All posts by Gavin Giovannoni

Detail, DMTsDetail, Treatment strategy

What are the attributes of the specific DMTs?

Multiple sclerosis (MS) treatment has evolved rapidly, with 11 classes of disease-modifying therapy (DMT) now available in the UK. I will summarise them briefly and explain how they fit within a treatment paradigm for effective and safe use.

Maintenance therapies versus immune reconstitution: what’s the difference?

There is a divide between the two main treatment philosophies: maintenance ̶ escalation versus immune reconstitution therapies (IRTs).

An IRT is given as a short course – a one-off treatment in the case of autologous haematopoietic stem cell transplantation (AHSCT) or intermittently for alemtuzumab, cladribine or mitoxantrone. IRTs are not given continuously, and additional courses are given only if inflammatory activity recurs. IRTs can induce long-term remission and, in some cases, potentially a cure.

Maintenance therapies, by comparison, are given continuously without an interruption in dosing (‘continuous’ administration may be daily, one or more times weekly, monthly or even once every few months). Although maintenance therapies can induce long-term remission, they cannot, by definition, result in a cure. The recurrence or continuation of inflammatory activity indicates a suboptimal response to treatment and typically requires a treatment switch. Ideally, this switch should be an escalation to a more effective class of DMT.

An article in our list of key questions, entitled How do I want my MS to be treated?, provides a more detailed comparison of maintenance and IRT therapies, including frequency of administration, efficacy, risks, use in pregnancy, vaccine response and potential for a cure.

The DMTs currently licensed in the UK (in August 2024) are listed in the table under the relevant category.

table format updated 180625 SS

Disease-modifying therapies for MS licensed in the UK. *Please note, Bonspri is available in other markets but not the UK.

How effective are the different DMTs?

The measures used to assess the effectiveness of a DMT include its ability to reduce or prevent relapses, focal inflammatory activity (that is, new or enlarging lesions) on magnetic resonance imaging (MRI), and disability progression. Additional factors that can help to assess the relative efficacy of DMTs include the proportion of clinical trial subjects who experience improvement in disability and the impact of the treatment on brain volume loss.

The MS-Selfie InfoCards are an easy-to-use resource to help people with MS compare the key features of each DMT. They contain bite-sized information designed to aid treatment choices and an overview of the key aspects of each DMT.

Efficacy of the licensed DMTs for MS can be visualised as pyramid, with the moderately effective treatments at the bottom and the more effective approaches at the top. What determines the most appropriate DMT efficacy level for an individual depends on several factors, such as baseline prognostic profile, family planning requirements, local or national treatment guidelines, socioeconomic factors, consideration of any co-existing illnesses, cognitive impairment, risk aversion and lifestyle issues.

Pyramid format updated 180625 SS

UK licensed DMTs for MS, in ascending order of efficacy.
HSCT/AHSCT, haematopoietic stem cell transplantation/autologous haematopoietic stem cell transplantation.

What is the goal of treatment? Introducing NEIDA as a target

In the past, we used no evident disease activity (NEDA) as a treatment target. ‘Disease activity’ included progression or disease worsening independent of relapse activity (termed smouldering MS). Although some of the more effective DMTs may modify this stage of the disease, many neurologists feel uncomfortable switching or stopping a DMT based simply on smouldering MS disease activity. 

Relapses and ongoing focal MRI activity are associated with a worse short-term to intermediate-term prognosis. These observations have led to the increasing adoption of ‘no evident inflammatory disease activity’ (NEIDA) as a new treatment target. For more information about treatment targets, please see the article in our key questions, Do I understand the concepts of treat-2-target and NEDA?

Many healthcare professionals (HCPs) remain sceptical of using NEIDA as a treatment target, fearing that this could lead to more people with MS being on ‘riskier’ high-efficacy therapies. However, achieving long-term remission, or NEIDA, is a well-established treatment target in other autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease. People with MS treated-to-target of NEIDA from the outset do better than those whose treatment is escalated following breakthrough disease (at a clinical or subclinical/MRI level)1. I would, therefore, strongly encourage people with MS and their HCPs to adopt NEIDA as an initial treatment target.

Flipping the pyramid

The effectiveness, or relative effectiveness, of individual DMTs becomes less critical in the context of a treatment target of NEIDA. Choosing a DMT with a lower efficacy rate simply means that a greater proportion of treated people with MS will need to be switched to higher efficacy therapies over time to achieve NEIDA. We refer to the latter of these three approaches – starting with high-efficacy treatment – as flipping the pyramid. In recent trials of alemtuzumab, ocrelizumab, ofatumumab and ublituximab, people with MS randomised to 2 years of lower efficacy DMTs (interferon-beta-1a or teriflunomide) had poorer outcomes than those receiving highly active therapy from the outset. Real-world data from registries also support this; groups of people with MS with delayed access to high-efficacy DMTs did worse than those who received high-efficacy treatments early.1,2

Horizontal versus vertical switching

If we consider the conventional step care paradigm, people with MS who switch horizontally from interferon-beta to glatiramer acetate, or vice-versa (i.e. from one moderate efficacy DMT to another moderate efficacy DMT) do less well than those who switch vertically to fingolimod, a highly effective DMT. Similarly, people with MS escalating to natalizumab, a very high-efficacy DMT, do better than those being escalated to the less effective, but still high-efficacy, DMT fingolimod. 

Continuous and intermittent immunosuppression

Another useful way of classifying DMTs is whether they are immunosuppressive, that is, they reduce the activation, or effectiveness, of the immune system. Drug regulators stipulate that a drug may be classified as immunosuppressive if it (1) causes significant lymphopaenia (low lymphocyte count) or leukopenia (low white blood cell count), (2) is associated with opportunistic infections, (3) reduces the antibody and immune response to vaccines and (4) increases the risk of secondary malignancies.

The duration and intensity of immunosuppression further determine the risks. For example, short-term or intermittent immunosuppression associated with IRTs front-loads the risks, which are substantially lower once the immune system has reconstituted itself. In comparison, long-term continuous or persistent immunosuppression, which occurs with some of the maintenance DMTs, accumulates problems over time, particularly opportunistic infections and secondary malignancies. You can read more detail on this topic in the key question How immunosuppressed am I? The following table summarises the main attributes of intermittent and persistent immunosuppression.

How immunosuppressed are you table updated format 180625 SS

The main characteristics of continuous (persistent) and short-term (intermittent) immunosuppression. Modified from Giovannoni, Curr Opin Neurol.2
AHSCT, autologous haematopoietic stem cell transplantation; PML, progressive multifocal leukoencephalopathy.

Adverse effects, monitoring and risk reduction

The complications associated with immunosuppression vary from DMT to DMT. Each individual drug summary in the DMTs section of MS-Selfie contains detailed information about the main adverse events, key monitoring requirements, use (or contraindication) during pregnancy and breastfeeding, and response to vaccines. The MS-Selfie InfoCards provide bite-sized summaries of several practical aspects, including side effects, to enable easy comparison of any treatments you are considering; some of this information is collated below for easy reference.

Short-term versus long-term adverse effects

Each drug has been given scores from 1 to 10 based on published analyses of its short-term and long-term side effects. Short-term refers to side effects that emerge when a treatment is started and decrease in severity or disappear within days or weeks. A well-known example of short-term side effects on starting interferon-beta is flu-like symptoms that typically abate within 4 ̶ 8 weeks.

A long-term side effect persists for months or doesn’t disappear on continuing the DMT. Examples include intermittent but persistent flushing after taking dimethyl fumarate, or low B lymphocyte counts with anti-CD20 therapies that may lead to low antibody or immunoglobulin levels (hypogammaglobulinaemia).

A low score denotes few or rare side effects; a high score denotes many or frequent side effects. The score does not correlate to a percentage. More information can be found in each drug summary and the manufacturer’s Summary of Product Characteristics.

Scores for short-term and long-term side effects assigned to the individual DMTs summarised in the MS-Selfie InfoCards, based on a published network meta-analysis.3
Alem, alemtuzumab; GA, glatiramer acetate; HSCT, haematopoietic stem cell transplantation; IFN-beta; interferon-beta; Nat, natalizumab.

Monitoring and risk reduction

Numerous tests are carried out at the start of treatment, and ongoing monitoring is required for many factors, to reduce the risk from adverse events. The key question, How can I reduce my chances of adverse events on specific DMTs?, explains what needs to be done at the start of DMT administration (baseline) and during subsequent monitoring. The specifics vary from DMT to DMT; please refer to the individual summaries for details such as baseline tests, follow-up, infection prevention, cancer risk, pregnancy, breastfeeding and vaccination. It is important to remember that all licensed MS DMTs have had a thorough risk ̶ benefit assessment, and their benefits are considered to outweigh the potential risks.

Administration and other practical considerations

Routes and frequency of administration

The MS-Selfie InfoCards contain a symbol for each DMT, showing how it is administered. Some DMTs are available in more than one formulation (e.g. tablets and injection). The frequency of administration varies greatly from DMT to DMT; please consult the relevant summary in the DMTs section and discuss your preferences and priorities with your MS HCP.

The route of administration for each drug in the MS-Selfie InfoCards is clearly identified by the relevant symbol. (If a DMT is available in more than one formulation, there is a separate card for each delivery route.)

Number of clinic visits

It may be important for you to consider the frequency of clinic visits. This will depend on factors such as the delivery route of your DMT, the monitoring requirements of the drug regulators and the risk of specific side effects. The table below summarises the assessments from the MS-Selfie InfoCards. This is another factor to consider in discussions with your MS HCPs about the most appropriate DMT for you.

Conclusions

People with MS must understand the objectives of MS treatments and the different treatment strategies currently available to achieve these objectives. Although the MS therapeutic landscape is complex and hence may seem overwhelming, framing the choices using a relatively simple construct should help each individual to make informed decisions about managing their MS. MS-Selfie aims to guide you in the process of deciding on the most appropriate therapeutic strategy and specific DMT for treating your disease.

References

  1. Rotstein D, et al. Association of No Evidence of Disease Activity with no long-term disability progression in multiple sclerosis: a systematic review and meta-analysis. Neurology 2022;99:e209̶ ̶ 20.
  2. Giovannoni G. Disease-modifying treatments for early and advanced multiple sclerosis: a new treatment paradigm. Curr Opin Neurol 2018;31:233 ̶ 43.
  3. Samjoo IA, et al. Efficacy classification of modern therapies in multiple sclerosis. J Comp Eff Res 2021;10:495–507.
Hot topics

ECTRIMS Patient Community Day

ECTRIMS Patient Community Day took place on Friday 20 September 2024 – an online and onsite event hosted by the European Committee for Treatment and Research in Multiple Sclerosis and supported by MS-Selfie.

MS-Selife supported this event because we passionately believe that such collaborations provide us with an invaluable opportunity to push the boundaries of our knowledge and forge a stronger, more resilient path of collective support and well-being.

Watch the recording below:

To view in other languages, click here
Switching

Switching-2-anti-CD20s

Possible reasons to switch

  • Anti-CD20 therapies are highly effective DMTs with a high rate of no evident inflammatory disease activity.
  • They have been shown to slow down disability worsening and brain volume loss; they reduce the annual relapse rate compared with interferon-beta and teriflunomide.
  • Anti-CD20 therapies are generally available for use as ‘first-line’ treatment for DMT-naïve people with MS. This has transformed management of the disease by allowing the adoption of a strategy that starts with high-efficacy DMTs (‘flipping the pyramid’).
  • In general, the anti-CD20 therapies are safe during breastfeeding because very little drug gets into the breast milk.
  • Rituximab has recently been included on the WHO’s Essential Medicines List as a treatment for MS. (Being first approved for use in cancer and then in rheumatoid arthritis, it is now ‘off patent’.) It can therefore be accessed for off-label use in countries where other anti-CD20s are not available.

Reasons for caution

  • Infusion-related reactions are relatively common and are experienced by about one in three subjects with the first and second infusions.
  • Other common adverse effects include infections (particularly respiratory), low antibody levels in the blood (lymphopaenia), blunted vaccine responses and (rarely) delayed neutropenia. Lymphopaenia and neutropenia may both be associated with an increased rate of infections.
  • Anti-CD20s may be associated with anti-drug antibodies and neutralising antibodies (rates vary with the different formulations).

Interferon and glatiramer acetate

An anti-CD20 therapy can be started immediately after discontinuing interferon-beta or glatiramer acetate. All the recommended baseline screening tests and vaccination reviews must be done before starting one of the anti-CD20s.

Natalizumab

Owing to the risk of rebound activity on stopping natalizumab, a prolonged wash-out period is not recommended. Most often, switching from natalizumab to an anti-CD20 or another DMT is to reduce the risk of carry-over progressive multifocal leukoencephalopathy from natalizumab. In our centre, we do an MRI and a lumbar puncture for cerebrospinal fluid analysis to exclude JC virus-DNA on polymerase chain reaction testing. Provided these two tests are clear, we typically initiate the anti-CD20 as soon as possible after the last natalizumab infusion. All the recommended baseline screening tests and vaccination reviews must be done before starting an anti-CD20.

S1P modulators (fingolimod, siponimod, ozanimod and ponesimod)

Because fingolimod has quite a long half-life, some neurologists recommend a short washout period, i.e. 4 ̶ 6 weeks, before switching to another DMT; this may be appropriate, depending on the reason for switching. I recommend waiting for the total peripheral lymphocyte counts to exceed 800/mm3 to exclude the uncommon occurrence of lymphopaenia following S1P modulator administration. All the recommended baseline screening tests and vaccination reviews must be done before starting an anti-CD20. If you are switching because of abnormal liver function tests on an S1P modulator, you would ideally want the liver enzymes to normalise or at least drop to below three times the upper limit of normal before starting an anti-CD20.

Fumarates

All the recommended baseline screening tests and vaccination reviews must be done before starting an anti-CD20. If lymphopaenia is the main reason for switching from fumarate, I recommend waiting for the total peripheral lymphocyte counts to exceed 800/mm3 before starting an anti-CD20. 

Teriflunomide

All the recommended baseline screening tests and vaccination reviews must be done before starting an anti-CD20. I recommend the total peripheral lymphocyte counts are above 800/mm3 before starting an anti-CD20. We don’t routinely do an accelerated washout of teriflunomide before starting an anti-CD20. 

Anti-CD20 therapies (selective cell depleting DMTs)

If patients switch between formulations of anti-CD20 therapies out of choice (patient preference), it can be done without safety concerns or needing to wait for B-cell counts to recover. If patients are switching for loss of efficacy, I suggest checking for antidrug antibodies and reviewing the diagnosis of MS to try and understand why the individual has not responded to the specific anti-CD20 and/or its formulation. 

Mitoxantrone/alemtuzumab/cladribine/AHSCT

Before starting an anti-CD20 therapy, I recommend waiting for the neutrophil and total peripheral lymphocyte counts to go above 1000/mm3 and 800/mm3, respectively. An exception to this would be the cases of severe rebound that are rarely seen after alemtuzumab. In these circumstances, the anti-CD20 therapy is given to treat very active, often pseudotumoral or tumefactive, MS. All the recommended baseline screening tests must be done before starting an anti-CD20 therapy.

DMTsShort

Anti-CD20 therapies – short summary

Summary

Anti-CD20 therapies are a class of monoclonal antibodies that bind to CD20 on the surface of B cells. They work by depleting peripheral B-cells. Four anti-CD20 antibodies are available for treating MS and are administered by intravenous or subcutaneous injection. The three licensed agents for treating relapsing forms of MS are ocrelizumab (Ocrevus), ofatumumab (Kesimpta) and ublituximab (Briumvi). In addition, ocrelizumab is the only anti-CD20 therapy with a license to treat primary progressive MS. In many countries, rituximab (MabThera) is used off-label. Rituximab will be increasingly used as it has recently been included on the WHO’s essential medicines list as a treatment for MS.  

Most B-cell killing due to anti-CD20 is done through immunological processes that burst or lyse the cells, releasing their contents. This can cause a cell lysis syndrome or infusion reaction, which in the case of anti-CD20 therapies tends to be mild to moderate. The infusion reactions are typically managed by predosing with steroids, antihistamines and/or antipyretics (paracetamol/acetaminophen or a non-steroid anti-inflammatory such as ibuprofen). The doses and dosing schedules of the anti-CD20 therapies differ.

Ocrelizumab (600 mg), ublituximab (450 mg) and rituximab (1000 mg) are given as 6-monthly intravenous infusions and ofatumumab (20 mg) as monthly subcutaneous injections.

The anti-CD20 therapies are highly effective DMTs with a high rate of no evident inflammatory disease activity (NEIDA), slowing down disability worsening and brain volume loss. A recent real-world study suggests that ocrelizumab is more effective than rituximab. However, as these agents have yet to be compared head-to-head in a clinical trial, it is difficult to claim one is more or less effective than the others. 

Rituximab and ublituximab are the least humanised of the anti-CD20s and are associated with a higher rate of antidrug antibodies (ADAs), which are usually neutralising antibodies (NAbs). It is reported that 6.4% of ublituximab-treated subjects and even more rituximab-treated patients develop ADAs. In comparison, 1 ̶ 2% of ocrelizumab-treated patients and fewer than 0.5% of ofatumumab-treated patients develop ADAs as these therapeutic antibodies are more humanised than the others and less likely to induce an antidrug immune response. The ADAs are important considerations when choosing between these products. 

The most common adverse effects of anti-CD20 therapies are mild infusion-like reactions (generally not seen with subcutaneous ofatumumab), infections, low antibody levels in the blood (hypogammaglobulinaemia), blunted vaccine responses and (rarely) delayed neutropenia. In the ocrelizumab trials, the number of malignancies (including breast cancers) was increased. The incidence was, however, within the background rate expected for an MS population, and post-marketing studies have not shown an increased rate of malignancies. 

Anti-CD20 therapies are generally available first line to treat DMT-naive patients. As a class, anti-CD20 therapies have transformed the management of MS by allowing the adoption of a treatment strategy of using high-efficacy DMTs as the first treatment, which I refer to as ‘flipping the pyramid’. Importantly, ocrelizumab has also ushered in the era in which we can treat some patients with primary progressive MS. 

Trade names

Ocrevus, Kesimpta, Bonspri, Briumvi, MabThera.

Mode of action

Via peripheral B-cell depletion. It is hypothesised that anti-CD20 therapies work via several mechanisms involving the B cell and possibly through a small population of CD20-expressing T cells.

Efficacy

High, with a positive impact on annual relapse rate, 3-month disability progression, no evident disease activity (NEDA) rates and slowing of accelerated brain volume loss. 

Class

Maintenance therapy – continuous B-cell depletion.

Immunosuppression

Yes, long-term.

Dosing

Ocrevus (ocrelizumab) dosing

600 mg administered as two infusions of 300 mg (with a 2-week gap). Subsequent doses of 600 mg ocrelizumab every 6 months.

Kesimpta/Bonspri (ofatumumab) dosing

20 mg administered by subcutaneous injection at weeks 0, 1 and 2, then monthly dosing from week 4.

Briumvi (ublituximab) dosing

150 mg intravenous infusion (first infusion); 450 mg intravenous infusion 2 weeks later. All subsequent doses are administered as a single 450 mg intravenous infusion every 24 weeks. 

MabThera (rituximab) dosing

Generally, 1000 mg intravenously on days 1 and 15 then 1000 mg intravenously every 6 months. Rituximab is off patent and dosing regimens vary.

Pre-treatment and prophylaxis treatment

100 mg of corticosteroid is administered intravenously before infusion to help manage infusion reactions; this may not be needed with later infusions. Premedication is not necessary with subcutaneous ofatumumab. Prophylactic antivirals or antibiotics are not required. 

Main adverse events

  • Infections, usually minor, are the most common adverse event. Herpes infections are reported more frequently than with other DMTs. 
  • Infusion-related reactions are relatively common with the first and second infusions. The risk of anaphylaxis is very low.
  • Laboratory abnormalities such as decreased antibody levels, lymphopaenia or neutropaenia are associated with a higher risk of infection.
  • Standard breast cancer screening measures are mandated for women aged 50 ̶ 70 years.

Pharmacovigilance monitoring requirements 

  • Standard blood tests and comprehensive screening for infection, pregnancy and blood pressure are done at baseline.
  • Vaccine review is recommended, followed by vaccination where indicated.
  • Follow-up blood tests are not mandated, but our centre performs them every 6 ̶ 12 months.
  • A rebaseline MRI scan should be done ~6 months after starting an anti-CD20 therapy, ideally including Gd-enhancement. A monitoring MRI is performed annually after that.
  • In the event of pregnancy, the next infusion should be delayed until after delivery.
  • In general, the anti-CD20 therapies are safe when breastfeeding, except during weeks 2 ̶ 3 post-partum when colostrum is produced.

Further details about anti-CD20 therapies

Switching-2-anti-CD20s

DMTsDetail

Anti-CD20 therapies  

Summary

Anti-CD20 therapies are a class of monoclonal antibodies that bind to CD20 on the surface of B cells. They work by depleting peripheral B-cells. Four anti-CD20 antibodies are available for treating MS and are administered by intravenous or subcutaneous injection. The three licensed agents for treating relapsing forms of MS are ocrelizumab (Ocrevus), ofatumumab (Kesimpta) and ublituximab (Briumvi). In addition, ocrelizumab is the only anti-CD20 therapy with a license to treat primary progressive MS. In many countries, rituximab (MabThera) is used off-label. Rituximab will be increasingly used as it has recently been included on the WHO’s essential medicines list as a treatment for MS.  

Most B-cell killing due to anti-CD20 is done through immunological processes that burst or lyse the cells, releasing their contents. This can cause a cell lysis syndrome or infusion reaction, which in the case of anti-CD20 therapies tends to be mild to moderate. The infusion reactions are typically managed by predosing with steroids, antihistamines and/or antipyretics (paracetamol/acetaminophen or a non-steroid anti-inflammatory such as ibuprofen). The doses and dosing schedules of the anti-CD20 therapies differ.

Ocrelizumab (600 mg), ublituximab (450 mg) and rituximab (1000 mg) are given as 6-monthly intravenous infusions and ofatumumab (20 mg) as monthly subcutaneous injections.

The anti-CD20 therapies are highly effective DMTs with a high rate of no evident inflammatory disease activity (NEIDA), slowing down disability worsening and brain volume loss. A recent real-world study suggests that ocrelizumab is more effective than rituximab. However, as these agents have yet to be compared head-to-head in a clinical trial, it is difficult to claim one is more or less effective than the others. 

Rituximab and ublituximab are the least humanised of the anti-CD20s and are associated with a higher rate of antidrug antibodies (ADAs), which are usually neutralising antibodies (NAbs). It is reported that 6.4% of ublituximab-treated subjects and even more rituximab-treated patients develop ADAs. In comparison, 1 ̶ 2% of ocrelizumab-treated patients and fewer than 0.5% of ofatumumab-treated patients develop ADAs as these therapeutic antibodies are more humanised than the others and less likely to induce an antidrug immune response. The ADAs are important considerations when choosing between these products. 

The most common adverse effects of anti-CD20 therapies are mild infusion-related reactions (generally not seen with subcutaneous ofatumumab), infections, low antibody levels in the blood (hypogammaglobulinaemia), blunted vaccine responses and (rarely) delayed neutropenia. In the ocrelizumab trials, the number of malignancies (including breast cancers) was increased compared with the comparator. The incidence was, however, within the background rate expected for an MS population, and post-marketing studies have not shown an increased rate of malignancies. 

Anti-CD20 therapies are generally available first line to treat DMT-naive patients. As a class, anti-CD20 therapies have transformed the management of MS by allowing the adoption of a treatment strategy of using high-efficacy DMTs as the first treatment, which I refer to as ‘flipping the pyramid’. Importantly, ocrelizumab has also ushered in the era in which we can treat some patients with primary progressive MS. 

Trade names

Ocrevus (ocrelizumab), Kesimpta/Bonspri (ofatumumab), Briumvi (ublituximab), MabThera (rituximab). Please note rituximab is off patent and many biosimilars are available globally; hence the treatment you receive may have a different tradename.

Mode of action

Anti-CD20 therapies work via peripheral B-cell depletion. It is unknown how B-cell depletion works as a treatment for MS. However, it is hypothesised that anti-CD20 therapies work via several mechanisms involving the B cell and possibly through a small population of CD20-expressing T cells:

  • preventing autoantigen presentation via the B cell
  • reducing B-cell-derived proinflammatory cytokines
  • reducing B-cell production of autoantibodies
  • depleting pro-inflammatory effector CD20-expressing T cells
  • as an anti-EBV agent: EBV (Epstein-Barr virus) resides in memory B cells, and depleting these cells decreases EBV viral loads. However, it is currently unknown what role EBV plays in the pathogenesis of MS. 

Efficacy

High. Compared with active comparators (interferon-beta and teriflunomide), anti-CD20 therapies reduce the annual relapse rate by ~50% and 3-month disability progression by one-third. The no evident disease activity (NEDA) rates across 2 years of the pivotal trials are ~50%, and these drugs slow down accelerated brain volume loss to ~0.3 ̶ 0.4% per annum. This rate of brain volume loss, however, is still higher than the <0.2% per year that is found in age-matched healthy individuals.

Class

Maintenance therapy – continuous B-cell depletion.

Immunosuppression

Yes, long-term.

Dosing and availability

Ocrevus (ocrelizumab) dosing

The initial 600 mg dose is administered as two separate intravenous infusions, first as a 300 mg infusion, followed 2 weeks later by a second 300 mg infusion. These initial infusions are given over 2.5 hours. Subsequent doses of ocrelizumab are administered as a single 600 mg intravenous infusion every 6 months. The infusion rate will vary from 2.0 to 3.5 hours, depending on how well it is tolerated. It is recommended that a minimum interval of 5 months should be maintained between each dose of ocrelizumab.

Kesimpta/Bonspri (ofatumumab) dosing

The recommended dose is 20 mg ofatumumab administered by subcutaneous injection with initial dosing at weeks 0, 1 and 2, followed by monthly dosing, starting at week 4.

Kesimpta is sold in an autoinjector, and Bonspri is sold as a vial for self-administration. Bonspri is only available in some middle-income and low-middle-income countries, where it is sold at a discount to Kesimpta.

Briumvi (ublituximab) dosing

The first dose is administered as a 150 mg intravenous infusion over 4 hours (first infusion), followed 2 weeks later by a 450 mg intravenous infusion over one hour (second infusion). All subsequent doses are administered as a single 450 mg intravenous infusion every 24 weeks over one hour. 

Ublituximab is the latest anti-CD20 therapy to be shown to be effective in MS and it may not yet be available in your country. 

MabThera (rituximab) dosing

Please note rituximab is off patent, and many biosimilars are now available across the world. The most common dose is 1000 mg of intravenous rituximab on days 1 and 15 and then 1000 mg intravenously every 6 months. There are variations to this dosing scheme, with many neurologists reducing the dose or extending the interval between doses to try and reduce the risk of long-term adverse effects. 

Pre-treatment and prophylaxis treatment

For the anti-CD20 therapies, 100 mg of methylprednisolone (or an equivalent corticosteroid) is administered intravenously approximately 30 minutes before each infusion to reduce the frequency and severity of infusion reactions. This can be combined with chlorpheniramine 10 mg. Paracetamol 1g and/or ibuprofen 400 mg is given on an ‘as-required’ basis for pyrexia, myalgias or pain, which can rarely occur as part of the infusion reaction. As the infusion reactions are only a problem with the first and second courses, many centres now omit methylprednisolone and antihistamines once patients are B-cell depleted and established on the treatment. The infusion reactions are due to a cell lysis syndrome. Once B-cell depletion is established, there are too few circulating B cells to cause a cell lysis syndrome. Prophylactic antivirals or antibiotics are not required with the anti-CD20 therapies. 

Please note premedication is not necessary with subcutaneous ofatumumab.

Off-label rituximab

Rituximab is off patent and is relatively cheap, which explains why it is one of the drugs on the MS-Selfie off-label essential DMT list for treating MS in resource-poor environments. It is also worth noting that rituximab is one of three DMTs added to the WHO List of Essential Medicines to treat MS. 

Main adverse events

Infusion-related reactions

Infusion-related reactions (IRRs) are relatively common and are experienced by about one in three subjects with the first and second infusions. Typical IRRs include pruritus, rash, urticaria, erythema, flushing, low blood pressure, pyrexia, fatigue, headache, dizziness, throat irritation, oropharyngeal pain, nausea, tachycardia, shortness of breath and throat or laryngeal swelling. The risk of anaphylaxis is very low.

Infection

Infections, particularly of the respiratory tract, are the most common adverse event with anti-CD20 therapies. Infections tend to be minor, but occasional severe infections occur. Herpes infections, including herpes zoster and oral or genital herpes simplex virus infection, are reported more frequently in patients treated with anti-CD20 therapies than in those receiving other DMTs. 

Laboratory abnormalities

Anti-CD20 treatment decreases total immunoglobulins (antibodies), mainly driven by reduced IgM (immunoglobulin M) and IgA levels. Decreased levels of IgG tend to occur later and are associated with a higher risk of infection and severe infections. Not all patients treated with anti-CD20s develop low antibody levels in the blood.

A minority of people with MS treated with anti-CD20 therapies develop mild lymphopaenia; a small number (<1%) develop grade 3 lymphopaenia (<500 cells/mm3). An increased rate of serious infections has been seen during episodes of lymphopaenia.

A small number of patients treated with anti-CD20s develop neutropaenia, generally mild and transient; fewer than 1% developed grade 3 (500 ̶ 1000 cells/mm3) or grade 4 neutropaenia (<500 cells/mm3) in the trials. Please note that neutropaenia can occur several months after starting anti-CD20 therapy and has been associated with infections. 

To minimise infectious complications, we recommend all patients have a vaccine review and ensure they are up to date with their seasonal flu and COVID-19 vaccines. In addition, we recommend all patients have the pneumococcal vaccine (Pneumovax) and the varicella zoster virus (VZV) vaccine (Shingrex) before starting anti-CD20 therapy (please see our derisking guide and article on reducing side effect risk). Some people with MS may want to consider additional vaccines before starting an anti-CD20 therapy. 

As anti-CD20 therapies are immunosuppressive, they increase the likelihood of infections. To derisk infections, we recommend routine baseline screening for human immunodeficiency virus (HIV), syphilis, hepatitis B and C and tuberculosis. In addition, we screen for exposure to VZV and if seronegative we strongly recommend VZV vaccination before starting therapy. 

Malignancy

An increased number of malignancies (including breast cancer) were seen in ocrelizumab-treated subjects in clinical trials. However, the incidence appears to be within the background rate expected for an MS population. Patients must follow standard breast cancer screening guidelines, i.e. monthly self-examination, and women between 50 and 70 years of age should have a mammogram every 3 years. Other potential cancers linked to anti-CD20 therapies include basal cell carcinoma.

Pharmacovigilance monitoring requirements 

Baseline

Full blood count, urea and electrolytes, liver function tests, thyroid function tests, serum immunoglobulin levels, serology (VZV, HIV 1 and 2, hepatitis B and C, TB ELISpot), up-to-date cervical smear and/or human papillomavirus testing, a pregnancy test and baseline blood pressure are done.

Follow-up

No routine follow-up blood tests are mandated. However, we now monitor the full blood count and serum immunoglobulin levels every 6 ̶ 12 months when patients come for their infusions or annual follow-up appointments. The latter is particularly relevant for patients on subcutaneous ofatumumab. 

Rebaselining

A rebaseline MRI scan needs to be done after starting an anti-CD20 therapy. I recommend that an MRI is done at ~6 months after starting treatment and that Gd-enhancement is ideally included as part of the rebaselining MRI. A monitoring MRI is then done annually after that (resources permitting). 

Women of childbearing potential and pregnancy

The SmPCs recommend that women of childbearing age should use contraception while receiving anti-CD20 treatment and, in the case of ocrelizumab, for up to 12 months after the last infusion. However, I tend to give women who want to start or extend their families the option of starting an anti-CD20 and falling pregnant in their own time. There are several reasons for this. Most women don’t fall pregnant immediately; it takes, on average, four ovulation cycles and often much longer. Anti-CD20 therapies do not affect fertility and are not teratogenic (i.e. it does not affect the developing baby). In addition, the placenta does not mature until towards the end of the second trimester, when it allows antibodies (anti-CD20 is an antibody) to cross from the maternal circulation into the developing baby’s circulation. So once a woman falls pregnant, we delay the next infusion until after the baby’s delivery. Even if small amounts of anti-CD20 cross over into the baby’s circulation, it tends to cause a transient B-cell depletion in the baby.

Breastfeeding

In general, monoclonal antibodies, including the anti-CD20 therapies, are safe during breastfeeding because little drug gets into the breast milk; the small amounts that reach the breast milk will be metabolised in the baby’s gastrointestinal tract. The exception is in the first 2 ̶ 3 weeks post-partum when a woman’s breasts produce colostrum, and the newborn’s intestinal tract is immature and can transfer antibodies across the intestinal surface.

Colostrum, or first milk, is produced immediately after the newborn’s delivery and for about 2 ̶ 3 weeks after delivery. Colostrum is exceptionally high in antibodies and other factors to protect the newborn against disease and infection. As the newborn’s gastrointestinal tract is immature, many of the proteins in colostrum are absorbed and will have systemic immune effects. 

Most of the antibodies in colostrum are IgA and IgM produced by plasma cells in the breast. Therefore, I suspect that circulating IgG, including the anti-CD20, is transferred into breast milk in small amounts. However, the breast epithelial cells express the so-called neonatal Fc-receptor, the molecular shuttle for transporting antibodies into milk. In addition, this neonatal Fc receptor shuttle is also expressed in the newborn intestine. So, the molecular mechanisms are in place potentially to increase your developing baby’s exposure to anti-CD20. 

Neonatal Fc Receptor - for MS-Selfie gg1-RB

Neonatal Fc-receptors expressed on breast epithelial cells transport small amounts of antibodies into breast milk.

If you plan to breastfeed, which I recommend, you will want to avoid ocrelizumab while your breasts produce colostrum. There are no black-and-white answers to any problem in MS. Delaying recommencing ocrelizumab treatment for a few weeks post-partum outweighs the chances of rebound disease activity. 

Fertility

Animal studies and experience in humans reveal no issues concerning fertility in women receiving anti-CD20 treatment. 

Vaccination

It is recommended that anti-CD20-treated patients are immune to the VZV before starting treatment. Patients should also be offered the pneumococcal (Pneumovax) and VZV (Shingrex) component vaccines to boost immunity before treatment. Antibody response, but not T-cell responses, to neoantigens (new vaccines) is blunted in patients on anti-CD20 therapies. Therefore, patients on such therapies can receive inactivated vaccines and mount a partial response to them. Live attenuated vaccines are not recommended for these patients. 

Travel

People with MS need to be aware that being on an anti-CD20 may affect travel; for example, some countries require you to be vaccinated against yellow fever, a live attenuated vaccine. Therefore, the yellow fever vaccine must be given before starting anti-CD20 treatment.

High-dose versus low-dose anti-CD20

To move our treatment target in MS beyond NEIDA, the new focus must be on preventing end‑organ damage and the processes driving smouldering MS; that target therefore includes:

  • stopping disability progression
  • normalising brain volume loss
  • flattening the area under the neurofilament level curve
  • stopping slowly expanding lesions from getting bigger
  • clearing the cerebrospinal fluid of oligoclonal IgG bands
  • if possible, promoting repair and recovery of the nervous system. 

What good is it to be free of relapses and focal MRI activity if your MS gets worse? This is why the concept of using low-dose anti-CD20 therapy seems flawed. Trial participants exposed to lower doses of ocrelizumab in the phase 3 trials, owing to greater body size, do as well as those exposed to higher doses in relation to relapses and MRI activity, but not in relation to worsening disability or smouldering disease. 

The phase 3 ocrelizumab trials in both relapsing and primary progressive MS used a fixed dose of 600 mg of ocrelizumab intravenously every 6 months.1,2 Therefore, smaller people with MS got a relatively larger dose of ocrelizumab than larger people. For example, someone weighing 60 kg got 10 mg/kg of ocrelizumab 6-monthly compared to 5 mg/kg for someone with MS weighing 120 kg. By measuring drug concentrations, trial subjects could be divided into four groups or quartiles representing four dosing levels. Although the treatment effect of ocrelizumab on relapses and MRI activity showed no difference between the four groups in these pivotal studies, post-hoc analyses showed that subjects who received higher doses and had more significant B-cell depletion were less likely to exhibit disease progression than those on low doses. This higher-dose treatment effect on smouldering MS, i.e. beyond NEIDA, was seen in both the relapsing and primary progressive populations.3

It is clear from these post-hoc analyses that higher, not lower, doses of anti-CD20 therapy may be needed to tackle smouldering MS. Currently, these observations apply only to the initial 2 years of treatment. Hence, we don’t know if people with MS will only need higher doses as an induction strategy to purge the various B-cell compartments of pathogenic (disease-causing) cells. 

Once you have purged these B-cell compartments after 2 years of high-dose anti-CD20 treatment, you may not need to maintain people with MS on such high doses, which would continue suppressing normal B-cell biology and immune responses – with long-term complications. 

Two large phase 3 trials are ongoing, testing high-dose ocrelizumab (1200 and 1800 mg every 6 months) compared with standard-dose ocrelizumab (600 mg every 6 months) in both relapsing and primary progressive MS. The results of these trials should answer some of the lingering questions about dosing of anti-CD20 therapies.

Please note that lower dose anti-CD20 therapies are a moving target. Anti-CD20 dosing should not be based on B-cell counts in the peripheral blood, which are a poor surrogate for what is happening in the deep tissues and central nervous system. We need better and more accessible biomarkers to study these B-cell compartments. Receiving ocrelizumab less frequently than the licensed 6-monthly dose and rituximab, ofatumumab or ublituximab could potentially be considered as low-dose anti-CD20 therapy. 

Summaries of Product Characteristics (SmPC)

Ocrevus (ocrelizumab), Kesimpta (ofatumumab), Briumvi (ublituximab), MabThera (rituximab).

Switching-2-anti-CD20 therapy

Interferon and glatiramer acetate

An anti-CD20 therapy can be started immediately after discontinuing interferon-beta or glatiramer acetate. All the recommended baseline screening tests and vaccination reviews must be done before starting one of the anti-CD20s.

Natalizumab

Owing to the risk of rebound activity on stopping natalizumab, a prolonged wash-out period is not recommended. Most often, switching from natalizumab to an anti-CD20 or another DMT is to reduce the risk of carry-over progressive multifocal leukoencephalopathy from natalizumab. In our centre, we do an MRI and a lumbar puncture for cerebrospinal fluid analysis to exclude JC virus-DNA on polymerase chain reaction testing. Provided these two tests are clear, we typically initiate the anti-CD20 as soon as possible after the last natalizumab infusion. All the recommended baseline screening tests and vaccination reviews must be done before starting an anti-CD20.

S1P modulators (fingolimod, siponimod, ozanimod and ponesimod)

Because fingolimod has quite a long half-life, some neurologists recommend a short washout period, i.e. 4 ̶ 6 weeks, before switching to another DMT; this may be appropriate, depending on the reason for switching. I recommend waiting for the total peripheral lymphocyte counts to exceed 800/mm3 to exclude the uncommon occurrence of lymphopaenia following S1P modulator administration. All the recommended baseline screening tests and vaccination reviews must be done before starting an anti-CD20. If you are switching because of abnormal liver function tests on an S1P modulator, you would ideally want the liver enzymes to normalise or at least drop to below three times the upper limit of normal before starting an anti-CD20.

Fumarates

All the recommended baseline screening tests and vaccination reviews must be done before starting an anti-CD20. If lymphopaenia is the main reason for switching from fumarate, I recommend waiting for the total peripheral lymphocyte counts to exceed 800/mm3 before starting an anti-CD20. 

Teriflunomide

All the recommended baseline screening tests and vaccination reviews must be done before starting an anti-CD20. I recommend the total peripheral lymphocyte counts are above 800/mm3 before starting an anti-CD20. We don’t routinely do an accelerated washout of teriflunomide before starting an anti-CD20. 

Anti-CD20 therapies (selective cell depleting DMTs)

If patients switch between formulations of anti-CD20 therapies out of choice (patient preference), it can be done without safety concerns or needing to wait for B-cell counts to recover. If patients are switching for loss of efficacy, I suggest checking for antidrug antibodies and reviewing the diagnosis of MS to try and understand why the individual has not responded to the specific anti-CD20 and/or its formulation. 

Mitoxantrone/alemtuzumab/cladribine/AHSCT

Before starting an anti-CD20 therapy, I recommend waiting for the neutrophil and total peripheral lymphocyte counts to go above 1000/mm3 and 800/mm3, respectively. An exception to this would be the cases of severe rebound that are rarely seen after alemtuzumab. In these circumstances, the anti-CD20 therapy is given to treat very active, often pseudotumoral or tumefactive, MS. All the recommended baseline screening tests must be done before starting an anti-CD20 therapy.

References

  1. Hauser SL, et al. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med 2017; 376: 221 ̶ 34. doi: 10.1056/NEJMoa1601277.
  2. Montalban X, et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med 2017; 376: 209 ̶ 20. doi: 10.1056/NEJMoa1606468.
  3. Hauser SL, et al. Association of higher ocrelizumab exposure with reduced disability progression in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm 2023; 10:e200094. doi:10.1212/NXI.0000000000200094.
DMTsShort

Cladribine – short summary

Summary

Cladribine is an immune reconstitution therapy (IRT) that works by depleting your lymphocytes and allowing them to recover over several months. It is selective, mainly targeting B lymphocytes. After your immune system recovers, hopefully without the cells that cause MS, it can fight infections, respond to vaccines and provide peripheral immune surveillance for tumours. Cladribine is given as two courses of oral tablets, each of 2 treatment weeks, during which a patient receives 10 or 20 mg daily for 4 or 5 days.

Cladribine’s mode of action triggers a process called programmed cell death or apoptosis. This means that lymphocytes don’t release their contents via cell lysis but are gradually taken up by cells of the immune system by phagocytosis. As a result, lymphocyte cell death occurs slowly after cladribine administration, and there is no cell lysis syndrome. Therefore, cladribine-treated patients with MS don’t get infusion-type reactions, nor do they need steroids and antihistamines to prevent such reactions.

Cladribine is a highly effective disease-modifying therapy (DMT) with a high rate of no evident inflammatory disease activity (NEIDA), and it slows down disability worsening. It is very well tolerated, with very few side effects. The most common adverse effects are infections, usually mild. A minority of patients may experience a non-specific headache post-cladribine. No delayed secondary autoimmunity is seen, differentiating cladribine from other IRTs used to treat MS.

Cladribine is unlikely to be associated with an increased risk of secondary malignancies, but it is contraindicated in MS patients with active malignancies. Many patients treated with cladribine go into long-term remission. Whether these individuals are cured or not will require much longer follow-up. Cladribine works similarly to alemtuzumab (Lemtrada) or AHSCT (autologous haemopoietic stem cell transplantation) but is a much safer treatment option.

Trade name

Mavenclad.

Mode of action

As an IRT, cladribine aims to kill the cells that cause MS and then reboot the immune system to reset the regulatory mechanisms that keep autoreactive cells under control. It works similarly to alemtuzumab and AHSCT but does not cause infusion-type reactions.

Efficacy

High, with a positive impact on annual relapse rate, 3-month disability progression and rates of no evident disease activity (NEDA).

Class

Selective immune reconstitution therapy (IRT).

Immunosuppression

Yes, short-term, whilst the immune system is depleted.

Dosing

Two courses of oral tablets over 2 years, with a recommended cumulative dose of 1.75 mg/kg per year.

  • Year 1: month 1, week 1, days 1 ̶ 5; month 2, week 1, days 1 ̶ 5. Each treatment week consists of 4 or 5 days on which a patient receives 10 or 20 mg daily.
  • Year 2: as in year 1 but starting the first dosing week any time up to month 6.

No further cladribine treatment is required in subsequent years unless there is a recurrence of disease activity. No anti-inflammatory pretreatments or prophylactic antivirals and/or antibiotics are required to prevent infusion reactions or infections with cladribine. For fuller details, please refer to Dosing section of cladribine full details summary.

Main adverse events

  • Herpes zoster due to reactivation of the varicella-zoster virus (VZV).
  • Increased likelihood of infections.

Pharmacovigilance monitoring requirements

  • Full range of tests and infection screening at baseline, plus negative urine pregnancy test.
  • Cladribine is contraindicated in MS patients with active malignancies.
  • Full blood count and liver function tests 2 and 6 months after the start of treatment in each treatment year.
  • Be vigilant for unexplained bleeding, bruising, nausea, vomiting, abdominal pain, fatigue, loss of appetite, jaundice and/or dark urine and any symptoms of an infection.
  • A rebaseline MRI is recommended 18 ̶ 24 months after starting treatment, including Gd-enhancement. A monitoring MRI annually thereafter.

Further details about cladribine

Switching-2-cladribine

Switching

Switching-2-cladribine

Possible reasons to switch

  • Cladribine is a highly effective DMT; follow-up of participants from clinical trials suggests it has a long-lasting treatment effect, especially when used early in the disease course.
  • It has demonstrated improvements in annual relapse rate, disability progression and decreased brain volume loss compared to placebo.
  • Cladribine-treated patients with MS don’t get infusion-type reactions, nor do they need steroids and antihistamines to prevent such reactions.
  • Cladribine works similarly to alemtuzumab and AHSCT but is a much safer treatment option. It is very well tolerated, with very few side effects.

Reasons for caution

  • Cladribine is an immunosuppressive therapy and may increase the likelihood of infections. Routine infection screening before starting treatment is essential, as is ongoing monitoring and prompt treatment if infection is detected.
  • Herpes zoster is the most common clinically significant adverse event reported with cladribine.
  • A lymphocyte count above 800/mm3 is recommended before starting course 2 of cladribine (in year 2) and before switching to cladribine from most other DMTs.
  • Disease breakthrough after the second course of cladribine (before the end of year 2) is considered a treatment failure, particularly if associated with poor depletion of lymphocytes.
  • Cladribine is contraindicated in MS patients with active malignancies. All cladribine-treated people with MS are advised to follow standard, country-specific cancer screening guidelines.
  • Cladribine may cause birth defects. Patients are advised not to fall pregnant or father a child until at least 6 months after the last exposure to cladribine.
  • Cladribine will cross over into the breast milk. We advise pregnant women to wait until 10 days after the last exposure to cladribine before breastfeeding.

Interferon and glatiramer acetate

In general, cladribine can be started immediately after discontinuation of interferon or glatiramer acetate. All the recommended baseline screening tests and vaccination reviews must be done before starting cladribine.

Natalizumab

Owing to the risk of rebound activity on stopping natalizumab, a prolonged wash-out period is not recommended. Most often, the reason for switching from natalizumab to cladribine, or another DMT, is to reduce the risk of carry-over PML from natalizumab. In our centre, we do an MRI and a lumbar puncture for cerebrospinal fluid analysis to exclude JC virus-DNA on polymerase chain reaction testing. Provided these two tests are clear, we would typically initiate cladribine as soon as possible after the last natalizumab infusion. All the recommended baseline screening tests and vaccination reviews must be done before starting cladribine.

S1P modulators (fingolimod, siponimod, ozanimod and ponesimod)

Because fingolimod has quite a long half-life, some neurologists recommend a short washout period, i.e. 4 ̶ 6 weeks; this may be appropriate, depending on the reason for switching. I recommend waiting for the total peripheral lymphocyte counts to exceed 800/mm3 to exclude the uncommon occurrence of persistent lymphopaenia following S1P modulator administration. All the recommended baseline screening tests and vaccination reviews must be done before starting cladribine. If you are switching because of abnormal liver function tests on an S1P modulator, you would ideally want the liver enzymes to normalise or at least drop to below three times the upper limit of normal before starting cladribine.

Fumarates

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting cladribine. If lymphopaenia is the main reason for switching from a fumarate, I recommend waiting for the total peripheral lymphocyte counts to exceed 800/mm3 before starting cladribine.

Teriflunomide

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting cladribine. I recommend that the total peripheral lymphocyte counts are above 800/mm3 before starting cladribine. We don’t routinely do an accelerated washout of teriflunomide before starting cladribine.

Anti-CD20 therapies (selective cell depleting DMTs)

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting cladribine. If patients are switching for safety concerns, it would be advisable to wait for B cell counts to recover first. If patients are switching for lack or loss of efficacy on an anti-CD20, there is no need to wait for B-cell recovery.

Mitoxantrone/alemtuzumab/AHSCT

I recommend waiting for the neutrophil and total peripheral lymphocyte counts to go above 1,000/mm3 and 800/mm3, respectively. All the recommended baseline screening tests must be done before starting cladribine.

DMTsDetail

Cladribine

Summary

Cladribine is an immune reconstitution therapy (IRT) that works by depleting your lymphocytes and allowing them to recover over several months. It is selective, mainly targeting B lymphocytes. After your immune system recovers, hopefully without the cells that cause MS, it can fight infections, respond to vaccines and provide peripheral immune surveillance for tumours. Cladribine is given as two courses of oral tablets, each of 2 treatment weeks, during which a patient receives 10 or 20 mg daily for 4 or 5 days.

Cladribine’s mode of action triggers a process called programmed cell death or apoptosis. This means that lymphocytes don’t release their contents via cell lysis but are gradually taken up by cells of the immune system by phagocytosis. As a result, lymphocyte cell death occurs slowly after cladribine administration, and there is no cell lysis syndrome. Therefore, cladribine-treated patients with MS don’t get infusion-type reactions, nor do they need steroids and antihistamines to prevent such reactions.

Cladribine is a highly effective disease-modifying therapy (DMT) with a high rate of no evident inflammatory disease activity (NEIDA), and it slows down disability worsening. It is very well tolerated, with very few side effects. The most common adverse effects are infections, usually mild. A minority of patients may experience a non-specific headache post-cladribine. No delayed secondary autoimmunity is seen, differentiating cladribine from other IRTs used to treat MS.

Cladribine is unlikely to be associated with an increased risk of secondary malignancies, but it is contraindicated in MS patients with active malignancies. Many patients treated with cladribine go into long-term remission. Whether these individuals are cured or not will require much longer follow-up. Cladribine works similarly to alemtuzumab (Lemtrada) or AHSCT (autologous haemopoietic stem cell transplantation) but is a much safer treatment option.

Trade name

Mavenclad.

Mode of action

Cladribine or 2-chloro-2′-deoxyadenosine [2-CdA] is a purine analogue. It is taken up by cells via specific transporter proteins. Cladribine is inactive but, once inside a cell, it is activated by the addition of three phosphate groups by an enzyme called deoxycytidine kinase (DCK). In its triphosphorylated state, it is incorporated into DNA, which then blocks further extension of the DNA chain by the so-called DNA polymerases. The cell senses its inability to extend or repair its DNA, which triggers a process called programmed cell death or apoptosis. Cells that die by apoptosis don’t release their contents via cell lysis but are gradually taken up by cells of the reticuloendothelial system by phagocytosis. Therefore, lymphocyte cell death occurs slowly after cladribine administration, and there is no cell lysis syndrome. This explains why cladribine-treated patients with MS don’t get infusion-type reactions, nor do they need steroids and antihistamines to prevent these reactions.

A group of enzymes called the 5′-nucleotidases (5’-NT) can dephosphorylate activated cladribine. Purines and purine analogues are usually broken down by an enzyme called adenosine deaminase (ADA), but cladribine is relatively resistant to breakdown by ADA. The ratio of DCK:5’-NT, which is very high in lymphocytes compared to other cell types, and cladribine’s resistance to metabolism by ADA explain why cladribine selectively targets lymphocytes (particularly B lymphocytes) and not other cells. Interestingly, when it comes to lymphocytes, B cells are more sensitive to cladribine than T cells, i.e. they are depleted to a greater extent, and cells from the innate immune system are relatively resistant to the effects of cladribine. This unique depletion pattern, particularly of memory B cells, explains why cladribine-treated patients are not at high risk of opportunistic or common bacterial infections or of delayed secondary autoimmunity.

As an IRT, cladribine works by rebooting the immune system. It aims to kill the cells that cause MS or reset the regulatory mechanisms that keep autoreactive cells under control when the immune system recovers.

Efficacy

High. Compared to placebo, cladribine reduced the annual relapse rate in the pivotal trial by nearly 60% and 3-month disability progression by one-third. The rates of no evident disease activity (NEDA) across the 2 years of the trial were close to 50%. Cladribine also slowed down accelerated brain volume loss by ~0.56% per annum. The impact on brain volume loss was more pronounced in patients with clinically isolated syndrome (<0.2% per annum), indicating that cladribine’s effect is greatest when used early. Cladribine is licensed in the UK as a therapy for people with rapidly evolving severe MS naive to treatment or as a second- or third-line therapy for people with highly active MS. It works similarly to alemtuzumab and AHSCT but is a much safer treatment option.

A minority of patients treated with cladribine go into long-term remission with NEIDA. In a long-term follow-up study of 394 participants from the pivotal phase 3 trials population, over 50% of subjects had not started another DMT more than 13 years after last exposure to cladribine, indicating it has a long-term treatment effect.1 Whether some of these individuals are cured or not requires much longer follow-up. Cladribine penetrates the central nervous system (CNS), with levels in the spinal fluid reaching around 25% of those in the blood; this is a sufficiently high level for cladribine to have a treatment effect in CNS-resident lymphocytes.

Class

Selective immune reconstitution therapy (IRT).

Immunosuppression

Yes, short-term, whilst the immune system is depleted. The immune system is competent once reconstitution occurs, typically 6 ̶ 9 months after treatment.

Dosing

Cladribine is given as two courses of oral tablets with a recommended cumulative dose of 3.5 mg/kg body weight over 2 years, i.e. 1.75 mg/kg per year. Each treatment course consists of 2 treatment weeks, one at the beginning of the first month and one at the beginning of the second month of the respective treatment year. The treatment course in year 2 can be delayed for up to 6 months if the lymphocyte counts have not recovered above 800/mm3 (Table 1).  Each treatment week consists of 4 or 5 days on which a patient receives 10 or 20 mg (one or two tablets) daily (Table 2).

Table 1. Dose of cladribine per treatment week by patient weight in each treatment year.

Following completion of the two treatment courses, no further cladribine treatment is required in subsequent years unless there is a recurrence of disease activity. Additional courses are given if breakthrough activity occurs later. Although the label states that no treatment is required in years 3 and 4, retreatment can be safely given with a similar safety profile to the initial two courses. The problem with retreatment in years 3 and 4 relates mainly to reimbursement of the drug because it is licensed as a treatment for a period of 4 years. In many countries, Merck, the manufacturer of Mavenclad, will provide the drug for free in years 3 and 4.

Table 2. Cladribine 10 mg tablets per weekday, given over 4 or 5 days.
Dosage (number of tablets per week) is based on patient’s weight (see Table 1).

Recurrent MS disease activity

If you have recurrent disease activity in year 1 after the first cladribine course, we can bring the second course forward by 3 ̶ 4 months, provided your total lymphocyte count has recovered to 800/mm3. Breakthrough disease activity in year 1 occurs in about one in ten patients. This does not necessarily mean cladribine has failed you, but simply means you need the second course to control your MS disease activity. Disease breakthrough after the second course of cladribine in year 2, particularly if associated with poor depletion of lymphocytes, is considered a treatment failure. Poor depletion of lymphocytes occurs in a very small number of people with MS (<2 ̶ 3% of treated subjects) and likely indicates resistance to cladribine’s mode of action.

As with other IRTs, recurrent MS disease activity after year 2 does not necessarily mean cladribine has failed you. It is simply an indication for retreatment, i.e. giving a third or fourth course of cladribine. Under the NHS England treatment algorithm, we only have permission to administer additional courses after year 4. This is based on NHS England’s cost-effectiveness model and not the science behind cladribine’s mode of action. Please note that if someone has breakthrough MS disease activity after cladribine, there is no reason why another MS DMT cannot be started, provided all the baseline tests are done for that DMT first.

Pre-treatment and prophylaxis treatment

Importantly, no anti-inflammatory pretreatments or prophylactic antivirals and/or antibiotics are required to prevent infusion reactions or infections with cladribine. This differentiates cladribine from the other IRTs, i.e. mitoxantrone, alemtuzumab and AHSCT.

Parenteral cladribine

Oncologists have used intravenous and subcutaneous cladribine (brand names Leustat and Litak) for decades to treat a rare type of leukaemia called hairy cell leukaemia and some types of lymphoma. Therefore, some units offer off-label parenteral cladribine to treat MS. Parenteral cladribine is off patent and is relatively cheap. Hence, it is one of the drugs on the MS-Selfie off-label essential DMT list for treating MS in resource-poor environments. Cladribine as a 10-mg tablet is one of three DMTs added to the 2023 WHO List of Essential Medicines, which indirectly supports the use of parenteral cladribine in its place. The latter will hopefully change when oral cladribine comes off patent and cheaper generic tablets are licensed and become available.

Main adverse events

Herpes zoster virus reactivation

The most common clinically significant adverse event reported with cladribine is herpes zoster, due to reactivation of the varicella-zoster virus (VZV). In clinical trials, the risk of zoster was increased when associated with grade 3 or 4 lymphopenia (<500/mm³). Grade 3 or 4 lymphopaenia was most common in year 2 and tended to occur in subjects who received the second course of cladribine before their lymphocyte counts had recovered to above 800/mm3 following the first course. Delaying the second course of cladribine until the lymphocyte count recovers to above 800/mm3 is recommended: it decreases the likelihood of grade 3 or 4 lymphopaenia and means that VZV infection is less common. In the UK, the Shingrex vaccine is now recommended to all patients with MS before starting immunosuppressive therapies; this is to boost immunity to VZV and further lower the risk of developing zoster (see further information on decreasing your chances of adverse events and Derisking guide).

Infections and other adverse events

As cladribine is an immunosuppressive therapy, it may increase the likelihood of infections. To derisk infections, we recommend routine baseline screening for human immunodeficiency virus (HIV), syphilis, hepatitis B and C and tuberculosis. In addition, we screen for exposure to VZV and, if seronegative, we recommend VZV vaccination before starting cladribine. This is because cladribine only partially depletes the T lymphocytes but leaves enough of them to protect from opportunistic infections, which are uncommon in cladribine-treated patients. For example, to my knowledge, there has been no progressive multifocal leukoencephalopathy (PML) in people with MS treated with cladribine. A minority of patients may experience a non-specific headache post-cladribine. No delayed secondary autoimmunity is seen, differentiating cladribine from other IRTs used to treat MS.

Cladribine is unlikely to be associated with an increased risk of secondary malignancies, but it is contraindicated in MS patients with active malignancies.

Less common adverse events after cladribine include liver toxicity, rash, hypersensitivity reactions, hair loss and neutropaenia.

Understanding the apparent ‘cancer signal’

The Mavenclad SmPC (Summary of Product Characteristics) states that cladribine is associated with an increased incidence of cancers. This risk has dissipated as more data have emerged. Therefore, on balance and based on the evidence and further analyses explained below, I don’t think cladribine is associated with a secondary malignancy risk.

Clinical trial results

Results from the phase 3 CLARITY trial (two doses of oral cladribine versus placebo in relapsing forms of MS) showed an imbalance in cancers, which resulted in an obvious cancer signal, i.e. an increased risk of developing cancer in the future. Four subjects in the two treatment arms developed cancers, compared with no cancers in the placebo arm, i.e. a two-to-zero ratio.2 When you have zero in the denominator, there will always be a signal. This is why the regulators include cancer as a risk in the Mavenclad label and why it is part of a black-box warning in the USA.

When my colleagues assessed the cancer rate in cladribine-treated trial subjects, they found it was very similar to cancer rates associated with other MS DMTs.3 The cancer rate, however, was abnormally low in the placebo-treated arm of the CLARITY trial. This low cancer rate in the comparator (placebo) arm rather than a high rate in the treatment arm is, I believe, what was driving the apparent cancer signal in the trial. Just one cancer in the placebo arm would have removed the treatment-associated cancer signal.

Cancer types and timing

Moreover, emerging data suggest the risk recorded in the Mavenclad label is not an obvious cancer signal, at least not in the short-to-intermediate term. The types of cancers seen in CLARITY (one case each of breast cancer, pancreatic cancer, melanoma and choriocarcinoma of the uterus) are not those associated with immunosuppression. Apart from choriocarcinoma, which is derived from the placenta and is pregnancy related, the other three cancers may take years to evolve and were probably developing before cladribine exposure. The cancers typically seen with immunosuppression are basal and squamous cell cancers of the skin and lymphomas; reassuringly, we haven’t seen excess numbers of cancers these in cladribine-treated patients.

When we followed up the placebo-treated patients a few years after the phase 3 trials, they had a higher cancer rate than patients in the active treatment arms who were exposed to cladribine. This suggests the placebo-treated subjects didn’t develop their cancers during the trial but did so afterwards; this type of lag-time bias can happen by chance.

Comparison with global cancer rates

We then compared the cancer rate in the cladribine-treated patients to what is expected in the general population. To do this you compare the rates in cladribine-exposed patients to the cancer rate in the global cancer registry. This gives a standardised incidence rate (SIR) very close to one, i.e. the expected cancer rate. Over time, the SIR has remained close to one (no increased risk); more importantly, however, the confidence intervals around this value have become very small or narrow. This makes it highly likely that no cancer signal is associated with cladribine treatment.

Another clue to the cladribine cancer signal being a false-positive comes from the oncology registers of patients who have received cladribine and related drugs for hairy cell and chronic lymphoid leukaemia. In this register, there was no increased cancer signal despite these patients being much older than people with MS treated with cladribine.4

Perception inferred from oncology indication

Finally, contrary to what many people think, cladribine is not a mutagen. Although it works through DNA mechanisms, by triggering apoptosis or cell death, it does not cause direct mutations in DNA. The correct term for a drug like this is a clastogen. I suspect the legacy of cladribine has been determined by the fact it was repurposed from oncology; therefore, it is assumed by inference to be a mutagen that must damage DNA and be cytotoxic. Cladribine’s mode of action is very nuanced, and it is not a cytotoxic therapy. Cladribine gradually causes apoptosis of cells that occurs over weeks to months and is not associated with cell lysis syndrome.

Although the Mavenclad SmPC states cladribine is contraindicated in people with MS with active malignancies, the decision is more  complex than this and an individual benefit:risk evaluation should be performed before initiating cladribine. Because cladribine is an IRT with only moderate, short-term immunosuppression it provides an advantage in some patients with prior malignancy because it puts MS into remission and allows normal immune function after immune reconstitution. Please note that all cladribine-treated people with MS should be advised to follow standard cancer screening guidelines, which differ from country to country.

Pharmacovigilance monitoring requirements

Baseline

Full blood count, urea and electrolytes, liver function tests, thyroid function tests, serum immunoglobulin levels, serology (VZV, human immunodeficiency virus 1 and 2, hepatitis B and C, TB ELISpot), up-to-date cervical smear and/or human papillomavirus testing, a pregnancy test and baseline blood pressure are done.

Follow-up

Lymphocyte counts should be determined before initiating the second course of cladribine in year 2. A full blood count and liver function tests are done 2 and 6 months after the start of treatment in each treatment year. If the lymphocyte count is below 500 cells/mm³, some neurologists advise viral prophylaxis and actively monitor lymphocyte counts until they increase again. This is not my practice because the onset of zoster infection is not always synchronised with the period of lymphopaenia and if you don’t treat cladribine-induced lymphopaenia there is little point in monitoring it frequently. Cladribine-treated patients are told to be vigilant for any clinical signs and/or symptoms such as unexplained bleeding, bruising, nausea, vomiting, abdominal pain, fatigue, loss of appetite, jaundice and/or dark urine and a temperature or other symptoms of an infection. As with all immunosuppressive therapies, it is essential to detect infections early to treat them promptly.

Rebaselining

A rebaseline MRI scan needs to be done after cladribine. I recommend this is done 18 ̶ 24 months after starting treatment and that Gd-enhancement is included as part of the rebaselining MRI. A monitoring MRI is then done annually thereafter.

Women of childbearing potential and pregnancy

If you are a woman of childbearing age, before starting cladribine we require a negative urine pregnancy test. Cladribine is potentially teratogenic, i.e. it may cause birth defects. We don’t advise patients to fall pregnant or father a child until at least 6 months after the last exposure to cladribine. However, in the case of an unplanned pregnancy in the so-called at-risk period, we would not recommend a termination of pregnancy. Cladribine has a short half-life and is undetectable after a week of dosing. We simply refer patients to the high-risk pregnancy clinic for close monitoring. Ideally, women with MS should delay falling pregnant until after they have completed their second course of cladribine. If a woman falls pregnant before the second course, we simply delay the treatment until after delivery and once breastfeeding has stopped.

Breastfeeding

We don’t recommend cladribine whilst breastfeeding. It is a small molecule and will cross over into the breast milk. We advise pregnant women to wait until 10 days after the last exposure to cladribine before breastfeeding.

Fertility

There is no evidence that cladribine affects either male or female fertility. In animal studies, cladribine did not affect male fertility, but transiently decreased sperm counts. This is why we recommend that men treated with cladribine wait for 6 months after completing a treatment course before trying to father a child.

Vaccination

It is recommended that cladribine patients are immune to VZV prior to treatment. Patients should also be offered the Shingrex component or inactive vaccine to boost immunity to VZV prior to treatment. There is no reason why patients receiving cladribine can’t receive component or inactivated vaccines. However, the use of live attenuated vaccines may carry a risk of infections and – based on the current recommendation – should be avoided whilst immunosuppressed. However, once patients have reconstituted their immune function, they can receive live vaccines safely. The latter is one of the advantages of cladribine and other IRTs.

Travel

People with MS need to be aware that being on cladribine may affect travel; for example, some countries require vaccination against yellow fever, which is a live attenuated vaccine. The yellow fever vaccine will therefore have to be given prior to starting cladribine or after immune reconstitution if planning travel to countries affected by yellow fever.

Summary of Product Characteristics (SmPC)

Mavenclad.

Switching-2-cladribine

Interferon and glatiramer acetate

In general, cladribine can be started immediately after discontinuation of interferon or glatiramer acetate. All the recommended baseline screening tests and vaccination reviews must be done before starting cladribine.

Natalizumab

Owing to the risk of rebound activity on stopping natalizumab, a prolonged wash-out period is not recommended. Most often, the reason for switching from natalizumab to cladribine, or another DMT, is to reduce the risk of carry-over PML from natalizumab. In our centre, we do an MRI and a lumbar puncture for cerebrospinal fluid analysis to exclude JC virus-DNA on polymerase chain reaction testing. Provided these two tests are clear, we would typically initiate cladribine as soon as possible after the last natalizumab infusion. All the recommended baseline screening tests and vaccination reviews must be done before starting cladribine.

S1P modulators (fingolimod, siponimod, ozanimod and ponesimod)

Because fingolimod has quite a long half-life, some neurologists recommend a short washout period, i.e. 4 ̶ 6 weeks; this may be appropriate, depending on the reason for switching. I recommend waiting for the total peripheral lymphocyte counts to exceed 800/mm3 to exclude the uncommon occurrence of persistent lymphopaenia following S1P modulator administration. All the recommended baseline screening tests and vaccination reviews must be done before starting cladribine. If you are switching because of abnormal liver function tests on an S1P modulator, you would ideally want the liver enzymes to normalise or at least drop to below three times the upper limit of normal before starting cladribine.

Fumarates

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting cladribine. If lymphopaenia is the main reason for switching from a fumarate, I recommend waiting for the total peripheral lymphocyte counts to exceed 800/mm3 before starting cladribine.

Teriflunomide

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting cladribine. I recommend that the total peripheral lymphocyte counts are above 800/mm3 before starting cladribine. We don’t routinely do an accelerated washout of teriflunomide before starting cladribine.

Anti-CD20 therapies (selective cell depleting DMTs)

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting cladribine. If patients are switching for safety concerns, it would be advisable to wait for B cell counts to recover first. If patients are switching for loss of efficacy on an anti-CD20, there is no need to wait for B-cell recovery.

Mitoxantrone/alemtuzumab/AHSCT

I recommend waiting for the neutrophil and total peripheral lymphocyte counts to go above 1,000/mm3 and 800/mm3, respectively. All the recommended baseline screening tests must be done before starting cladribine.

References

  1. Giovannoni G, et al. Long-term follow-up of patients with relapsing multiple sclerosis from the CLARITY/CLARITY Extension cohort of CLASSIC-MS: An ambispective study. Mult Scler 2023;29:719 ̶ 30.
  2. Giovannoni G, et al.  A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med 2010;362:416 ̶ 26.
  3. Pakpoor J, et al. No evidence for higher risk of cancer in patients with multiple sclerosis taking cladribine. Neurol Neuroimmunol Neuroinflamm 2015;2:e158.
  4. Cheson BD, et al. Second malignancies as a consequence of nucleoside analog therapy for chronic lymphoid leukemias. J Clin Oncol 1999;17:2454-60.
DMTsShort

Alemtuzumab – short summary

Summary

Alemtuzumab is a monoclonal antibody that targets the surface molecule CD52 on white blood cells or leukocytes. It is given as two courses of intravenous infusions. The first course is five infusions, usually given over five consecutive days in year 1. The second course is three infusions over three consecutive days in year 2. Alemtuzumab works by depleting your white cells and then allowing them to recover over several months. It is an immune reconstitution therapy (IRT); hence, after your immune system returns to normal, hopefully without the cells that cause MS, it can fight infections, respond to vaccines and provide peripheral immune surveillance for tumours. Alemtuzumab is the most effective licensed MS DMT in network analyses comparing it to other DMTs. It promotes a high rate of ‘no evident disease activity’ and prevents or slows down disability worsening; many patients treated with alemtuzumab also notice a sustained improvement in disability. In addition, alemtuzumab effectively ‘normalises’ the accelerated brain volume loss that occurs in people with MS. Its effect on brain volume loss can be explained partially by the fact that alemtuzumab was used early and in relatively young patients with MS in the clinical trials.

The most common adverse effects are infusion reactions, infections and delayed secondary autoimmunity. The adverse event profile changes when alemtuzumab is used in older patients, particularly those with comorbidities. A minority of patients treated with alemtuzumab go into long-term remission with no evident inflammatory disease activity (NEIDA) and no evidence of ongoing end-organ damage. Whether these individuals are cured will require much longer follow-up. Alemtuzumab works similarly to AHSCT (autologous haemopoietic stem cell transplantation) but is a much safer treatment option. 

Trade name

Lemtrada.

Mode of action

An immune reconstitution therapy (IRT) that works by rebooting the immune system. 

Efficacy

Very high.

Class

IRT.

Immunosuppression

Yes, short-term, whilst the immune system is depleted.

Dosing

Two annual courses with up to two additional treatment courses later if needed.

  • Year 1: five 12 mg doses given as five daily intravenous infusions (60 mg total).
  • Year 2: three 12 mg doses given as three daily intravenous infusions (36 mg total). 

Alemtuzumab can be administered successfully by the subcutaneous route in patients who cannot take steroids.

Pre-treatment and prophylaxis treatment

Our centre has a protocol of drugs we administer before alemtuzumab infusions to prevent inflammatory reactions, pain, infection and other common side effects. Guidance about listeriosis prevention is also important.

Main adverse events

  • Infusion reactions: most infusion reactions are mild to moderate; severe infusion reactions are uncommon in patients pretreated with steroids.
  • Infections, notably during the first 4 weeks after starting treatment. Common community-acquired infections (usually mild) can occur later; more serious, opportunistic infections occur in only 2 ̶ 3% of treated patients.
  • Delayed secondary autoimmunity. The most common autoimmune diseases are Grave’s disease, immune thrombocytopenic purpura and Goodpasture’s syndrome. These autoimmune diseases are treatable, generally monophasic (occur just once) and reversible. 
  • Additional adverse events (e.g. cardiovascular and respiratory) have been seen in older people with more advanced MS and multiple comorbidities or risk factors.

Pharmacovigilance monitoring requirements 

  • Standard blood tests and comprehensive screening for infection, pregnancy and blood pressure are done at baseline.
  • A full blood count and urine assessments are done monthly after starting alemtuzumab and up to 4 years after the last course.
  • Unexplained clinical signs and/or symptoms must be detected early and treated promptly. Delayed secondary autoimmunity complications can be avoided with vigilance and monthly blood monitoring.
  • A rebaseline MRI scan should be done 18 ̶ 24 months after starting treatment, including Gd-enhancement. A monitoring MRI is performed annually after that. 
  • Women of childbearing age require a negative urine pregnancy test before starting alemtuzumab. Breastfeeding is not advised. 

Further details about alemtuzumab

Switching-2-alemtuzumab

Switching

Switching-2-alemtuzumab

Possible reasons to switch

  • Alemtuzumab is the most effective licensed MS DMT in network analyses that compare it to other DMTs.
  • It promotes a high rate of ‘no evident disease activity’.
  • Many patients treated with alemtuzumab notice a sustained improvement in disability.
  • Alemtuzumab effectively ‘normalises’ the accelerated brain volume loss that occurs in people with MS.

Reasons for caution

  • Infusion reactions, infections and delayed secondary autoimmunity are the most common adverse effects of alemtuzumab.
    • Most infusion reactions are mild to moderate.
    • Infection risk is greatest during the first 4 weeks after starting course 1 of alemtuzumab, but infections (sometimes serious) can occur after this time.
    • Patients considering alemtuzumab treatment must be prepared for monthly blood and urine monitoring and the significant risk of developing a secondary autoimmune disorder.
  • The risk:benefit ratio of alemtuzumab changes dramatically in older patients with more advanced MS, particularly those with comorbidities.
  • It is not advisable for women receiving alemtuzumab to fall pregnant or breastfeed whilst significantly immunosuppressed.

Interferon and glatiramer acetate

Generally, alemtuzumab can be started immediately after discontinuing interferon or glatiramer acetate. Before starting alemtuzumab, all the recommended baseline screening tests and vaccination reviews must be done.

Natalizumab

A prolonged wash-out period is not recommended due to the risk of rebound activity on stopping natalizumab. Most often, the reason for switching from natalizumab to alemtuzumab or another DMT is to reduce the risk of carry-over PML (progressive multifocal leukoencephalopathy) from natalizumab. In our centre, we do an MRI and a lumbar puncture for cerebrospinal fluid analysis to exclude JC virus-DNA on polymerase chain reaction testing. Provided these two tests are clear, we would typically initiate alemtuzumab immediately after the last natalizumab infusion. We offer a 6 ̶ 12-month bridge on fingolimod to patients at very high risk of carry-over PML. This bridge on fingolimod, which is reversible, means we can exclude carry-over PML that typically declares itself within 6 months. Before starting alemtuzumab, all the recommended baseline screening tests and vaccination reviews must be done.

S1P modulators (fingolimod, siponimod, ozanimod and ponesimod)

Because fingolimod has quite a long half-life, some neurologists recommend a short washout period, i.e. 4 ̶ 6 weeks; this may be appropriate, depending on the reason for switching. I recommend waiting for the total peripheral lymphocyte counts to exceed 800/mm3 to exclude the uncommon occurrence of persistent lymphopaenia following S1P modulator administration. Before starting alemtuzumab, all the recommended baseline screening tests and vaccination reviews must be done. If you are switching because of abnormal liver function tests on an S1P modulator, you would ideally want the liver enzymes to normalise or at least drop to below three times the upper limit of normal before starting alemtuzumab.

Fumarates

All the recommended baseline screening tests and vaccination reviews must be done before starting alemtuzumab. If lymphopaenia is the main reason for switching from fumarate, I recommend waiting for the total peripheral lymphocyte counts to exceed 800/mm3 before starting alemtuzumab. 

Teriflunomide

All the recommended baseline screening tests and vaccination reviews must be done before starting alemtuzumab. I recommend waiting for the total peripheral lymphocyte counts to exceed 800/mm3 before starting alemtuzumab. We don’t routinely do an accelerated washout of teriflunomide before starting alemtuzumab. 

Anti-CD20 therapies (selective cell depleting DMTs)

All the recommended baseline screening tests and vaccination reviews must be done before starting alemtuzumab. If patients are switching for safety concerns, it is advisable to wait for B-cell counts to recover before starting alemtuzumab. Some neurologists prefer starting alemtuzumab before B-cell recovery as a potential strategy to prevent secondary autoimmunity. If patients are switching for loss of efficacy on an anti-CD20, there is no need to wait for B-cell recovery. 

Cladribine (selective cell depleting DMT)

All the recommended baseline screening tests and vaccination reviews must be done before starting alemtuzumab. I recommend waiting for the total peripheral lymphocyte counts to exceed 800/mm3.

Mitoxantrone

I recommend waiting for the neutrophil and total peripheral lymphocyte counts to go above 1,000/mm3 and 800/mm3, respectively, before starting alemtuzumab. All the recommended baseline screening tests and vaccination reviews must be done first.

HSCT

I recommend waiting for the neutrophil and total peripheral lymphocyte counts to go above 1,000/mm3 and 800/mm3, respectively, before starting alemtuzumab. All the recommended baseline screening tests must be done first.