal levels of hematologic measures but does not treat the underlying systemic disease. Methods We conducted two prospective phase 2 trials in which patients with atypical hemolytic-uremic syndrome who were 12 years of age or older received eculizumab for 26 weeks and during long-term extension phases. Patients with low platelet counts and renal damage (in trial 1) and those with renal damage but no decrease in the platelet count of more than 25% for at least 8 weeks during plasma exchange or infusion (in trial 2) were recruited. The primary end points included a change in the platelet count (in trial 1) and thrombotic microangiopathy event-free status (no decrease in the platelet count of >25%, no plasma exchange or infusion, and no initiation of dialysis) (in trial 2). Results A total of 37 patients (17 in trial 1 and 20 in trial 2) received eculizumab for a median of 64 and 62 weeks, respectively. Eculizumab resulted in increases in the platelet count; in trial 1, the mean increase in the count from baseline to week 26 was 73x10(9) per liter (P<0.001). In trial 2, 80% of the patients had thrombotic microangiopathy event-free status. Eculizumab was associated with significant improvement in all secondary end points, with continuous, time-dependent increases in the estimated glomerular filtration rate (GFR). In trial 1, dialysis was discontinued in 4 of 5 patients. Earlier intervention with eculizumab was associated with significantly greater improvement in the estimated GFR. Eculizumab was also associated with improvement in health-related quality of life. No cumulative toxicity of therapy or serious infection-related adverse events, including meningococcal infections, were observed through the extension period. Conclusions Eculizumab inhibited complement-mediated thrombotic microangiopathy and was associated with significant time-dependent improvement in renal function in patients with atypical hemolytic-uremic syndrome. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
New England Journal of Medicine
volume
368
issue
23
pages
2169 - 2181
publisher
Massachusetts Medical Society
external identifiers
  • wos:000319948900005
  • scopus:84878589219
  • pmid:23738544
ISSN
0028-4793
DOI
10.1056/NEJMoa1208981
language
English
LU publication?
yes
id
7c05d973-6f33-4d20-8559-2aa0701cc0bc (old id 3921110)
date added to LUP
2016-04-01 11:11:08
date last changed
2020-10-07 02:14:17
@article{7c05d973-6f33-4d20-8559-2aa0701cc0bc,
  abstract     = {Background Atypical hemolytic-uremic syndrome is a genetic, life-threatening, chronic disease of complement-mediated thrombotic microangiopathy. Plasma exchange or infusion may transiently maintain normal levels of hematologic measures but does not treat the underlying systemic disease. Methods We conducted two prospective phase 2 trials in which patients with atypical hemolytic-uremic syndrome who were 12 years of age or older received eculizumab for 26 weeks and during long-term extension phases. Patients with low platelet counts and renal damage (in trial 1) and those with renal damage but no decrease in the platelet count of more than 25% for at least 8 weeks during plasma exchange or infusion (in trial 2) were recruited. The primary end points included a change in the platelet count (in trial 1) and thrombotic microangiopathy event-free status (no decrease in the platelet count of &gt;25%, no plasma exchange or infusion, and no initiation of dialysis) (in trial 2). Results A total of 37 patients (17 in trial 1 and 20 in trial 2) received eculizumab for a median of 64 and 62 weeks, respectively. Eculizumab resulted in increases in the platelet count; in trial 1, the mean increase in the count from baseline to week 26 was 73x10(9) per liter (P&lt;0.001). In trial 2, 80% of the patients had thrombotic microangiopathy event-free status. Eculizumab was associated with significant improvement in all secondary end points, with continuous, time-dependent increases in the estimated glomerular filtration rate (GFR). In trial 1, dialysis was discontinued in 4 of 5 patients. Earlier intervention with eculizumab was associated with significantly greater improvement in the estimated GFR. Eculizumab was also associated with improvement in health-related quality of life. No cumulative toxicity of therapy or serious infection-related adverse events, including meningococcal infections, were observed through the extension period. Conclusions Eculizumab inhibited complement-mediated thrombotic microangiopathy and was associated with significant time-dependent improvement in renal function in patients with atypical hemolytic-uremic syndrome.},
  author       = {Legendre, C. M. and Licht, C. and Muus, P. and Greenbaum, L. A. and Babu, S. and Bedrosian, C. and Bingham, C. and Cohen, D. J. and Delmas, Y. and Douglas, K. and Eitner, F. and Feldkamp, T. and Fouque, D. and Furman, R. R. and Gaber, O. and Herthelius, M. and Hourmant, M. and Karpman, Diana and Lebranchu, Y. and Mariat, C. and Menne, J. and Moulin, B. and Nuernberger, J. and Ogawa, M. and Remuzzi, G. and Richard, T. and Sberro-Soussan, R. and Severino, B. and Sheerin, N. S. and Trivelli, A. and Zimmerhackl, L. B. and Goodship, T. and Loirat, C.},
  issn         = {0028-4793},
  language     = {eng},
  number       = {23},
  pages        = {2169--2181},
  publisher    = {Massachusetts Medical Society},
  series       = {New England Journal of Medicine},
  title        = {Terminal Complement Inhibitor Eculizumab in Atypical Hemolytic-Uremic Syndrome},
  url          = {https://lup.lub.lu.se/search/ws/files/2450576/4146451},
  doi          = {10.1056/NEJMoa1208981},
  volume       = {368},
  year         = {2013},
}