Switching from an anti-CD20: the why and the how

Many people with multiple sclerosis on ocrelizumab or rituximab are wanting to switch to another disease-modifying therapy. In this Newsletter I explain why and how to do it.

Over the last 12 months, I have had an increasing number of queries from my patients, readers of this newsletter and HCPs about switching from an anti-CD20 therapy (ocrelizumab or rituximab) to another DMT. The questions have generally been about what agents to switch to, the timing and how to do it safely. This answer to these questions is quite complex and the answers depend on why someone is switching from an anti-CD20. 

So why are you switching from ocrelizumab or rituximab to another DMT; vaccine readiness, ongoing disease activity, smouldering MS, tolerability, safety issues?

Vaccine readiness

I have addressed this question already in another MS-Selfie Newsletter. If it is for the COVID-19 vaccine I would go ahead and get vaccinated as soon as possible. When it comes to the booster dose you can delay or miss one or two doses of an anti-CD20 therapy to allow peripheral B-cell reconstitution before having the next dose. This is to allow you to make an antibody response to the vaccine. 

What level of B-cell reconstitution will be sufficient for an adequate antibody response has yet to be clearly defined, but it looks as if you will need to have more than 10 CD19+ B-cells per mm3 in the peripheral blood. Obviously, the more B-cells you have in the blood the more B-cells you will have in your lymph nodes the greater the chance of making a good antibody response. The downside of this approach is will you need to do this every time you have to have a vaccine? Clearly, this is not feasible with annual flu and possibly COVID-19 vaccines, five-yearly pneumococcal vaccines and possibly intermittent travel vaccines. If vaccine immunity is important to you I suggest you switch to a class of treatment that doesn’t impact vaccine immunity; this will exclude the S1P modulators which clearly blunt vaccine immunity as well. 

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Evident Inflammatory Disease Activity (EIDA)

If the reason you want to switch is lack of efficacy, i.e. EIDA or evidence of ongoing inflammatory disease activity in the form of relapses or ongoing MRI activity (new lesions of Gd-enhancing lesions), the decision is easier and it is better to switch sooner than later. Please note if you have a relapse or MRI activity in the first 6 months of starting an anti-CD20 therapy I wouldn’t switch. Not all treatments work immediately. If you have disease activity it is worth asking to see if you are B-cell depleted. Some people on anti-CD20 therapies develop anti-drug antibodies (ADA) and/or neutralizing antibodies that stop the drug from working. If the latter is the case, which is more common on rituximab, it may mean you need to switch to a more humanised monoclonal antibody such as ocrelizumab or ofatumumab. 

Although in the case of EIDA you can switch to any other class of DMT after an anti-CD20 therapy the general rule would be to switch to another high efficacy DMT. This includes both maintenance therapies (natalizumab, S1P modulators) or immune reconstitution therapies such as cladribine or alemtuzumab. As the reason for switching is disease activity I would not wait for B-cell reconstitution and to switch as soon as possible provided all the basic baseline checks have been done for the particular switch DMT. 

There is one caveat is that when someone fails a high efficacy DMT such as an anti-CD20 therapy it is always reasonable to take a step back and review the MS diagnosis. I have discussed this before; 1 in 20 or 5% of people diagnosed with MS don’t have MS and the reason why they may fail a DMT is that they have a disease that is not responsive to MS treatments. 

Smouldering MS

Please note if you are NEIDA (no evident inflammatory disease activity) and you are getting worse in terms of disability progression, you probably have smouldering MS (see Newsletter Getting Worse). We have no idea if switching treatments in this situation will result in stopping the worsening disability. In the past, I have argued that we may in fact need higher doses of anti-CD20 therapy than the currently licensed dose to tackle this problem. The logic behind this is higher doses of anti-CD20 are needed to penetrate into the central nervous system (CNS), across the blood-brain-barrier, to scrub the CNS clean of B-cells. However, I suspect in the future we will have to add-on treatments to tackle the processes that drive smouldering MS that is also referred to in patients with relapse onset MS as progression independent of relapses (PIRA). 

If you have smouldering MS and are labelled as having secondary progressive MS there are no licensed treatments in the UK that you can easily switch to.  However, many neurologists are reluctant to label their patients as having SPMS and hence this may allow switching to another class of treatment. In this situation, because of lack of inflammatory disease activity, it would make sense to wait for some degree of B-cell reconstitution before using immune reconstitution therapies (IRTs)  such as cladribine, alemtuzumab or HSCT to limit the possibility of long term lymphopaenia. 

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Tolerability and safety

In my experience, most patients tolerate anti-CD20 therapy relatively well with the exception of natalizumab switchers. Several of my patients who have switched from natalizumab to ocrelizumab experience recurrent brain fog and fatigue. This seems to be the experience of other MSologists as well. It suggests that some of the brain fog pwMS complain about after stopping natalizumab must be driven by inflammation in the CNS and presumably by the trafficking of T-cells and innate immune cells back into the brain and spinal cord. This is a form of sickness behaviour, which are the symptoms and behavioural responses that are hardwired to help us survive infections. Clearly, in MS, sickness behaviour is maladaptive and contributes to MS-related fatigue and other problems. In some cases, these symptoms have been so bad that patients have requested to go back onto natalizumab despite the risk of PML (progressive multifocal leukoencephalopathy). The latter is not uncommon and makes sense now that we have several strategies to mitigate the risks of developing PML.

The biggest tolerability issue with anti-CD20 therapies is infusion reactions, which tend to occur to a large extent with the first set of infusions. Saying this a handful of patients have persistent mild infusion-type reactions and fatigue with subsequent infusions. 

The biggest perceived problem with long term anti-CD20 therapy is the development of hypogammaglobulinaemia (low antibody levels) and increased risk of infections and potentially secondary malignancies that occur with longer treatment duration. The risk of infections and secondary malignancies are clearly more common the older you are. Many of my colleagues think that reducing the frequency of dosing of anti-CD20 therapy will address this problem. I suspect it won’t. It takes 2-3 years or longer for immunoglobulin levels to return to normal after stopping an anti-CD20 therapy. So unless you give immunoglobulin replacement therapy in the form of IVIG, increasing the gap between infusions won’t derisk this issue. 

So if you have had a serious infection, developed secondary cancer, or are worried about developing these complications in the future you should switch DMTs. In this situation, I would not recommend switching to another maintenance immunosuppressive therapy as the risk will be carried over onto the new agent and may actually increase depending on which DMT you choose.  This is the ideal situation to derisk your DMT and go onto a safer immunomodulatory therapy such as teriflunomide, interferon-beta or glatiramer acetate. 

For several years now I have been arguing for using an induction-maintenance strategy to treat MS; in particular using B-cell depletion (anti-CD20, cladribine or alemtuzumab) as an induction therapy to be followed by teriflunomide as a maintenance therapy to keep MS in remission. This strategy makes a lot of sense, particularly in older patients who have immune senescence or comorbidities. The reason why I like teriflunomide is that it has broad antiviral effects, including effects against EBV, that may prevent EBV infection of new memory  B cells as they form in the lymph nodes. In this latter situation, you actually want teriflunomide to be onboard when B-cell reconstitution is occurring so I would not recommend waiting for B-cell reconstitution to occur before switching to teriflunomide. The same argument could apply to interferon-beta which also has broad antiviral properties. Please note the induction-maintenance EBV-B-cell hypothesis is exactly that and should be tested as part of a clinical trial and not be the reason for using this strategy in clinical practice. 

If you have had very active MS in the past and are worried about de-escalating to a lower efficacy therapy you could potentially switch to an IRT (cladribine or alemtuzumab) after an anti-CD20. These treatments have the advantage of not causing prolonged immune suppressions as they allow the immune system to reconstitute. As the reason for switching in this situation is not lack of efficacy, but concerns about long term safety, I would recommend waiting for some degree of B-cell reconstitution before using IRTs such as cladribine, alemtuzumab or HSCT to limit the possibility of long term and potentially persistent lymphopaenia. Saying this not allowing B-cell reconstitution before giving alemtuzumab may mitigate the secondary autoimmune risks associated with alemtuzumab, but again this is speculative and needs to be tested in clinical trials. 

Conclusions

I personally don’t think there are any DMTs that can’t be used after an anti-CD20 therapy. The timing of the switch clearly depends on what the reason for switching is and it is not always necessary to wait for B-cell reconstitution to occur. It is important to remember that you need to do all the necessary baseline checks before starting a follow-on DMT and it is always wise to review the diagnosis of MS. 

I am aware that this MS-Selfie Newsletter is quite complex, but switching between DMTs is not a trivial subject. Please note that although ofatumumab is given as a monthly subcutaneous injection the issues highlighted above, in relation to rituximab and ocrelizumab will apply to ofatumumab as well. 

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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.