Case study: switching from ocrelizumab to HSCT

This patient wants to go beyond no inflammatory disease activity and does not want to be immunosuppressed long-term. Should he have HSCT or will alemtuzumab achieve what he wants?

Photo by National Cancer Institute on Unsplash

Case Study

I am 39 and actively employed. In 2015 when I was 33 I presented with paresthesia in both legs due to a spinal cord lesion at T5. My brain MRI was reported as being normal. I was subsequently given a diagnosis of CIS. Four and a half years later (September 2019) I had a return of numbness in both feet. Further lesions were revealed at T9 and T11, there was no change in the brain MRI. A lumbar puncture in May 2020 resulted in a diagnosis of MS. However, at this stage, I had suffered a further relapse. I started ocrelizumab in July 2020 and had further courses in Feb 2021 and August 2021. I had 2 shots of the Oxford-AstraZeneca COVID-19 vaccine between my February and August ocrelizumab infusions but contracted COVID-19 in July. I feel that I have only just about recovered from COVID-19. 

I am scheduled to go to Moscow for HSCT in November. Should I delay this? 

Image from Wikipedia

Prof G’s Opinion

There are no right or wrong answers. As always I would recommend answering the following 12 questions:

1. What is multiple sclerosis (MS)?

2. Am I sure that I have MS?

3. What type of MS do I have?
   
   I am going to assume for the purposes of this case study that this patient knows what MS is, he has been adequately diagnosed and based on what he has told me has relapse-onset MS.
   

1. What prognostic group do I fall into?
   
   I would say he falls into at least the intermediate or poor prognostic group, i.e. he is male, with spinal cord disease and a positive CSF. In my clinic, I would want to get a lot more baseline information to see if the profile can be further defined. Based on the limited information given I would favour a high-efficacy DMT.
   

2. What is the risk of not being treated with a disease-modifying therapy (DMT)?
   
   High due to his baseline profile. This is not someone I would feel comfortable with watchful waiting. The fact that he had spinal cord CIS and was not offered treatment is questionable. In an ideal world, he should have had a lumbar puncture and CSF examined in 2015 and possibly offered treatment then. Most MSologists now actively treat CIS. DMTs in CIS is about prevention; preventing further damage and maximising outcomes for the long term.
   

3. Do I have active MS?
   
   Based on the fact that he has been treated with ocrelizumab it is likely this patient’s MS is inactive. However, to be confident I would need to see his serial MRI scans and possibly do a lumbar puncture to see if he has raised neurofilament levels. In terms of NHS England’s treatment algorithm, it would be important to find out if this patient has active MS to be able to offer him escalation therapy above ocrelizumab (anti-CD20).
   

4. Am I eligible for treatment with a DMT?
   
   Yes, he is eligible for treatment and is on one of our platform/escalation therapies. I personally don’t think anti-CD20 therapy is at the top of the DMT ladder in terms of efficacy. Based on end-organ damage (brain volume loss) and preventing secondary progressive MS and targeting smouldering MS I think alemtuzumab and HSCT are superior to anti-CD20 therapies. However, both alemtuzumab and HSCT come with risks that need to be personalised. It is clear that this patient has made arrangements to be treated abroad with HSCT. I understand why, because he won’t be eligible for HSCT in the UK. In London, you have to fail at least two DMTs one of which has to be a high efficacy DMT to be eligible for HSCT. However, there is a loophole in those patients with early progressive MS don’t necessarily have to fail two DMTs. So if this patient has any evidence of worsening disability documented he may be able to be treated with AHSCT in one of the London BMT Units for early progressive MS.
   

5. What is the difference between a maintenance/escalation DMT and an IRT (immune reconstitution therapy)?
   
   In my opinion, IRTs are the only treatments that are addressing the cause of MS and hence have the potential to cure MS. We will know in the near future how many pwMS in very long-term remission post -alemtuzumab, -HSCT or -cladribine are truly MS free.
   
   The mortality associated with HSCT makes people shudder. Although the risk of dying from one of the complications of HSCT is quoted as being between 1 in 333 (0.3%) to 1 in 50 (2%) many pwMS are prepared to take this risk in the UK or abroad. Despite HSCT being a viable treatment option for pwMS in England and now Scotland many UK MSologists don’t routinely put this option on the table when discussing switching treatments with their patients who are failing other high-efficacy therapies. Why?
   
   Even going to the easy-to-use, easy-to-monitor, oral cladribine option we are seeing slow adoption of IRTs. In general, HCPs don’t understand IRTs, in particular, the concepts of frontloading of risk and long-term remission.
   
   DMTs are about protecting the end-organ or brain and keeping it as healthy as possible so that pwMS can live a normal life as possible and have the necessary reserve to deal with ageing when it sets in.  Is this message difficult to communicate? Knowing this brain volume data why wouldn’t we want to at least offer an IRT to all our patients with active disease and I mean first, second or third line? It is clear the sooner you are treated with an IRT the better you do on average.
   

6. Do I understand the difference between short-term intermittent and long-term continuous immunosuppression?
   
   It is clear that maintenance DMTs such as ocrelizumab result in long term immunosuppression and this patient demonstrates that he did not respond to the COVID-19 vaccine. We have had several other patients who have had both doses of the COVID-19 vaccine and have subsequently developed COVID-19. Fortunately, none of the patients has died from the infection, but three of them ended up being admitted to hospital with severe infection.
   
   With an IRT the risk is frontloaded and the immunosuppression short-lived. Once the immune system has reconstituted vaccine responses are normal.
   
   With HSCT there is a risk of secondary malignancy that may be quite high and depends on what chemotherapy is used for myeloablation. Another risk is infertility. This patient is quite young and may want to start or extend his family and hence may want to bank sperm.
   

7. Do I understand the concept of treat-2-target?
   
   It is apparent from this patient’s choice that he understands what the treatment target is in MS. It is clear he is not happy with anti-CD20 therapy and wants his MS treated beyond no inflammatory disease activity or NEIDA.
   

8. What are the attributes of the specific DMTs?
   
   I would need to spend a lot of time with this patient explaining the difference between alemtuzumab and HSCT. Based on his situation I would look hard and make the case for alemtuzumab and if there is no evident inflammatory disease activity, i.e. relapses, new MRI lesions or raised CSF neurofilament levels I would interrogate him with neurological stress tests (cognition and exercise) to see if we can document worsening disability. If there is, we could make the case for AHSCT via our London HSCT network.
   
   Would I try and talk this patient out of HSCT? Yes, only if he was eligible for alemtuzumab under the NHS. If not I would try and make the case for him to be treated with HSCT in the UK. I personally don’t like patients going abroad for treatment. This is a philosophical issue and is about equity of care and access to treatment. Why should one person with MS be able to access HSCT because they can afford it when so many others can’t? The founding principles of the NHS are equity and free and universal healthcare at the point of access. Going abroad for HSCT undermines these principles.
   

9. How can I derisk or reduce my chances of getting certain adverse events on specific DMTs?
   
   There is a well-defined protocol for derisking HSCT and alemtuzumab, which includes baseline blood tests for infection screening, antibiotic and antiviral prophylaxis after treatment and monitoring. However, as will all treatments, but particularly with HSCT and alemtuzumab, it is a bit of a lottery. A few patients will have serious life-threatening complications. However, the risks are countered by the benefits. This patient clearly does not want to have regrets in the future.
   
   What about timing? I see no reason for him waiting to have HSCT if that is what he has decided. As HSCT is myeloablative the fact that he has no B-cells is not critical. If he is concerned he could wait 6-9 months until he has some B-cell reconstitution before having HSCT. If he is eligible for alemtuzumab I would not wait for B-cell reconstitution as delaying the return of B-cells post alemtuzumab may reduce the chances of secondary autoimmunity. The one caveat to this advice is that we are still in the middle of a COVID-19 pandemic; for logistical reasons and to reduce his risk of being exposed to new variants waiting for 6-9 months for pandemics to settle down may be wise. 

Beyond the B-cell

I am aware that a lot of attention has been focused on the B-cell as if it was the holy grail of MS treatments. It is not.

I have made the case that the B-cell is important, probably as an antigen-presenting cell, but it is not the ‘be all and end all’ of MS treatments. It is clear that rebound post-natalizumab is driven by B-cells and the positive data on the BTK inhibitor would indicate that the B-cells are working via the B-cell receptor on antigen presentation. If only we knew what these antigens were we would have a much better handle on the cause of MS.

I know this science stuff is hard, but it is important. At the end of the day, the nuts and bolts of MS must be molecular; molecules mean treatment targets and potentially more focused and hopefully better and safer treatments in the future.

I have stressed that simply targeting B-cells in both the periphery and central nervous system will not be enough to effectively treat MS in the long term. When we look at end-organ damage markers in pwMS who are on B-cell therapies they have ongoing brain volume loss, albeit at a lower rate, and enlarging lesions (T1 black holes), which are both indicative of ongoing smouldering MS. So what do we need to do? I have provided circumstantial evidence that NIRTs (non-selective immune reconstitution therapies), alemtuzumab and HSCT, have an edge on the B-cell therapies and this may be because they are also targeting T-cells. The latter, however, comes at a price of greater adverse events in relation to immunosuppression. The proportion of pwMS on NIRTs who experience disability improvement seems higher when compared to the anti-B cell agents, which indicates that NIRTs are doing something else over and above their effect on the B-cell compartment. 

However, based on their overall safety profile it is unlikely that the NIRTs (alemtuzumab & HSCT) will be a therapeutic strategy that the wider MS community will adopt with vigour. 

Is there anything else we can do to improve the profile of B-cell therapies to make them better? Yes, I think there is. Targeting the plasma cell, in addition to the B-cell. Data on plasma cells goes back decades and surprisingly the plasma cell has never been a major therapeutic target in MS. John Prineas, one of my MS heroes, has always stressed the importance of the plasma cell in MS.

You are aware of the recent publication showing that about 55% of Polish pwMS treated with intravenous cladribine lost their oligoclonal bands 10 or more years after treatment and if they did lose their OCBs they tended to have lower EDSS scores. We have known for years that pwMS, with either relapse-onset or primary progressive diseases, who don’t have OCBs do better. There is also evidence from biomarker and pathology studies that the OCBs may be driving several of the disease processes that have been linked to advanced or progressive MS, i.e. microglial activation and grey matter pathology. Based on these observations, we hypothesise that OCBs are very likely to be pathogenic in MS, which is why we are embarking on a research programme to try and target the plasma cells within the CNS of pwMS. Do you think we are crazy?

To get a handle on the plasma cell we have to study what happens in the spinal fluid. There are simply too many plasma cells in the periphery which will drown out any signal from the CNS. To participate in the studies we are planning we will have to perform serial, annual, lumbar punctures or spinal taps to see if our add-on therapy is killing and/or reducing the number of plasma cells in your brain and spinal cords. The good news is that we have de-risked the lumbar puncture with the use of atraumatic needles and screening. I never thought I would be saying this but most of our patients don’t mind having LPs, particularly when they understand the reason behind the LP.  CSF neurofilament levels are now part of our prognostic profile of pwMS at baseline and we are increasingly using them to assess response, or lack of response, to treatment. So if you want to be treated and treated-2-target beyond NEDA, and beyond the B-cell, then having an LP is important.

Our SIZOMUS study targeting CNS plasma cells with Ixazomib, a proteasome inhibitor, will lead to a mindset that goes beyond the B-cell to target some of the mechanisms that are responsible for smouldering MS. So another option for this patient is to volunteer for a research study such as SIZOMUS, which is an add-on study. 

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust. The advice is intended as general advice and should not be interpreted as being personal clinical advice. If you have problems please tell your own healthcare professional who will be able to help you.