An important highlight of ECTRIMS this year was the data on the safety of the anti-CD20 therapies as a class. It is clear that prolonged, and sustained, B-cell depletion is not safe. Hypogammaglobulinaemia will become a problem with the risk of both common and opportunistic infections.
Stephen Hauser presented the 7-year ocrelizumab safety data and there is a clear uptick in infections in year 7. His poster also included a probable opportunistic infection signal. As of January 2019, there were six potential serious opportunistic infections that had been reported from the ocrelizumab clinical trials.
- Systemic Pasteurella infection in a patient with RMS following a cat bite (resolved)
- Multisegmental herpes zoster infection in a patient with RMS, treated with intravenous (IV) acyclovir (resolved)
- Enterovirus-induced fulminant hepatitis in a diabetic patient with RMS, resulting in liver transplant
- Candida sepsis in a patient with PPMS who had stopped OCR treatment 11 months previously and was receiving cancer chemotherapy (resolved)
- Viral meningitis in a patient with RMS, cerebrospinal fluid positive for varicella-zoster, treated with IV acyclovir (resolved)
- Herpes zoster (monodermatomal) in a patient with RMS treated for a neutropenic fever (not assessed as an opportunistic infection) (resolved)
Continuous anti-CD20 therapy prevents you from forming germinal centres (where B-cells get educated and selected to make antibodies) in lymph nodes and the spleen. In other words, the anti-CD20 therapies result in what I refer to as a functional splenectomy. This causes a scotoma, or blind spot, in your immune system which means you can’t mount a vigorous immune response to new infectious agents or vaccines. In reality, your immune responses are muted.
I highlighted in my hot topics talk on ‘DMTs in RRMS 2019: what remains to be achieved’ about the problems of having a functional splenectomy on anti-CD20 therapies. I recommended that all MSers be vaccinated with the polyvalent pneumococcal vaccine (Pneumovax) and possibly the vaccines for Haemophilus influenzae type B and Meningococcus. In addition, all MSers should have the annual flu vaccine, but with the inactivated component flu vaccine and not the live flu vaccine. In fact, MSers on anti-CD20 therapy should avoid coming into contact with recipients of the live flu vaccine in case it becomes more virulent and infects them. Please note the live flu vaccine is used in the UK in young children and it is recommended that children who have parents or family members at home on immunosuppressive therapies should not have this vaccine.
Another option open to people on longterm anti-CD20 therapy is antibiotic prophylaxis against infections with these encapsulated bacteria. I suspect this may be necessary when MSers develop hypogammaglobulinaemia and recurrent infections, similar to the NMO cases described below. It is clear that anti-CD20 therapies will need annual immunoglobulin levels measured so that if hypogammaglobulinaemia develops MSers can we warned. I suspect immunoglobulin replacement therapy will only be required in the case of recurrent infections, for example, sinus or chest infections; for example, the NMO patient on longterm rituximab who developed bronchiectasis.
I would also recommend that MSers on immunosuppressive therapies wear a medic-alert bracelet that states they are on an anti-CD20 therapy. This would help HCP in an emergency if you are too sick to provide a history. An American colleague told me about one of his ocrelizumab-treated patients, who was fit and well, who died suddenly in the emergency department after presenting with a high temperature and not feeling well. I suspect the cause of death was probably septic shock from one of the encapsulated bacteria discussed above.
The facts that (1) the clinical development programme of ocrelizumab was stopped in rheumatoid arthritis and lupus because of infections and excessive number of deaths, (2) that there is a herpes zoster signal on ocrelizumab, (3) there is blunted vaccine response, in particular to pneumococcus, and (4) ocrelizumab reduces immunoglobulin levels explains why there are infectious complications on ocrelizumab.
So if you are on rituximab, ocrelizumab, ofatumumab or any othe anti-CD20 please be vigilant and take care. On the other side of the coin are the benefits of these treatments and their ease of use and low monitoring burden. As with all DMTs the risks need to be balanced against the benefits.
Tallantyre et al. Secondary Antibody Deficiency and infection following B-cell depletion for CNS neuroinflammation. ECTRIMS Online Library. Oct 25, 2017; 199742; EP1722
B-cell depleting anti-CD20 monoclonal antibody therapies have demonstrated promising clinical efficacy in suppressing relapses in individuals with neuromyelitis optica (NMO) and multiple sclerosis (MS). However, uncertainties remain about the optimum treatment schedule. In rheumatological disease, anti-CD20 agents are most often employed for short-term induction therapy and are subsequently replaced by longer-term maintenance therapy. In contrast, repeated cycles of anti-CD20 monoclonal antibody therapy are proposed as maintenance therapy for CNS neuro-inflammatory disorders. Post-marketing surveillance will be essential to fully uncover the long-term safety profile of repeated B-cell depletion. Hypogammaglobulinaemia is a recognised consequence in a proportion of patients treated with medium- to long-term B-cell therapy and may play a role in the increased incidence of infection observed in the anti-CD20 arms of treatment trials. We report 5 cases of serious infection associated with hypogammaglobulinaemia occurring in patients receiving rituximab for NMO. The cases were all female, all had low IgG with variable reductions in IgM and IgA. The cases had a mean treatment duration of 3.1 years, but not all cases had had extensive exposure (treatment duration range 0.5 – 6.2y). We review the evidence relating to hypogammaglobulinaemia following anti-CD20 treatment for neuroinflammatory disorders and propose an algorithm for monitoring and treatment of this recognised complication.
CoI: multiple
Prof G, you recommend all pwMS wear a alert bracelet, may I suggest everyone that is on medication who has an iPhone completes the emergency details on their phone. This information is then available to emergency services and HCP even when the phone is locked. I have used this many times.
The following site gives you information about who should use a medic alert bracelet in the US: https://www.americanmedical-id.com/faq
It is not about having MS, but being on immunosuppressive therapies.
As someone who has received Alemtuzuab I wear a Medic Alert bracelet. This lets all HCPs know the blood transfusion requirement and provides the phone numbe that allows them to access my all pertinent details, including a copy of my ADRT.
Had my bracelet over two years now, wearing it constantly, so don’t even notice it’s there anymore. What is, is my peace of mind, as don’t always have phone on me.
Recommend anyone with MS takes a look at the website – MA is recognised by the NHS.
What effect does low IgG have for people prone to anaphylactic shock?
IgG levels per se are not related to anaphylaxis risk which is mainly driven by IgE antibodies. You only need very small numbers of IgE levels to cause anaphylaxis in relation to an allergen.
How about less frequent Ocrevus dosing after two years? Switching after four years to cladribine? What is the age when the immunosupressives aren’t needed anymore? How does this affect the PPMS patients?
This is why we have recommended the Adaptive Dosing Study or ADIOS study.
This raises a few concerns
1. Do emergency departments know what anti-CD20 means?
2. What level of IgG is considered too low?
3. Will IVIG treatment solve the problem?
4. Is there any long-term way out for patients on anti-CD20?
It does require re-dosing at intervals (in my experience). It is not an induction treatment
No I would not expect them to know what anti CD 20 means. Good point.
And yes please state what level of IgG is too low as my nurse told me my level was below normal two weeks ago but they went ahead with the ocrevus infusion. She said she would mention it to my neuro but i never heard any more…
You may find this review on ‘Immunoglobulin replacement therapy in secondary hypogammaglobulinemia‘ helpful.
How low an IgG level will be to trigger replacement therapy will depend on whether or not the low levels are associated with infections. I doubt immunologists would initiate immunoglobulin replacement therapy in MSers who have not had any infections. The review article below refers to 6-monthly monitoring but doesn’t make any specific recommendations on when to start immunoglobulin replacement therapy.
1. Do emergency departments know what anti-CD20 means? YES, anti-CD20 therapy has been around for decades.
2. What level of IgG is considered too low? This will depend on whether or not the low levels are associated with infections. I doubt immunologists would initiate immunoglobulin replacement therapy in MSers who have not had infections.
3. Will IVIG treatment solve the problem? Possibly, IVIG is used in genetic and other forms of hypogammaglobinaemia with good results.
4. Is there any long-term way out for patients on anti-CD20? Yes, please read my post on the ADIOS study. The Swedes are testing adaptive dosing already.
Which make natalizumab the unquestionable champion of the risk/benefit for JCV- negative RRMSers when compared to ther high efficacy DMTs in the UK (alemtuzumab, ocrelizumab, cladribine and HSCT)
How to figure cladribine should be in that group of poor risk/benefit?
Not sure what you mean
Sorry, should have said… not sure why the poster grouped cladribine with alemtuzumab, ocrelizumab and HSCT in terms of risk. While natalizumab is definitely high efficacy and for JCV -ve, pretty low risk cladribine is high efficacy (maybe not as high as natalizumab, but I wouldn’t have put it in the same risk category as the other 3.
Once the cells have gone they have gone using the above 4, so if need to fight infection with those cells. However ocrelizumab is in a special category because if those cells are B cells and express CD20 then they have no way back, for alemtuzumab and cladribine and HSCT the immune depleter has gone within a day to a couple of weeks and so if virus comes the immune cells can respond, so a low risk of PML. However, ocrelizumab is capable of depleting for at least 5-6 half-lives (the time taken for half the drug to go. The half life is about 30 days so getting every 6 months you are permanently depleted.
For some reason I can’t reply to MDs reply below… but in response to his reply, yes exactly, so why would Cladribine be in the same risk category as Ocrelizumab, or even HSCT (I took the original poster t be talking holistically about risk/benefit, not just PML).
I was not talking about PML but used it as an example
Yes so why group cladribine with alemtuzumab, ocrelizumab and HSCT. Ocrelizumab takes out CD20 B cells, alemtuzumab and HSCT each have risks all of their own, so why would you group cladribine with them in risk/efficacy analysis.
I feel like a bloody Guinea pig in a cage being observed with these revelations. It makes no sense lemtrada was changed to a third line drug and now this comes out about ocrelizumab and it’s acceptable?! I’m horrified. Knew my instincts about starting it were right. Definitely will not be continuing this drug with these risks.
How on Earth do I know if someone has just had a live flu vaccine for example and that I should stay away from them?
“On the other side of the coin are the benefits of these treatments and their ease of use and low monitoring burden. As with all DMTs the risks need to be balanced against the benefits.” You’re having a laugh? I’m a mother with a family to take care of and a future to look forward to.
The infection risk will increase with time. The MSers on anti-CD20 therapies as part of clinical trial programmes are the guinea pigs and not you.
But it is true, is it not, that the full picture of a therapy’s side effects – and benefits – only emerge once the therapy is released upon a large number of patients?
Yes spot on. This is why companies have to put a system in place to monitor adverse events.
Will any of this come out as official advice to those of us who have just started ocrelizumab? I have children who will be due the flu vaccine soon and it would be helpful to have something to point to if I don’t consent and make arrangements for them to have the alternative inactive version.
Unfortunately, my disability following treatment with Cladribine has worsened even further to the extent I now need to use a wheelchair regularly outdoors and reading this post makes me wonder if it would be wiser to go on a safer maintenance therapy such as Teriflunemide rather than Ocrelizumab for the next DMT to try to halt the deterioration? Or take nothing at all bearing in mind I am over 50???
Sorry to hear your disability has worsened, did you ask to see if you deplete following treatment, it seems some people do not respond.
We presented this at ECTRIMS 2019. However no DMT is 100% effective not even HSCT. Whilst I can’t comment on where to go next. There are big differences in efficicy between these types of treatment
I got a long email from Roche today in relation to this post. I am surprised they bother reading this blog.
Roche just doesn’t get the concept of ‘Known-Unknowns’ and black swan events. It’s as if they are data junkies feeding on their own cool-aid. The pharmacovigilance data they get is out of date the day it arrives on their servers. It is hard to believe that the email I received is from a company that canned the SLE and RA ocrelizumab programmes because of an infection signal and that was at a lower dose of ocrelizumab than we are now using in MS.
Roche/Genentech have mountains of rituximab data to feed on and learn from and understand the immunology of longterm B-cell depletion in humans. Do they really think indefinite B-cell depletion won’t come without an infection risk? How can any company that presents data that MSers on ocrelizumab can’t mount an appropriate immune response to pneumococcal vaccine ignore, or play down, the infection risk to encapsulated bacteria?
Clearly, Roche staff don’t look after patients with MS and have no idea what it is like to counsel patients about the risks and benefits of DMTs. Being transparent and honest is the only way to approach the risks and benefits of treatment; this includes ‘known-unknowns’, which this is post is trying to address.
On the other side of the coin is the benefits of anti-CD20 therapy. In the context of active MS, they probably outweigh the risks of the ‘known-unknowns’; at least in the short- to intermediate-term. With regards to the long-term, only time will tell.
Hi Prof G.
Sorry for my English, french guy.
While a pretty big fan of your blog posts and work in general (definitely convince that relapse and MRI T1/T2 are only the manifestations of something really more profound in the body), I am a bit lost right now :
– On one hand, you are one of the profound defenders of the Highly Active DMT (like ocrelizumab) as first-line.
– But, on the other hand, you argue here that prolonged anti CD 20 therapies are not safe. I have been on Tecfidera since my diagnostic one year ago and I am NEDA with it (and EDSS at 0). Despite being NEDA, my neuro (who have pretty much the same convictions than you) proposed me ocrelizumab last week because she knows I want to stop MS as hard as possible.
So, what should I (we) do?
Anti-CD20 therapies are a game-changer in that many more people will be treated early with highly effective therapies. They are also relatively safe in the short to intermediate-term. All I am concerned about is the long-term safety of prolonged and profound B cell depletion. It is best to acknowledge this risk and deal with it before it becomes a major problem. One way of addressing is this is via our ADIOS trial, optimising vaccinations before starting anti-CD20 therapy and monitoring and managing the hypogammaglobulinaemia when it emerges. All DMTs have risks and most of these risks can be derisked, which is a good thing.
What I am trying to tell the companies that market anti-CD20 therapies in MS that they need to avoid the Ostrich Syndrome (head in the sand) and proactively manage and study the risks of prolonged B-cell depletion, otherwise the problem will come back and bite them (known-unknowns are vicious).
Another point; my longterm safety concerns are not going to change my use of anti-CD20 therapies only how I monitor and deal with the potential long-term complications.
Thank Professor for your answer. Last thing : you often say that highly active DMT as first line is only for “active MS” and not for “non active MS”. But I am not sure to understand what can be really considered as “non active MS”. Being NEDA on moderate or plateforme DMT has to be considered as “non active MS” ? According to what you argue (NEDA does not mean that there is no organs damages, brink shrinkage, etc.) I do not understand when it is really possible to affirm that the MS is “non active” ? So why doing this distinction between active and non active ?
Yes, this term active MS is a difficult one and refers to the Lublin definition. I agree with you many people with inactive MS (no relapses or focal MRI activity), probably have active MS under the microscope and they often know it as they are deteriorating despite being NEDA-2. We need a campaign to get rid of this classification system, but before doing this we need data so as to come up with an alternative definition that can be used clinically.