Researchers from France observed an over-representation of CFH variants in patients with paroxysmal nocturnal hemoglobinuria (PNH) and found that patients with such variants were more likely to be transfusion-dependent when receiving eculizumab (Soliris®).

Next-generation sequencing unveiled rare variants in CFH, C3, and CFI, in 10.7%, 4.8%, and 3.6% of PNH patients, respectively. CFH variants, but not C3 and CFI variants, were significantly over-represented among PNH patients compared to either healthy controls or public data. Patients with CFH variants were older at the time of diagnosis.

Moreover, univariate analysis showed that CFH variants, as well as transfusion requirements prior to eculizumab, were associated with transfusion dependency 6 months after eculizumab initiation.

“Patients bearing these CFH variants may respond differently to proximal complement inhibitors. Screening for CFH variants may help clinicians understand the suboptimal response to terminal inhibition and possibly adapt treatment with new proximal complement inhibitors,” the researchers wrote in Blood.

Almost all (8 out of 9) patients bearing CFH variants received transfusion after the eculizumab loading dose, and 2 developed thromboses. None of these patients had severe aplastic anemia during follow-up (median follow-up, 5.8 years).

Three out of the 8 rare CFH variants identified in the study were pathogenic and associated with alternative pathway deregulation. These 3 patients and 1 patient bearing a CFI pathogenic variant were transfusion-dependent at 6 months after eculizumab initiation.

Furthermore, 3 previously unstudied CFH variants may affect FH-cell binding, but additional functional studies are needed to understand the relevance of CFH variants in PNH pathogenesis.

Prata et al screened 84 PNH patients treated with eculizumab for at least 6 months for genetic variants in CFH, CFI, and C3. They highlighted the retrospective design, possible referral bias, and lack of subgroup or multivariate analyses as major limitations of the study.

Reference

Prata PH, Galimard J-E, Sicre de Fontbrune F, et al. Rare germline complement factor H variants in patients with paroxysmal nocturnal hemoglobinuria. Blood. Published online January 13, 2023. doi:10.1182/blood.2022017019