Eculizumab withdrawal- safe and reasonable?

Article No. 405

20 December 2020

In the past month there has been a spate of articles on the topic of withdrawal of eculizumab treatment from aHUS patients. Much has been learned about the risk of doing so from articles such as those which have recently featured on the aHUS alliance Global Action website ( Articles 398     399  and 400).
And along comes another.
This one is from The Dutch aHUS Group. Using data from its CUREiHUS trial registry.
CUREiHUS has featured on this website before. See article HERE which explains its aims and purpose.
The publication is an interim safety study. The final report on the trial is due to be published in 2021.
In The Netherlands there has been a restrictive eculizumab treatment strategy since 2016. It is being done to provide evidence to the Dutch health policy makers that eculizumab is more economical to use than was thought, i.e.  based on label prescription dosing and duration.
The article’s title is Outcome of atypical haemolytic uraemic syndrome relapse after eculizumab withdrawal
and the full article can be read using the above link.
Although the title suggests this is about withdrawal of treatment, withdrawal in this case includes those patients who have had their doses tapered i.e given lower levels of drug and/or for longer infusion intervals.
The trial had identified 11 possible patients with an  aHUS relapse and who had returned to “intensified” eculizumab treatment.
In Article 400 , aHUS alliance Global Action listed a number of key points about treatment withdrawal that had been learned from the recent articles. Below an attempt is made to compare these with the results published in the Dutch aHUS Group’s article.
for the majority of patients treatment withdrawal is successful;( Global Action)
The article focuses on the patients who have experienced relapse. There were eleven patient relapses but the total number included in the study or who have not relapsed is not reported. From previous data provided those relapsing would be a minority of aHUS patients trialists. 
although not yet complete, data exists to make an informed decision by clinician and patient;
Although much more information now exists than was available at the start of the CUREiHUS trial, all patients participating have given “informed” consent. 
-patient understanding and attitude to risk is important;
Not addressed in this article, this is going to be a key part of the patient counselling prior to a decision particularly how to reassure those more risk averse when the risk is low.
complement genetic variant knowledge is important, not just knowing which component is  defective component but knowing the way in which it is defective
This research reports the patients genetic susceptibility variants. , 6 had known high risk CFH variants, 2 had high risk C3 variants , 1 had a moderate risk CFH variant, 1 had both a moderate risk CFH and C3 variant. 10 of the 11 suspected relapses had genetic variants and those variants are specified.
not having a genetic mutation increases the chances of no relapse remission;
Only 1 patient was idiopathic, with no known genetic reason
patient characteristics like gender and age can influence relapse, but children can successfully discontinue treatment;
8 of the patients were female. All patients were aged 26 years  or older -average age 34 years. Children not reported on.
treatment withdrawal should not be attempted through non-compliance – withdrawal should be discussed with clinicians
Not applicable as all patients were registered in an approved study on advice of clinicians. Study pre-empted a possible national health policy that of all patients were to withdrawn from treatment.
kidney function can still improve or at least  remain the same for those who relapse
8 of the 11 patients returned to on/or about baseline levels of kidney function prior to withdrawal. 2 showed no recovery ( both transplant patients) and 1 partial recovery once eculizumab was re-initiated.  At their most recent follow up, the three patients had still shown no improvement  in their kidney function, and two of them  had worsened.
Two of the other 8 patients’ kidney function had also worsened. The article delves into the special circumstances of transplant renal performance because rejection factors may also be at play and not aHUS. 
withdrawal from treatment should be considered not less than six months after initiation and not  whilst C5a-9 remains active;
The dutch protocol is the withdrawal is considered at 3 months following treatmwnt commencing. 8 of the  11 relapsing patients had a transplant, a known and constant aHUS trigger risk. 7 of the patients had not been on eculizumab, nor received prophylactic eculizumab with their transplant operation.  The other patient  had been treated with eculizumab whilst on dialysis prior to transplant. There was evidence of complement activity if not a TMA.
close monitoring from the time of  withdrawal is needed to ensure the process is safe.
It is not clear what monitoring procedures had been  put in place, if any; but overall there was an average delay of 12 days from spotting a kidney problem to  a return to  intensified eculizumab treatment. There was difference in response for those with native kidneys,  0 days delay , and those with transplants, 43 day delay on average. The range of delays was between 0 to 199 days, 
 Close monitoring in the post withdrawal period, whether carried out by clinicians or patients themselves is essential and might be life long requirement, although tapering off with time.
As is a clear care pathway to  a quick return to treatment when needed. Patients should be told of what that pathway is and assured that pre approved eculizumab will be immediately available if needed. This will be particularly important for those who have not received eculizumab before at the time of their transplant.
The conclusion from this interim safety report is that eculizumab treatment withdrawal and tapering remains a safe and reasonable thing to do. But there are specific challenges for determining aHUS relapse or rejection as the cause of an aHUS patient’s renal function deterioration which need to be addressed.
This article both confirms and adds to the growing withdrawal from treatment knowledge. The full CUREiHUS study results are awaited with much anticipation.
With STOPECU having reported and CUREiHUS results imminent that just leaves SETS- the UK’s stopping eculizumab treatment safely study outstanding and due to report in 2022.
All will make the “for the as long as is needed”  decisions even more evidenced based.

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