Discontinuing Eculizumab is Safe and Feasible in Patients With Atypical Hemolytic Uremic Syndrome

Discontinuation of anti-C5 agent eculizumab is feasible and safe in patients with atypical hemolytic uremic syndrome (aHUS), particularly in the 40% to 60% of patients with aHUS who have no detected complement gene variants, according to a study published in Blood.

These findings, according to lead author Fadi Fakhouri, MD, PhD, of Lausanne University Hospital in Switzerland, provide “guidance for clinicians and patients regarding the debated issue of anti-C5 drug discontinuation in aHUS patients, which can hopefully be helpful for achieving an optimal use of an efficacious and costly treatment.”

In this prospective, open-label study, Dr. Fakhouri and colleagues enrolled 57 children and adults who had received at least six months of treatment with eculizumab for primary aHUS. The primary endpoint of the study was aHUS relapse during a two-year follow-up period after eculizumab discontinuation. Patients were assessed by their treating nephrologist at least once per month for three months, then every three months thereafter.

Prior to enrollment, patients were screened for variants and complex rearrangements in complement factor H (CFH), complement factor I (CFI), membrane-cofactor protein (MCP), C3, complement factor B (CFB), thrombomodulin, and diacylglycerol kinase epsilon (DGKe) genes. The researchers also assessed plasma C3, C4, CH50, factor H and I, soluble C5b-9 (sC5b-9) and CD46 expression at baseline, within 14 days after the last eculizumab infusion, and at one, three, six, nine, 12, 18, and 24 months.

The mean duration of eculizumab treatment for the overall population was 16.5 months. A total of 28 patients (51%) had a rare variant in at least one complement gene, including MCP (n=12), CFH (n=6), CFI (n=6), C3 gene (n=2), and combined variants in the C3/CFI (n=1) and MCP/CFI genes (n=1).

More than one-third of patients had chronic kidney disease in stage 3 (30%) or stage 4 (7%) at the time of eculizumab discontinuation.

During a mean follow-up period of 19.8 months, 13 patients (23%) had an aHUS relapse. The average time between treatment discontinuation and aHUS relapse in both children and adults was 10.2 months.

The researchers performed a multivariable analysis to determine patient and disease characteristics associated with an increased risk of aHUS relapse (TABLE). These included:

  • female gender (odds ratio [OR] = 4.21)
  • the presence of a rare complement gene variant (OR=16.20)

Increased sC5b-9 plasma level at the time of eculizumab discontinuation was also associated with an increased risk of aHUS relapse in all patients (p=0.02), as well as in carriers of complement gene rare variants (p=0.02). In addition, a plasma sC5b-9 level ≥300 ng/mL at time of study enrollment was associated with aHUS relapse following treatment discontinuation (OR=20.96).

In contrast, requirement for dialysis during episodes of acute aHUS prior to eculizumab discontinuation was associated with a decreased risk (OR=0.17).

Among the 13 patients who experienced a relapse and had restarted treatment with eculizumab, 11 regained their baseline renal function. Also, two of the 13 patients with relapse experienced worsening of their pre-existing chronic kidney disease, and one patient experienced progression to end-stage renal disease.

The researchers noted that it was feasible for patients to discontinue eculizumab treatment for an extended period – a median of 23.6 months in children with aHUS and 24 months in adults with aHUS.

“This prospective study indicates that a strategy of eculizumab discontinuation in aHUS patients based on complement genetics is reasonable and safe,” they concluded. “Such strategy undoubtedly improves the management and quality of life of a sizeable proportion of aHUS patients.” Noting that eculizumab is an expensive therapy, the authors added that discontinuation of therapy resulted in an estimated total costs savings of approximately 32 million euros, or 39 million dollars, over two years.

“However, it needs to be stressed that patients from the present study, except one, had received eculizumab treatment for at least three to six months, and achieved a maximal kidney function recovery before inclusion,” the researchers wrote, noting a potential limitation of the study’s implications. Participants also were closely monitored after treatment cessation during follow-up.

“[The findings from this trial] can hopefully be helpful for achieving an optimal use of an efficacious and costly treatment.”

—Fadi Fakhouri, MD, PhD

Other limitations of this study included the small number of patients and the relatively short follow-up duration. “The long-term impact of repeated relapses on renal function remains unknown,” added Dr. Fakhouri. “Finally, the clinical usefulness of a biomarker, like sC5b-9, for the assessment of the risk of aHUS relapse after anti-C5 drug discontinuation requires further evaluation in larger cohorts.”

Study authors reported no relevant conflicts of interest.


Fakhouri F, Fila M, Hummel A, et al. Eculizumab discontinuation in children and adults with atypical haemolytic uremic syndrome: a prospective multicentric study. Blood. 2020 December 3. [Epub ahead of print]