Complement gene variant effect on relapse of complement-mediated thrombotic microangiopathy after eculizumab cessation

Abstract

Eculizumab is effective for complement-mediated thrombotic microangiopathy (CM-TMA), also known as atypical hemolytic uremic syndrome. Although lifelong therapy had been suggested, discontinuation does not universally lead to relapse. Comprehensive data evaluating risk factors for recurrence following discontinuation is limited. Our aim was to systematically review available literature assessing the role of complement genetic variants in this setting. Reports on CM-TMA and eculizumab withdrawal published before January 1st, 2021 were included. Key reasons for patient exclusion were no follow-up after drug withdrawal and patients lacking complement genetic testing. Two-hundred and eighty patients from 40 publications were included. Median age was 28 years-old and 25 patients had a known history of renal transplant. Complement genetic variants were identified in 60%, most commonly in CFH (n=59) and MCP/CD46 (n=38). Of patients with a complement gene variant, 51.3% had ≥1 likely pathogenic/pathogenic variant, while the remaining had variants of uncertain significance. Overall relapse rate after therapy discontinuation was 29.6%. Relapse rate was highest among patients with CFH variants and MCP/CD46 variants in canonical splice regions. Variants of uncertain significance (p<0.001) and likely pathogenic/pathogenic variants (p<0.001) were associated with increased relapse. Presence of a renal allograft (p=0.009); decreasing age (p=0.029); and detection of variants in CFH (p<0.001), MCP/CD46 (p<0.001) or C3 (p<0.001) were all independently associated with relapse after eculizumab discontinuation. Eculizumab discontinuation is appropriate in specific patients with CM-TMA. Caution should be exerted when attempting such a strategy in patients with high risk of recurrence, including a subgroup of patients with MCP/CD46 variants.

Eculizumab-Every Fifteen Days Forever?

“…Regardless of the above considerations, the new study, along with the previously published retrospective and prospective studies, 6 , 7 , 8 , 9 , S1-S4 show that even in the high-risk group of aHUS patients with pathogenic or likely pathogenic complement gene variants, 50% to 75% of patients will not relapse.…”

“…However, the risk of potentially fatal meningococcal infections, the need for repeated intravenous infusions, and the extremely high cost of the drug have provided the urgent need to find ways to discontinue treatment after achieving stable clinical remission. 6 …”

“…Case reports and series, as well as retrospective studies, have shown that eculizumab withdrawal may be feasible, but have also highlighted the risk of relapses, particularly in patients with complement gene variants. 6 A recent systematic review of the literature that includes 280 aHUS patients from 40 publications reports a 29.6% relapse rate after therapy discontinuation. 6 Decreasing age, the presence of a renal allograft, and the detection of rare variants in factor H, membrane-cofactor protein, or C3 genes were all independently associated with relapse.…”

“… 6 A recent systematic review of the literature that includes 280 aHUS patients from 40 publications reports a 29.6% relapse rate after therapy discontinuation. 6 Decreasing age, the presence of a renal allograft, and the detection of rare variants in factor H, membrane-cofactor protein, or C3 genes were all independently associated with relapse.…”

Differentiating and Managing Rare Thrombotic Microangiopathies During Pregnancy and Postpartum

“…Two recent studies and a systematic review of the literature demonstrated eculizumab discontinuation may be safe in those who achieved hematologic remission with stable kidney function for at least 3-6 months, based on using a monitoring protocol and absence of specific complement gene variants. [115][116][117] In 2019, ravulizumab, a long-acting version of eculizumab, was approved for CM-HUS, which extended the maintenance dosing to every 8 weeks. 118 In the pivotal trial that led to its approval, eight patients developed CM-HUS postpartum.…”