Stopping eculizumab in patients
Eculizumab is licenced for long term treatment of complement-mediated aHUS with withdrawal only considered if medically justified as described in the clinical scenarios below.
The single nucleotide polymorphisms (SNPs) in C5 (p.R885H; p.R885C) prevents eculizumab binding to C5 and blockade of the terminal pathway. If routine screening identifies either of these SNPs Eculizumab must be stopped and plasma exchange recommenced.
Recently genetic causes of Eculizumab no- responsive aHUS have been identified. Mutations in DGKE, MMACHC and INF2 predict Eculizumab non-response and will require Eculizumab withdrawal. Alternative treatment strategies will have to be considered.
There is currently no evidence as to the efficacy of Eculizumab in secondary TMAs or STEC–HUS and consequently NHS England do not fund its use in this situation. The decision to initiate Eculizumab may be made prior to the availability of diagnostic tests: this is to maximise clinical efficacy in patients who subsequently are confirmed to have primary complement mediated aHUS. Identification of an alternative diagnosis (such as secondary TMAs or STEC-HUS) will necessitate withdrawal.
In patients who present late in the course of complement-mediated aHUS, renal recovery may not be seen. Evidence of renal recovery following Eculizumab therapy has been seen even following 3 months of renal replacement therapy. For this reason a course of 3 months is usually given prior to review for signs of renal recovery. Lack of evidence of renal recovery at this point should necessitate discussion with the national centre as to whether therapy should be continued. This is to minimise the risk of adverse events, in particular meningococcal infection.
Withdrawal of Eculizumab in patients with aHUS
Eculizumab is licenced for the treatment of complement-mediated aHUS. The current licence is for continuous use of Eculizumab once treatment is initiated. This recommendation is based on:
- the known natural history of aHUS
- case reports of recurrence of thrombotic microangiopathy after a short course of treatment with Eculizumab
- recurrence of disease in patients who did not enter the extension phase of the clinical trials of Eculizumab in aHUS
However, there has been no systematic assessment of withdrawal of Eculizumab after control of active thrombotic microangiopathy. Therefore the recommendation to continued use is based on limited evidence and the need for ongoing research is a high priority.
To meet this high priority, SETS-aHUS has been designed in order to broaden the evidence base for treatment options once control of active TMA has been acheived with eculizumab.
SETS-aHUS hopes to provide evidence for an alternative strategy for treatment of aHUS based on monitoring and treatment re-introduction rather than continuous Eculizumab treatment. We predict that:
● Possibly over half of patients receiving maintenance Eculizumab treatment could be doing so unnecessarily but there is currently a lack of evidence to support this.
● Withdrawal of drug could lead to a reduction in the burden of treatment (intravenous injections every 2 weeks).
● The potential complications associated with Eculizumab use could be avoided.
● A system of surveillance will be needed to detect relapse early for rapid re-initiation of treatment to avoid complications associated with untreated relapse.
Further details of the SETS-aHUS trial that is opening in 2018 can be found here.
Recommended protocol following decision to withdraw eculizumab with aHUS
Outside the context of a clinical trial the decision to withdraw Eculizumab may be made by the clinical team responsible for the care of the patient in collaboration with the National Centre. This suggested protocol is designed to support the clinical team after this decision has been made.
1. The decision to stop Eculizumab should be made on an individual patient basis considering factors that will influence the likelihood and consequences of a relapse:
- The genetic / autoantibody status of the patient
- The severity of the initial presentation
- A previous history of relapsing TMA causing organ failure, for example transplant loss
2. Eculizumab should be continued for 6 months before withdrawal is considered. There is no evidence to support a recommendation of 6 months treatment. However it is known that there is a high risk of recurrence in patients treated with a short course of Eculizumab, suggesting that the trigger that precipitated the treated TMA may persist. In addition, after transplantation most recurrences of aHUS (>70%) occur within the first 6 months.
3. Patients should be monitored closely after withdrawal. This should be most intensive immediately after withdrawal as it is not known whether disease is controlled or in remission. However, there is no evidence to inform the frequency of testing, therefore the following is a suggested monitoring regime. In some patients, particularly after transplant, there is limited systemic evidence of a recurrent renal thrombotic microangiopathy (platelet, LDH, blood film and haptoglobins) and the only indication is a deterioration in renal function.
|Time since last Eculizumab dose||Suggested monitoring|
|Week 0-2||Baseline assessment: FBC, LDH, U&Es, bilirubin, haptoglobin|
|Week 2-6||Weekly FBC, LDH, U&Es, blood film, bilirubin, haptoglobin|
|After week 6||Fortnightly FBC, LDH, U&Es, blood film, bilirubin, haptoglobin**Replacing fortnightly Eculizumab infusions|
Monitoring of patients following withdrawal of eculizumab
4. Home monitoring with thrice weekly urinalysis is recommended. The patient is advised to return to hospital for evaluation if microscopic haematuria develops.
5. Patients should be informed about potential symptoms of relapse and advised to seek medical advice if these occur. They should also have the patient alert card (available from the NRCTC) to present to medical staff.
6. Antibiotic prophylaxis should be continued for 8 weeks after the last dose of Eculizumab.
7. Eculizumab should be available to treat relapse.