Complement gene variant effect on relapse of complement-mediated thrombotic microangiopathy after eculizumab
Aldo A Acosta-Medina1,2, Ann M Moyer3, Ronald S Go1
1Division of Hematology, Mayo Clinic, Rochester, MN.
Blood Advances
|May 9, 2022
Summary
Eculizumab discontinuation for complement-mediated thrombotic microangiopathy (CM-TMA) is feasible, but genetic variants in complement genes like CFH and MCP/CD46 increase relapse risk. Careful patient selection is crucial for safe eculizumab withdrawal.
Area of Science:
- Nephrology
- Immunology
- Genetics
Background:
- Eculizumab is effective for complement-mediated thrombotic microangiopathy (CM-TMA), a condition also known as atypical hemolytic uremic syndrome.
- While lifelong eculizumab therapy was considered, patient relapse after discontinuation is not universal, necessitating identification of recurrence risk factors.
- Data on genetic risk factors for CM-TMA relapse after eculizumab withdrawal remain limited.
Purpose of the Study:
- To systematically review the literature and assess the role of complement genetic variants in predicting relapse after eculizumab discontinuation in CM-TMA patients.
- To identify specific genetic variants and clinical factors associated with an increased risk of CM-TMA recurrence post-eculizumab withdrawal.
Main Methods:
- A systematic literature review of CM-TMA patients undergoing eculizumab withdrawal, published before January 1, 2021.
- Inclusion criteria required follow-up data post-withdrawal and complement genetic testing.
- Data from 280 patients across 40 publications were analyzed, focusing on complement gene variants and relapse rates.
Main Results:
- Complement genetic variants were identified in 60% of patients, most commonly in CFH and MCP/CD46.
- The overall relapse rate after eculizumab discontinuation was 29.6%.
- Relapse was significantly associated with the presence of likely pathogenic/pathogenic variants (P < .001), variants of uncertain significance (P < .001), renal allograft presence (P = .009), younger age (P = .029), and variants in CFH, MCP/CD46, or C3.
Conclusions:
- Eculizumab discontinuation can be a viable strategy for select CM-TMA patients.
- Patients with specific complement genetic variants (CFH, MCP/CD46, C3), a renal allograft, or younger age face a higher risk of relapse.
- Caution is advised when considering eculizumab withdrawal in patients with identified risk factors, particularly those with MCP/CD46 variants.
