Determination of Relapse Risk By Complement Gene Variants after Eculizumab Discontinuation in Complement-Mediated Thrombotic Microangiopathy: A Retrospective Review

Autor: Nahla M. Heikal, Meera Sridharan, Ann M. Moyer, Cheryl L. Tran, Jeffrey L. Winters, Ronald S. Go, Christianne Bourlon De Los Rios, Hassan B. Alkhateeb, Nelson Leung, Aldo A. Acosta-Medina, Dong Chen, Maria Alice V. Willrich, Ariela L. Marshall, Fernando C. Fervenza
Rok vydání: 2020
Předmět:
Zdroj: Blood. 136:25-26
ISSN: 1528-0020
0006-4971
Popis: Background Eculizumab, a monoclonal antibody targeting C5, is an effective treatment for complement-mediated thrombotic microangiopathy (CM-TMA), also known as atypical hemolytic uremic syndrome. Although lifelong therapy has been suggested, the optimal treatment schedule is unknown, while eculizumab discontinuation does not universally lead to relapse. Data evaluating risk factors associated with an increased risk of CM-TMA recurrence following eculizumab withdrawal are scarce. Prior to the eculizumab era, complement genetic studies have been used to assess morbidity and mortality in patients with CM-TMA. Our aim was to assess the impact of complement gene variants on CM-TMA relapse rate (RR) after eculizumab discontinuation. Methods Search protocols were developed for the Ovid and PubMed databases to identify existing reports on CM-TMA and eculizumab withdrawal published before February 1st 2020. Cases were cross-referenced to eliminate duplicates. Inclusion criteria included patients diagnosed with CM-TMA who had undergone eculizumab discontinuation. Reasons for exclusion were patients with no follow-up after eculizumab withdrawal and patients lacking complement gene testing. Patients undergoing eculizumab dose extension, but not discontinuation, were not included. Results Fifteen studies including 557 individuals were retrieved. Of these, 363 (65.2%) were excluded as outlined in Figure 1 and 194 cases were included in the final analysis with a global RR of 28.9% (n=56). Distribution based on gene impacted and variant type are presented in Table 1. RR was highest among patients with CFH variants (52.5% to 60%) -particularly if involving exon 22 or nonsense mutations-, MCP/CD46 variants (38.9% to 45%) -particularly if affecting splice regions-, and cases with multiple concomitant variants (57.1%) -particularly those including CFH or a CFH-CFHR1 Hybrid (Table 2). Patients with relapse were more likely to have the presence of a complement variant (p On univariate analysis, complement gene variants (OR 4.217 95%CI 1.97-9.026; p Conclusion Relapse after eculizumab discontinuation is rare in cases with no genetic variants identified but can increase to more than 80% in high-risk subgroups. Complement genetic testing is not required for CM-TMA diagnosis or for initiation of complement inhibiting therapy; however, our results demonstrate the value of complement genetic testing when stratifying risk of patients for consideration of eculizumab discontinuation. Disclosures Sridharan: Alexion: Honoraria.
Databáze: OpenAIRE
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