Tag Archives: switching

What are the attributes of the specific DMTs?

05/09/2024 Gavin Giovannoni

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.

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.

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.²AHSCT, 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

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.
Giovannoni G. Disease-modifying treatments for early and advanced multiple sclerosis: a new treatment paradigm. Curr Opin Neurol 2018;31:233 ̶ 43.
Samjoo IA, et al. Efficacy classification of modern therapies in multiple sclerosis. J Comp Eff Res 2021;10:495–507.

Switching

Switching-2-cladribine

30/10/2023 Gavin Giovannoni

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.

Switching

Switching-2-alemtuzumab

03/10/2023 Gavin Giovannoni

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

Switching

Switching-2-fumarates

31/08/2023 Gavin Giovannoni

Possible reasons to switch

Fumarates are licensed in the UK as first-line therapy for people with active MS. Their efficacy is moderate to high.
Although fumarates are not recommended during pregnancy or in women of childbearing potential not using appropriate contraception, they have no known potential to cause foetal abnormalities during pregnancy.
There is no evidence that fumarates affect either male or female fertility.

Reasons for caution

Most people with MS who start taking a fumarate develop gastrointestinal side effects such as cramps, abdominal pain and occasional diarrhoea. These are transient (8 ̶ 12 weeks).
Another common but transient side effect is flushing, or redness of the face and upper body.
The twice-daily dosing regimen can lead to poor adherence in some patients.
PML and other opportunistic infections are rare on fumarates. However, extra vigilance is recommended in patients who are lymphopaenic.

Please note that fumarates are not recommended as second-line therapy on the UK National Health Service. The following advice is for people with MS who are considering switching to a fumarate because of tolerance or safety issues with other DMTs.

Interferon and glatiramer acetate

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

Natalizumab

Owing to the risk of rebound activity on stopping natalizumab, a prolonged wash-out period is not recommended before starting a fumarate. Most often, the reason for switching from natalizumab to a fumarate (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 JCV-DNA on polymerase chain reaction. Provided these two tests are clear, we typically initiate a fumarate as soon as possible after the last natalizumab infusion. However, we tend not to use a fumarate post-natalizumab because the evidence that this drug class can prevent rebound activity is not as strong as for S1P modulators or anti-CD20 therapies. All the recommended baseline screening tests and reviews must be done before starting a fumarate.

S1P modulators

Some neurologists recommend a short washout period before switching from an S1P modulator (e.g. 4 ̶ 6 weeks in the case of fingolimod), because of the long half-life of this drug class. I recommend waiting for the total peripheral lymphocyte count to go above 800/mm³ to exclude the uncommon occurrence of persistent lymphopaenia post-fingolimod and other S1P modulators. It is important that all the recommended baseline screening tests and necessary reviews are done before starting a fumarate. If the switch is because of abnormal LFTs on an S1P modulator, the liver enzymes ideally need to normalise or at least drop to below three times the upper limit of normal before starting a fumarate.

Teriflunomide

It is important that all the recommended baseline screening tests and necessary reviews are done before starting a fumarate. If the main reason for switching from teriflunomide is leukopaenia or abnormal LFTs, I recommend waiting for the lymphocyte counts to go above 800/mm³ and for the liver enzymes to normalise or at least drop to below three times the upper limit of normal before starting a fumarate.

Alemtuzumab

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting a fumarate. I would recommend first waiting for the total peripheral lymphocyte counts to go above 800/mm³. A switch should be considered only if there are tolerance or safety issues with the current DMT. On the UK National Health Service (NHS), fumarates are not recommended after alemtuzumab, but this does not necessarily apply to other healthcare systems.

Anti-CD20 therapies (selective cell depleting DMTs)

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting a fumarate. On the NHS, a switch should be considered only if there are tolerance or safety issues with the current DMT. However, this does not necessarily apply to other healthcare systems.

Cladribine (selective cell depleting DMT)

Mitoxantrone

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting a fumarate. I recommend first waiting for the neutrophil and lymphocyte counts to go above 1,000/mm³ and 800/mm³, respectively. A switch should be considered only if there are tolerance or safety issues with the current DMT.

HSCT

It Is important that all the recommended baseline screening tests are done before starting a fumarate. I recommend first waiting for the neutrophil and lymphocyte counts to go above 1,000/mm³ and 800/mm³, respectively. A switch should be considered only if there are tolerance or safety issues with the current DMT.

Fumarate: maintenance to starting dose reduction

The starting dose of dimethyl fumarate, 120 mg twice a day for 7 days, is increased to the recommended maintenance dose of 240 mg twice a day after induction if well tolerated.
Likewise, the starting dose of diroximel fumarate, 231 mg twice a day for 7 days, is increased to the recommended maintenance dose of 462 mg twice a day if well tolerated.

A temporary dose reduction to 120 mg twice a day (dimethyl fumarate) or 231 mg twice a day (diroximel fumarate) may reduce the occurrence of flushing and gastrointestinal symptoms. However, the recommended maintenance dose of 240 mg twice a day or 462 mg twice a day for dimethyl fumarate or diroximel fumarate, respectively, should be resumed within the next 4 weeks. Fumarates should ideally be taken with food, particularly fatty foods, to improve their tolerability.

If you miss a dose, do not take a double dose. You may take the missed dose only if you leave 4 hours between doses. Otherwise, you should wait until the next scheduled dose.

Switching

Switching-2-HSCT (haematopoietic stem cell transplant)

08/08/2023 Gavin Giovannoni

Possible reasons to switch

HSCT is indicated as part of routine clinical care in the occasional patient with malignant MS who has failed licensed treatment options. In such patients, the benefits of HSCT outweigh the risks of the disease.
Provided you have sufficient reserve capacity in the brain and spinal cord, you will see spontaneous recovery from relapse-related disability once inflammation is switched off, and recovery mechanisms can proceed.
Please note the benefit ̶ risk ratio changes with more advanced disease; most HSCT units have age and disability cut-offs for people with MS.

Reasons for caution

There is a 0.3% ̶ 2% chance of dying from non-myeloablative HSCT, i.e. 1 in 330 to as high as 1 in 50.
The toxicity associated with the chemotherapy is severe, including nausea, vomiting, diarrhoea, hair loss, bleeding, infections, infertility and neurotoxicity.
There is a chance of developing a secondary cancer.
The short-term risks and side effects from the intense chemotherapy used in myeloablative HSCT are much worse than with non-myeloablative–HSCT, including possible solid organ toxicity or the need for platelet and blood transfusions.
The risk of infertility from the chemotherapy used in HSCT is high in both men and women; pregnancy is contraindicated.
You may need to be revaccinated with all your childhood vaccines about 2 years after HSCT to restore your immune responses to these common infections.

Weighing the risks

There are different intensities of bone marrow ablation. So-called myeloablative therapy aims to wipe out your immune system entirely and replace it with a new immune system. Non-myeloablative therapy is less intense: it partially depletes your immune system and allows it to be rebooted (partially). Non-myeloablative therapy is less toxic and less risky than myeloablative therapy, but also less effective. A recurrence of disease activity is therefore more likely after non-myeloablative HSCT than after myeloablative–HSCT.

No person will sign up to HSCT believing they will die or develop complications. However, inevitably some will be unlucky and have serious complications, delayed adverse events or even die from the procedure. If you decide to have HSCT as part of a trial or routine care, you need to ask yourself: What if I am the unlucky one? Am I ready to leave my family and loved ones prematurely? If you answer ‘yes’ to both questions, you are ready to take the risks.

HSCT repeat course

HSCT is not a typical IRT in that it is usually given as a single one-off treatment. Therefore, breakthrough MS disease activity after HSCT usually triggers the introduction of another licensed DMT. However, there are case reports of patients with MS and other autoimmune diseases having repeat HSCT.

DMTs

HSCT is indicated as part of routine clinical care in the occasional patient with malignant MS who has already failed licensed treatment options. In such patients, the benefits of HSCT outweigh the risks of the disease. Provided the baseline screening tests are acceptable and there are no specific contraindications in an individual patient, I see no reason why HSCT can’t be used after any licensed DMTs. However, there are some specific caveats highlighted below.

Interferon-beta and glatiramer acetate

Alemtuzumab and mitoxantrone (non-selective cell depleting DMTs)

A persistently low peripheral white cell count post-alemtuzumab or post-mitoxantrone, i.e. a neutrophil count <1000/mm³ or a total lymphocyte count <800/mm³, is a relative contraindication to HSCT. Another hit on the bone marrow and the primary and secondary lymphoid organs may worsen your leukopaenia and render you more immunosuppressed. The decision to use HSCT in this situation must be based on the potential benefits of HSCT versus its risks and the risks of untreated active MS. Please see the section on Special circumstances, below, relating to the possible development of chemotherapy-related cardiomyopathy post- mitoxantrone.

Cladribine (selective cell-depleting DMT)

A persistently low peripheral lymphocyte cell count post-cladribine, i.e. a total lymphocyte count <800/mm³, is a relative contraindication to HSCT. The effect of HSCT on primary and secondary lymphoid organs may worsen lymphopaenia. However, the decision to use HSCT after cladribine must be based on the potential benefits of HSCT versus the risks of lymphopaenia and the risks of untreated active MS.

Anti-CD20 therapies (selective cell depleting DMTs)

As ocrelizumab, ofatumumab, rituximab and ublituximab are selective B cell-depleting agents, it is theoretically much safer to use HSCT after one of these DMTs than after the other less selective and non-selective agents. An anti-CD20 is the safest cell depleting DMT to use before HSCT.

S1P modulators (fingolimod, siponimod, ozanimod and ponesimod)

Chemotherapy is used before HSCT to ‘mobilise’ the stem cells (that is, cause them to move from the bone marrow into the blood). Therefore, an adequate wash-out period is needed after stopping an S1P modulator before starting the HSCT procedure to allow recovery of peripheral lymphocyte counts. To prevent persistent lymphopaenia post-HSCT, the peripheral lymphocyte counts must return towards normal (>800/mm³) or be normal (>1,000/mm³) before starting HSCT.

Natalizumab

As HSCT is a non-selective IRT that can’t be rapidly reversed, it is critical to ensure against asymptomatic PML. Carry-over PML from natalizumab to HSCT would potentially be fatal. A baseline MRI scan and possibly a CSF examination must therefore be done before starting HSCT, to exclude possible PML.

Fumarates

Fumarates reduce the lymphocyte count by approximately 30% in people with MS, or by even more in some individuals. Therefore, patients with lymphopaenia while taking a fumarate may be more susceptible to developing clinically significant prolonged lymphopaenia post-HSCT.

Teriflunomide

Because teriflunomide is an antiproliferative agent, it may delay or prevent the recovery of the peripheral white cell count post-HSCT. One option is to do an accelerated teriflunomide washout to prevent this potential problem. Interestingly, rheumatologists who use leflunomide, a prodrug converted to teriflunomide, don’t use an accelerated washout when using antiproliferative agents post-leflunomide.

Special circumstances

Specific comorbidities and adverse events may make it difficult to start HSCT after certain DMTs, for example, the development of chemotherapy-related cardiomyopathy post-mitoxantrone.

Switching

Switching-2-teriflunomide

10/07/2023 Gavin Giovannoni

Possible reasons to switch

Teriflunomide reduces the relapse rate and acquisition of disability by ~30%.
It reduces MRI activity by ~70% and slows down brain volume loss.
It is not immunosuppressive; no increase in serious infections has been observed with teriflunomide.
Teriflunomide is not associated with a blunted antibody response to vaccines or low lymphocyte counts.
People who start teriflunomide as a second-line or third-line DMT do better than those using it first-line; the reason for this is unclear.

Reasons for caution

The European Medicines Agency (EMA) requires blood monitoring to be done every 4 weeks for 6 months and regularly after that when teriflunomide is started.
People with pre-existing liver disease or those who consume excessive quantities of alcohol may be at increased risk of developing elevated liver enzymes on teriflunomide.
It is unsuitable for women of childbearing age who are planning to start, or extend, their families. Women on teriflunomide should not breastfeed.
It takes many months to eliminate teriflunomide from the body on stopping treatment; therefore, contraception must be continued during the drug elimination period.
Severe hypersensitivity skin reactions have been reported on teriflunomide; please look out for any skin rash.

Interferon and glatiramer acetate

In general, teriflunomide can be started immediately after discontinuation of interferon or glatiramer acetate. It is important that all the recommended baseline screening tests and vaccination reviews are done before starting teriflunomide.

Natalizumab

Owing to the risk of rebound activity on stopping natalizumab, a prolonged wash-out period is not recommended before starting teriflunomide. Most often the reason for switching from natalizumab to teriflunomide, 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 teriflunomide as soon as possible after the last natalizumab infusion. We tend, however, not to use teriflunomide post-natalizumab because the data demonstrating that teriflunomide can prevent rebound activity is not as strong as for fingolimod and anti-CD20 therapies. All the recommended baseline screening tests and vaccination reviews must be done before starting teriflunomide.

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 go above 800/mm³ to exclude the uncommon occurrence of persistent lymphopaenia following S1P modulator administration. It is important that all the recommended baseline screening tests and vaccination reviews are done before starting teriflunomide. If you are switching because of abnormal liver function tests on a 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 teriflunomide.

Fumarates

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

Alemtuzumab

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting teriflunomide. I recommend waiting for the total peripheral lymphocyte counts to go above 800/mm³before starting teriflunomide.

Anti-CD20 therapies (selective cell depleting DMTs)

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting teriflunomide.

Cladribine (selective cell depleting DMT)

Mitoxantrone

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 and vaccination reviews must be done before starting teriflunomide.

HSCT

Switching

Switching-2-natalizumab

28/06/2023 Gavin Giovannoni

Possible reasons to switch

Natalizumab is a very high-efficacy DMT capable of achieving long-term NEIDA (no evident inflammatory disease activity) and limiting end-organ damage (brain volume loss) in most people with MS who receive it.
Following rebaselining, the average annual brain volume loss for patients treated with natalizumab is within the expected range for age-matched people without MS.
When natalizumab is used early in the disease course, many people with MS report a reduction in symptoms of disability, fatigue and brain fog.
Studies in humans suggest natalizumab exposure has no adverse effect on pregnancy outcomes.

Reasons for caution

Natalizumab is an immunosuppressive therapy and has been associated with opportunistic infections, of which the JC virus (JCV) is the commonest.
Patients who are seropositive for JCV are at greatly increased risk of developing progressive multifocal leukoencephalopathy (PML), a serious, potentially fatal complication of natalizumab treatment.
If you have a central nervous infection, care is needed when switching from an S1P modulator or fumarate to natalizumab because it will blunt the immune response towards the infectious agent.
If switching from teriflunomide to natalizumab to increase disease control or to attempt pregnancy, rapid teriflunomide elimination is needed because of its long half-life and potentially toxic effects on the foetus.
Cladribine, anti-CD20s, alemtuzumab, mitoxantrone and HSCT are all immunosuppressive therapies; if you are JCV-seropositive, switching from any of these DMTs to natalizumab will increase your risk of developing PML.

Natalizumab

Recent data have shown that increasing the dosing interval between natalizumab infusions (extended interval dosing, EID) will lower the risk of developing PML.

Restarting natalizumab

Before restarting natalizumab it is important to do routine blood tests, a baseline MRI and check for anti-natalizumab antibodies. The presence of anti-natalizumab antibodies increases the risk of developing infusion reactions and is a contraindication to restarting natalizumab. It is not uncommon for someone with MS to want to switch back to natalizumab after trying another DMT. Natalizumab is known to reduce MS-related fatigue and brain fog, and this often returns when it washes out. The ability to reduce PML risk with EID will increase the number of patients requesting to go back onto natalizumab to help manage such cognitive symptoms.

Other DMTs

In general, natalizumab can be used after any of the DMTs provided the baseline screening bloods are satisfactory and there are no contraindications to the specific DMT. Some important caveats are highlighted below.

Interferon-beta and glatiramer acetate

I have no concerns and would not recommend any specific washout period after stopping either IFN-beta or glatiramer acetate.

Alemtuzumab and HSCT (non-selective cell depleting DMTs)

If you wish to start natalizumab after alemtuzumab or HSCT because of recurrent disease activity, I suggest doing so as soon as possible. Alemtuzumab and HSCT are immunosuppressive therapies, however, so if you are JCV-seropositive they will greatly increase your risk of developing PML and will render the so-called anti-JCV index unreliable. If your MS is not active post-alemtuzumab or HSCT, I would question the need for natalizumab because both these DMTs can induce long-term remission.

Cladribine and anti-CD20 therapies (selective cell depleting DMTs)

If you wish to start natalizumab after cladribine or an anti-CD20 therapy because of recurrent disease activity, then I would suggest doing so as soon as possible. Cladribine and anti-CD20s are immunosuppressive therapies, however, so if you are JCV-seropositive they will increase your risk of developing PML and will render the so-called anti-JCV index unreliable. If your MS is not active post-cladribine or an anti-CD20, I would question the need for natalizumab because these DMTs can induce long-term remission.

S1P modulators (fingolimod, siponimod, ozanimod and ponesimod)

No washout period is required when switching from an S1P modulator to natalizumab. However, if you have an infectious complication, particularly a CNS infection, then you would be ill-advised to start natalizumab until the CNS infection has been cleared. Natalizumab will prevent lymphocyte trafficking into the CNS and hence will blunt the immune response to the infectious agent.

Fumarates (dimethyl fumarate and diroximel fumarate)

No washout period is required when switching from a fumarate to natalizumab. The same warning about CNS infections applies to fumarates as to S1P modulators mentioned above.

Teriflunomide

No teriflunomide washout period is required when switching to natalizumab. However, if your reason for switching to natalizumab is to control MS disease or fall pregnant, then you will need to undergo rapid teriflunomide elimination because of its long half-life and potential for teratogenicity.

Mitoxantrone

Mitoxantrone is an immunosuppressive therapy. Therefore, if you are JCV-seropositive it will increase your risk of developing PML and will render the so-called anti-JCV index unreliable.

Special circumstances

The presence of specific comorbidities and adverse events may make it difficult to start natalizumab after certain DMTs. These are, however, uncommon in routine clinical practice.

What about switching from natalizumab to another DMT?

A switch is relatively straightforward if you are JC virus-seronegative and are switching because of lack of efficacy or for a lifestyle choice, for example:

you are tired of monthly infusions (please note, however, there is now a subcutaneous formulation that is given as two injections)
you want an immune reconstitution therapy (IRT) that offers the freedom to fall pregnant without worrying about rebound activity
you simply prefer the long-term potential of an IRT.

In this situation, switching from natalizumab without a washout period, to prevent rebound disease activity after natalizumab, makes sense and should be a relatively safe option.

The situation if you are JC virus-seropositive is much more problematic because of the risk of carry-over PML. With a maintenance agent, such as an S1P modulator, we simply exclude asymptomatic PML by doing an MRI and, if you want to be extra vigilant, a lumbar puncture to look for JCV DNA in the spinal fluid. If these tests are clear, we start the S1P modulator as soon as possible after the last natalizumab infusion, knowing that if PML should develop we can stop the S1P modulator and it will be cleared from the body within 4 ̶ 6 weeks or less (depending which S1P modulator you are taking). This early switching strategy also prevents rebound activity when natalizumab wears off after approximately 3 ̶ 4 months.

With an IRT, such as alemtuzumab, things are more complicated because we can’t reverse its action. Hence, we must be confident that there is no carry-over PML. Why am I so concerned? Simple: if you develop carry-over PML post-alemtuzumab, before reconstitution of your immune system, you are likely to succumb to PML – which is potentially fatal. We rely on a functioning immune system, in particular a population of cells called CD8+ cytotoxic T lymphocytes, to clear the JC virus from the brain. CD8+ lymphocytes take many months to reconstitute post-alemtuzumab and other IRTs, during which time the PML is unchecked.

You might argue that by treating MS, a disabling disease, with immunosuppressive therapies we simply create another ticking time bomb and swap one disease, MS, for another disease, immunosuppression. The difference between these two diseases is that MS-related disability is in general irreversible and associated with loss of quality of life. Immunosuppression, on the other hand, can be derisked to some extent and its consequences – in particular, opportunistic infections – can be treated. For more information, please read the sections on each DMT.

We now know that people with MS who are JCV-seropositive either need to come off natalizumab or switch to EID, because of the risk of PML. For high-risk subjects who decide to stay on natalizumab we offer 3-monthly MRI studies to detect asymptomatic PML, which has a better prognosis than symptomatic PML.

Switching

Switching-2-S1P modulators

27/02/2023 Gavin Giovannoni

Possible reasons to switch

S1P modulators are highly effective DMTs and they have been shown to:
- decrease relapse rates
- reduce the development of new lesions visible on magnetic resonance imaging
- reduce disability worsening
- slow down brain volume loss.
For people with MS currently on natalizumab and concerned about progressive multifocal leukoencephalopathy (PML), switching to an S1P modulator may reduce the risk of carry-over PML.

Reasons for caution

S1P modulators cause a transient slowing of the heart rate; they are not recommended if you are already taking medicine(s) that slow your heart rate.
They cause systemic immunosuppression, which increases the risk of opportunistic infections, for example PML and cryptococcal fungal infections, and secondary malignancies.
Rebound MS disease activity often occurs when S1P modulators are stopped.
Visual disturbances can develop owing to swelling of the macula (the central part of the retina). The risk of macular oedema is increased if you have a history of inflammation in the eye or diabetes mellitus.
Most neurologists will avoid using S1P modulators in patients with pre-existing liver or lung disease.
Testing for human papillomavirus infection is recommended prior to starting treatment.
People with MS at high risk of skin lesions (e.g. from previous severe sun damage and/or skin cancer) should be referred for regular skin cancer screening.
Women of child-bearing potential should avoid pregnancy and breast feeding.

Interferon and glatiramer acetate

In general, S1P modulators can be started immediately after discontinuation of interferon or glatiramer acetate. It is important that all the recommended baseline screening tests and vaccination reviews are done before starting S1P modulators.

S1P modulator to S1P modulator switch

In general, switching from one S1P modulator to another is possible. I would recommend rechecking baseline investigations before making the switch and ensuring a 4-week washout with fingolimod, siponimod and ozanimod prior to starting the new agent. With ponesimod, I limit the washout to 7 days. Overlapping the washout of one S1P modulator with the titration phase of the newer agent should prevent rebound activity and limit off-target effects, particularly cardiac events.

Natalizumab

Most often the reason for switching from natalizumab to an S1P modulator is to reduce the risk of carry-over PML from natalizumab. In our centre, we do an MRI and lumbar puncture for cerebrospinal fluid analysis to exclude JC virus DNA on PCR (polymerase chain reaction test). Provided these two tests are clear, we typically initiate S1P modulators within 4 weeks of the last natalizumab infusion. A prolonged wash-out period (8 weeks or longer) is associated with rebound disease activity on stopping natalizumab and is therefore not recommended. It is important that all the recommended baseline screening tests and vaccination reviews are done before starting an S1P modulator.

Teriflunomide

Because teriflunomide has such a long half-life, some neurologists would recommend an accelerated washout using cholestyramine or activated charcoal. Rheumatologists rarely do this when switching patients with rheumatoid arthritis from leflunomide (teriflunomide prodrug) to other DMTs, so I am not sure this accelerated washout is necessary. It is important that all the recommended baseline screening tests and vaccination reviews are done before starting an S1P modulator.

If the main reason for switching from teriflunomide is leukopaenia or lymphopaenia I would recommend waiting for the neutrophil and lymphocyte counts to go above 1,000/mm³ and 800/mm³ respectively. Similarly, if the switch is for abnormal LFTs on teriflunomide you would ideally want the liver enzymes to normalise or at least drop to below 3x the upper limit of normal.

Fumarates

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting an S1P modulator. If the main reason for switching from a fumarate is lymphopaenia, I would recommend first waiting for the peripheral blood neutrophil and lymphocyte counts to go above 1,000/mm³ and 800/mm³, respectively.

Alemtuzumab

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting an S1P modulator. I would recommend first waiting for the total peripheral blood neutrophil and lymphocyte counts to go above 1,000/mm³ and 800/mm³, respectively.

Anti-CD20 therapies (selective cell depleting DMTs)

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting an S1P modulator.

Cladribine (selective cell depleting DMT)

Mitoxantrone

HSCT

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting an S1P modulator. I would recommend first waiting for the peripheral blood neutrophil and lymphocyte counts to go above 1,000/mm³ and 800/mm³ respectively.

Switching

Switching-2-interferon-beta

08/02/2023 Gavin Giovannoni

Possible reasons to switch

In general, interferon-beta (IFN-beta) is not immunosuppressive.
Monitoring requirements are not too onerous.
A failure to respond to other DMTs does not necessarily predict a lack of response to IFN-beta.
Pregnancy: IFN-beta has been shown to be safe in pregnancy.

Reasons for caution

IFN-beta formulations are generally poorly tolerated long-term, owing to injection site reactions and flu-like side effects, often resulting in low adherence.
Their efficacy in preventing brain volume loss and damage to nerve fibres is modest.
IFN-beta formulations can (to varying degrees) induce neutralising antibodies (NABs). The resulting anti-IFN-beta NABs may potentially cross the placenta and affect foetal development.
There is small increased risk of spontaneous abortion when falling pregnant while on IFN-beta treatment.

IFN-beta to IFN-beta switch

The only reason to switch between IFN-beta preparations is for local, or systemic, intolerance. Many patients with local skin, or injection site, reactions move to intramuscular IFN-beta-1a (Avonex), which does not cause local skin reactions. In contrast, many patients move from IFN-beta-1a (Avonex) to IFN-beta-1a (Rebif) or -1b (Betaferon) because of persistent flu-like reactions. Because Avonex allows the interferon receptors to regenerate before the next injections, mild flu-like symptoms can persist; this does not happen with Rebif and Betaferon. Betaferon is administered on alternate days; however, Rebif is given three times per week, and some patients experience mild flu-like side effects after the 2-day injection break (once each week) but not after a 1-day break (twice each week).

NABs

If you have developed NABs to one IFN-beta preparation these cross-react with the other preparations. In this situation NABs would simply neutralise the effect of a new IFN-beta formulation.

Lack of efficacy

I would not recommend switching between IFN-beta preparations because of lack of efficacy or perceived lack of efficacy. If you have had a suboptimal response to one IFN-beta preparation, it will make sense to switch classes. I generally tend to escalate treatment to a more efficacious DMT rather than switch to another moderate efficacy DMT: vertical escalation rather than horizontal switching.

Other DMTs

Provided the baseline screening blood tests are fine and there are no specific contraindications, I see no reason why IFN-beta can’t be used after any of the other licensed DMTs. Apart from NAbs inhibiting the action of other IFN-beta formulations, I am not aware that a failure to respond to a different DMT predicts a lack of response to another IFN-beta. However, if you are switching due to a suboptimal response, I would recommend a potentially more efficacious DMT. There is reasonable real-life data that shows switching upwards (escalation) gives a better overall response rate than switching to a similar efficacy DMT (horizontal switching).

Special circumstances

The presence of some specific comorbidities or adverse events may make it difficult to switch from one DMT to IFN-beta. For example, a persistent low lymphocyte count (<800), low neutrophil count (<1,000), low total white cell count (<1,500) and/or abnormal LFTs, that can occur with several DMTs, are relative contraindications to IFN-beta. Similarly, the presence of a monoclonal gammopathy (abnormal protein in the blood) is a contraindication to IFN-beta due to the risk of capillary leak syndrome (fluid on the lungs).

Switching

Switching-2-glatiramer acetate

07/02/2023 Gavin Giovannoni

Possible reasons to switch

Glatiramer acetate (GA) has one of the best safety records in pregnancy.
GA is relatively well tolerated in the short term and is not immunosuppressive.
Following an adverse event on another DMT, for example persistent lymphopaenia.
GA has no monitoring requirements.

Reasons for caution

Adherence can be a problem in the long term, owing to injection fatigue.
Long-term use of GA leads to lipoatrophy (loss of fatty tissue under the skin).
Its impact on preventing end-organ damage (brain volume loss) is only modest.

GA-20 to GA-40 switch

People with MS may decide to switch between GA preparations because of local skin reactions. GA-40 is administered only three times per week and has demonstrated better tolerability than the daily GA-20 formulation.

Lack of efficacy

I would not recommend switching between GA preparations because of a lack of efficacy or perceived lack of efficacy. If you have had a suboptimal response to one GA preparation it would make sense to switch classes. In general, I tend to escalate treatment rather than switch to another moderate efficacy DMT; vertical escalation rather than horizontal switching.

Other DMTs

Provided the baseline screening bloods are fine and there are no specific contraindications, I see no reason why GA can’t be used after any of the other licensed DMTs. However, if you are switching due to a suboptimal response, I would recommend a more efficacious DMT. There is reasonable real-life data that shows switching upwards (escalation) gives a better overall response rate than switching to a similar efficacy DMT (horizontal switching). I suspect that most people with MS who switch to GA will do so for family planning reasons, because GA has one of the best safety records in pregnancy. Another reason to switch may be an adverse event on another DMT, for example a persistent lymphopaenia.

Special circumstances

The presence of other specific comorbidities may make it difficult to switch from certain DMTs to GA. These could include generalised urticaria or a known allergic reaction to GA in the past.