Current evidence on the discontinuation of eculizumab in patients with atypical haemolytic uraemic syndrome

Abstract

Background. Atypical haemolytic uraemic syndrome (aHUS) is a rare, life-threatening disorder for which eculizumab is the only approved treatment. Life-long treatment is indicated; however, eculizumab discontinuation has been reported. Methods. Unpublished authors’ cases and published cases of eculizumab discontinuation are reviewed. We also report eculizumab discontinuation data from five clinical trials, plus long-term extensions and the global aHUS Registry. Results. Of six unpublished authors’ cases, four patients had a subsequent thrombotic microangiopathy (TMA) manifestation within 12 months of discontinuation. Case reports of 52 patients discontinuing eculizumab were identified; 16 (31%) had a subsequent TMA manifestation. In eculizumab clinical trials, 61/130 patients discontinued treatment between 2008 and 2015. Median follow-up post-discontinuation was 24 weeks and during this time 12 patients experienced 15 severe TMA complications and 9 of the 12 patients restarted eculizumab. TMA complications occurred irrespective of identified genetic mutation, high risk polymorphism or auto-antibody. In the global aHUS Registry, 76/296 patients (26%) discontinued, 12 (16%) of whom restarted. Conclusions. The currently available evidence suggests TMA manifestations following discontinuation are unpredictable in both severity and timing. For evidence-based decision making, better risk stratification and valid monitoring strategies are required. Until these exist, the risk versus benefit of eculizumab discontinuation, either in specific clinical situations or at selected time points, should include consideration of the risk of further TMA manifestations.

Atypical hemolytic uremic syndrome: a syndrome in need of clarity

“…Eculizimab was immediately resumed in all three patients and all patients completely recovered [85]. Data reported from the clinical trials of eculizimab reveal a recurrence rate following discontinuation of therapy of 20% (12/61 patients) [86]. This paper also reported on patients registered in the global aHUS registry.…”

“…This paper also reported on patients registered in the global aHUS registry. In patients <18 years of age, 28 patients (24%) had eculizimab discontinued and recurrence resulted in reinitiation of eculizimab in 7 patients (25%), whereas 48 adult patients (27%) discontinued therapy, with resumption of eculizimab in 5 patients (10%) [86]. Recurrence occurred in 16 of 52 patients (31%) in published case reports reviewed by the authors.…”

“…'Classical' or primary aHUS is defined as a primary dysregulation of AP activation. Although this suggests the need for long-term therapy in these patients, as previously described, there are presently limited data to assess in whom eculizimab therapy may be stopped [74,85,86]. In contrast, the therapy for secondary aHUS should be required only until the etiology for the direct Atypical hemolytic uremic syndrome | 343 endothelial cell damage and marked complement activation has resolved.…”

When to Stop Eculizumab in Complement-Mediated Thrombotic Microangiopathies

“…This concern is primarily driven by cost, as high as $700,000 USD per patient per year [16,17]. The opposing argument to continue eculizumab indefinitely is a relatively high rate of TMA relapse after therapy discontinuation, outlined in this review [18]. The ability to identify patients with a low risk of TMA relapse following eculizumab discontinuation is an attractive prospect in these diseases.…”

“…This entity, aHUS, is caused by the unregulated activation of the complement system due to inherited (genetic) or acquired (autoimmune) disruption of the alternate complement pathway [2,18]. Under normal conditions, the alternate complement pathway is constitutively active leading to spontaneous hydrolysis of C3 and deposition of the product C3b on multiple host cells in contact with plasma.…”