Specific aHUS Mutations Affect Relapse Risk After Soliris Discontinued, Data Show

The specific disease-causing mutations in a person with atypical hemolytic uremic syndrome (aHUS) affect their individual risk of relapse after discontinuing treatment with Soliris (eculizumab), new research shows.

aHUS is characterized by abnormal activity of the complement system, a group of immune proteins in the blood. Activation of this system can help fight off infections, but the abnormal activation that occurs in aHUS can lead to damage to blood vessels and organs.

While genetics alone isn’t enough to cause aHUS — environmental factors also play a role — mutations in certain complement-associated genes can increase the risk of aHUS.

Soliris is a medication developed by Alexion to treat aHUS, and works by blocking the activity of the complement system. It is a fairly new medication, with researchers still determining the optimal dosing schedule and which patients can safely discontinue treatment.

Discontinuing Soliris leads to an aHUS relapse in some people, but not others. Two recent studies, presented at this year’s American Society of Hematology Annual Meeting and Exposition, attempted to identify factors that could increase the risk of relapse.

Knowing these factors would help healthcare providers and patients make more informed decisions about treatment.

In one study, “Determination of Relapse Risk By Complement Gene Variants after Eculizumab Discontinuation in Complement-Mediated Thrombotic Microangiopathy: A Retrospective Review,” researchers from the Mayo Clinic and other institutions examined published scientific literature for people with aHUS who had discontinued Soliris treatment.

They identified 194 patients, 56 (28.9%) of whom relapsed after discontinuation. These individuals who relapsed were significantly younger than those who didn’t (mean age 22.4 vs. 32.33 years) and were more likely to have had previous aHUS events.

Of the analyzed patients, 118 had a detected complement-associated genetic mutation. After accounting for confounding factors, statistical analyses indicated that the risk of relapse was approximately 4.48 times higher in people with a complement mutation than in those without such mutations.

The highest risk was found for individuals with mutations in the gene CFH, who were about three times more likely to relapse after Soliris discontinuation compared with those without these mutations.

Furthermore, relapse risk appeared to differ based on specific mutations within the same gene. For example, relapses occurred in five out of six people (83%) with a mutation in part of the CFH gene called exon 22. In contrast, relapses happened in one out of three people (33%) with mutations in exon 18.

“Relapse after eculizumab [Soliris] discontinuation is rare in cases with no genetic variants identified but can increase to more than 80% in high-risk subgroup,” the researchers concluded. “Our results demonstrate the value of complement genetic testing when stratifying risk of patients for consideration of eculizumab discontinuation.”

A separate study, “Eculizumab discontinuation in children and adults with atypical haemolytic uremic syndrome: a prospective multicentric study,” also assessed aHUS relapse risk in a group of 55 aHUS patients in France who discontinued Soliris after participating in a clinical trial (NCT02574403). Of the 55 patients, 28 had mutations in complement genes.

A multivariate analysis showed that the risk of relapse was significantly higher among individuals with a complement mutation. Being female was also linked to a higher risk of relapse, but whether or not an individual needed dialysis for prior aHUS episodes was not associated with relapse risk following Soliris discontinuation.

“A strategy of eculizumab discontinuation in aHUS patients based on complement genetics is reasonable and safe,” the researchers concluded. “It improves the management and quality of life of a sizeable proportion of aHUS patients while reducing the cost of treatment.”

Collectively, these findings support the notion that an individual’s genetics can affect their risk of aHUS relapse after discontinuing Soliris.