Category Archives: DMTsDetail

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.

DMTsDetail

Anti-CD20 therapies

07/12/2023 Gavin Giovannoni

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

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.
Montalban X, et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med 2017; 376: 209 ̶ 20. doi: 10.1056/NEJMoa1606468.
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.

DMTsDetail

Cladribine

19/10/2023 Gavin Giovannoni

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

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.
Giovannoni G, et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med 2010;362:416 ̶ 26.
Pakpoor J, et al. No evidence for higher risk of cancer in patients with multiple sclerosis taking cladribine. Neurol Neuroimmunol Neuroinflamm 2015;2:e158.
Cheson BD, et al. Second malignancies as a consequence of nucleoside analog therapy for chronic lymphoid leukemias. J Clin Oncol 1999;17:2454-60.

DMTsDetail

Alemtuzumab

03/10/2023 Gavin Giovannoni

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.

Please note that, before its name change, alemtuzumab was called CAMPATH-1H. The following YouTube video gives you the history of CAMPATH-1H; it is worth watching.

Trade name

Lemtrada.

Mode of action

Alemtuzumab is a monoclonal antibody that depletes white blood cells by binding to a molecule on their surface called CD52. It lyses the cells or bursts them open, using different immunological mechanisms. When the white blood cells release their contents, which include cytokines, an infusion reaction may develop. Ideally, steroids, antihistamines and possibly an antipyretic should be given before each infusion to prevent or lessen the effect of the cell lysis or cytokine-release syndrome.

Alemtuzumab treatment aims to kill the cells that cause MS or reset regulatory mechanisms that will keep the autoreactive cells under control when the immune system recovers. It is an IRT and hence works by rebooting the immune system.

In addition to its anti-inflammatory effects, alemtuzumab results in the immune system producing growth factors that encourage the damaged nervous system to recover function. This may be why many people with MS notice recovery of some functions after alemtuzumab treatment.

Efficacy

Very high. It is licensed in the UK as a therapy for rapidly evolving severe MS, so far untreated, or as a second- or third-line therapy for people with highly active MS. In many network analyses, alemtuzumab is the most effective disease-modifying therapy (DMT) for MS, compared with other licensed therapies. Alemtuzumab positively impacts focal inflammatory activity (relapses and MRI activity) and prevents or slows down disability worsening: a significant number of treated patients (~40 ̶ 45%) notice a sustained improvement in disability. In addition, alemtuzumab effectively ‘normalises’ the accelerated brain volume loss that occurs in people with MS. The effect of alemtuzumab on brain volume loss can be explained partially by the fact that it is generally used early and in relatively young patients with MS. Alemtuzumab is less effective in older patients and those with more advanced MS.

A minority of patients treated with alemtuzumab go into long-term remission with NEIDA and no evidence of ongoing end-organ damage (no accelerated brain volume loss). Whether these individuals are cured will require much longer follow-up. Alemtuzumab works similarly to AHSCT but is a safer treatment option.

Class

Non-selective immune reconstitution therapy.

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

Alemtuzumab is given as two annual courses with up to two additional treatment courses if needed.

Year 1 treatment consists of five 12 mg doses of alemtuzumab as five daily intravenous infusions (60 mg of alemtuzumab total). These are usually given over consecutive days but can be interrupted if necessary (e.g. for a break over the weekend or while waiting for an infusion reaction to settle).
Year 2 treatment consists of three 12 mg doses of alemtuzumab as three daily intravenous infusions (36 mg of alemtuzumab in total).
Up to two additional treatment courses can be given later if needed, generally if breakthrough activity occurs.

Recurrent MS disease activity

Disease activity occurs in about one in ten patients on alemtuzumab after the first course. If you have recurrent disease activity after the first course in year 1, we can bring the second course forward by 3 ̶ 4 months. This does not necessarily mean alemtuzumab has failed you, but simply means you need the second course to control your MS disease activity. However, on rare occasions, patients develop severe rebound activity, typically in the 6 ̶ 9-month window after alemtuzumab. These patients often have multiple Gd-enhancing lesions on magnetic resonance imaging (MRI) and/or tumefactive lesions (large lesions that look like brain tumours), in which case we tend to switch them to an anti-CD20 therapy rather than continue with alemtuzumab.

As with other IRTs, recurrent MS disease activity after year 2 does not necessarily mean that alemtuzumab has failed. It is simply an indication for retreatment, i.e. giving a third or fourth course of alemtuzumab. Under the NHS England treatment algorithm, we only have permission to administer a third course. Please note that if someone has breakthrough MS disease activity after alemtuzumab, there is no reason any other MS DMT cannot be started provided all the baseline tests for that DMT are done first.

Pre-treatment and prophylaxis treatment

The following is the protocol we use to prevent immune cell lysis or cytokine-release syndrome and to reduce the infection risk.

Prednisolone 500 mg (a steroid) intravenously one hour before each alemtuzumab infusion (i.e. five infusions for course one and three infusions for course two).
Lansoprazole 15 mg once a day for one week as gastroprotection. Lansoprazole is only indicated if you are not taking a proton pump inhibitor.
Chlorpheniramine 10 mg (an antihistamine) intravenously 30 ̶ 60 minutes before each alemtuzumab infusion.
Paracetamol 1 g and/or ibuprofen 400 mg, as needed, for pyrexia, myalgias or pain. Alternating paracetamol and ibuprofen provides effective control of prolonged flu-like symptoms, including myalgias (sore muscles), pyrexia, rigors and pain.
Famciclovir 250 mg twice a day for one month or until the CD4+ count is ≥200 cells/µL (to prevent herpes virus infection).
Co-trimoxazole (an antibiotic) 960 mg three times a week for one month. If you are allergic to co-trimoxazole, we use ampicillin. Please note that co-trimoxazole combines trimethoprim and sulfamethoxazole; allergies to one or both components are common.
We have prepared an online tool and guide for listeria prophylaxis that you can download.

Subcutaneous alemtuzumab

Oncologists have used alemtuzumab for decades to treat leukaemia and lymphoma. They discovered that giving alemtuzumab via a subcutaneous route causes fewer or less severe infusion reactions than intravenous infusion, without compromising efficacy. Therefore, in some patients with MS who can’t take steroids because of a prior history of steroid-induced psychosis or poorly controlled diabetes, we have successfully administered alemtuzumab subcutaneously without steroid cover, with no significant infusion-like reactions.

Main adverse events

The adverse events related to alemtuzumab can be divided into three classes:

Infusion reactions

Infusion reactions are due to cytokine release from lysed cells during infusion. Since we started pretreating all patients with steroids before each infusion, severe infusion reactions are uncommon. Most infusion reactions are mild to moderate and include headache, rash, temperature/pyrexia, nausea, hives/urticaria, itchiness/pruritus, chills, flushing, fatigue, shortness of breath, chest tightness, tachycardia, bradycardia, dyspepsia, hypotension, hypertension and dizziness.

Some patients may notice dysgeusia or altered taste, likely due to the steroid infusion. Insomnia is another problem during the infusion and is probably due to flu-like side effects persisting into the evening and possibly a result of the steroids. Rarely, anaphylactoid reactions occur with alemtuzumab, requiring overnight hospital admission. In our experience, these tended to occur during course 1 with the day 4 infusion when steroids were not given. Since administering steroids and antihistamines before each infusion, we have not had a severe anaphylactoid reaction requiring hospital admission.

Infections

For the first 4 weeks after starting each course of alemtuzumab, treated patients are at risk of bacterial and herpes viral infections and are put on prophylactic antibiotics and antivirals (see pretreatment protocol above). They are also asked to start a listeriosis prevention diet to prevent exposure to the bacteria that causes listeriosis, an uncommon infection. After 4 weeks, once the monocytes (white blood cells) have recovered, the antibiotics and antiviral prophylaxis can usually be stopped.

Please be aware that infections can occur after the first 4 weeks, so people with MS treated with alemtuzumab must remain vigilant and seek advice if they develop any symptoms of infection. Common community-acquired infections to look out for are nasopharyngitis, urinary tract infection, upper respiratory tract infection, sinusitis, oral herpes, influenza and bronchitis. These infections tend to be mild. However, more serious, opportunistic infections occur in approximately 2 ̶ 3% of treated patients; some subjects in alemtuzumab trials had appendicitis, gastroenteritis, pneumonia, herpes zoster and tooth infection.

Cervical human papillomavirus (HPV) infection, including cervical dysplasia (abnormal growth) and anogenital warts, have been reported post-alemtuzumab, so we ask female patients to have an up-to-date cervical smear or vaginal HPV PCR. Warts are a relative contraindication to alemtuzumab therapy.

Cytomegalovirus infections (CMV), including CMV reactivation, have also been reported post-alemtuzumab. Most cases occurred within 2 months of alemtuzumab dosing. Similarly, Epstein-Barr virus (EBV) infection reactivation can occur.

Tuberculosis has also been reported post-alemtuzumab, so we screen for latent TB before initiating alemtuzumab treatment.

Superficial fungal infections, especially oral and vaginal candidiasis, can occur and must be managed with antifungals.

Progressive multifocal leukoencephalopathy (PML) is very rare post-alemtuzumab in patients with MS. I am aware of one fatal case of carry-over PML from a patient treated with natalizumab. This is why when switching from natalizumab to alemtuzumab, you must be careful to exclude asymptomatic PML (see Switching -2-alemtuzumab below).

Delayed secondary autoimmunity

After a course of alemtuzumab, the immune system reconstitutes itself over several months, with the B cells returning within 3 ̶ 4 months and the T cells returning between months 6 and 9. This may result in poor B-cell regulation, which might explain why people with MS treated with alemtuzumab are at risk of getting delayed, antibody-mediated autoimmune diseases.

The most common autoimmune disease is Grave’s disease or autoimmune hyperthyroidism. Post-alemtuzumab Grave’s disease is caused by stimulatory antibodies against a receptor on the thyroid gland. Grave’s disease post-alemtuzumab is atypical in that it often waxes and wanes and, in many cases, goes into remission. Grave’s disease occurs in approximately 40% of females and 20% of males treated with alemtuzumab. In my experience, it is usually easily managed and uncommonly causes any persistent problems. A few people with Graves’s disease develop comorbid thyroid eye disease, with swelling of the muscles and tissue in the orbit and proptosis (bulging of the eyes), which can be cosmetically unsightly. The orbital disease has now been found to be a separate but associated autoimmune disease with its own treatment. The incidence of Grave’s orbitopathy is low and occurs in 3 ̶ 4% of people with Grave’s disease, so that the risk post-alemtuzumab will be less than 1 in 500.

The second most common autoimmune disease is immune thrombocytopenic purpura (ITP), where your immune system makes antibodies against your platelets. This serious condition can be associated with bleeding if not detected and treated early. In my experience, it is a monophasic illness, and all the cases I have seen have made an uneventful recovery. However, the first case of ITP post-alemtuzumab identified had an intracranial haemorrhage and, sadly, died. We think life-threatening complications can be avoided by being vigilant and doing monthly blood monitoring to check platelet counts. The incidence of ITP post-alemtuzumab is ~2%, i.e. 1 in 50 treated patients will develop it. It is essential to realise that ITP is a treatable condition.

The third most common autoimmune disease post-alemtuzumab is Goodpasture’s syndrome, where your immune system makes antibodies against the glomerular basement membrane in the kidney, resulting in kidney dysfunction. If not detected early and treated, it can cause kidney failure. Occasionally, these autoantibodies attack the lungs and cause damage that typically presents as a cough and blood in the sputum. The incidence of Goodpasture’s syndrome post-alemtuzumab is approximately 1 in 800.

Many other rarer autoimmune diseases have been described in individual patients post-alemtuzumab. These include acquired haemophilia, thrombotic thrombocytopenic purpura (TTP), bullous pemphigoid, autoimmune hepatitis, autoimmune encephalitis, aplastic anaemia, autoimmune cytopaenias (in particular, neutropaenia), adult-onset Still’s disease (AOSD) and haemophagocytic lymphohistiocytosis (HLH). This list is likely to be incomplete. A common theme across these autoimmune diseases is that they are treatable and tend to be monophasic and reversible.

Please note these delayed secondary autoimmune diseases typically occur in the first 5 years after starting treatment with alemtuzumab, so the monthly blood and urine monitoring for these complications stops after year 5. However, if you need a third or fourth course of alemtuzumab, the monitoring must continue for 4 years after each additional course. Interestingly, the secondary autoimmunity that can occur after alemtuzumab is also seen after AHSCT (autologous haemopoietic stem cell transplantation), another IRT, but has not been seen after cladribine. Therefore, something happens to the recovering immune system in people treated with alemtuzumab or AHSCT, resulting in some individuals developing autoimmunity. This is important because if we can work out what happens, we may be able to prevent delayed secondary autoimmunity post-alemtuzumab; at present, there is no licensed treatment or strategy to do so.

I advise patients eligible for alemtuzumab that they should not take this treatment unless they are prepared to sign up for the monthly blood and urine monitoring and the risk of developing a delayed secondary autoimmune disorder.

Other adverse events

After alemtuzumab was licensed by the FDA in the USA as a third-line rescue therapy in MS, a new set of adverse events emerged. These included stroke, myocardial ischaemia, myocardial infarction, cervical artery dissection, pulmonary alveolar haemorrhage, pericarditis, pneumonitis and acalculous cholecystitis. We think these adverse events are related to the types of subjects treated with alemtuzumab in the USA, i.e. older people with more advanced MS and multiple comorbidities, such as hypertension and obesity, or risk factors like smoking. We didn’t see these complications in Europe, where we used alemtuzumab to treat very early MS. Therefore, it is essential to remember that the risk:benefit ratio of alemtuzumab changes dramatically in older patients with more advanced MS and a much higher likelihood of adverse events.

There is no definite cancer signal due to alemtuzumab treatment in people with MS. However, a small incidence of papillary cancer of the thyroid has been reported in alemtuzumab-treated patients. This is likely to result from ascertainment bias because patients with alemtuzumab-related hyperthyroidism are more likely to have ultrasound screening of the thyroid gland.

Neutralizing antibodies (NAbs)

NAbs are common after alemtuzumab but tend to disappear after the first course. However, we screen for NAbs before the third and fourth courses of alemtuzumab as they can blunt its therapeutic potential.

Pharmacovigilance monitoring requirements

Baseline

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

Follow-up

A full-blood count and urine dipstix assessments are done monthly after starting alemtuzumab and up to 4 years after the last course. 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. It is essential to detect secondary (delayed) autoimmunity and infections early to treat them promptly.

Rebaselining

A rebaseline MRI scan needs to be done after alemtuzumab. 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 performed annually after that.

Women of childbearing potential and pregnancy

If you are a woman of childbearing age, we require a negative urine pregnancy test before starting alemtuzumab infusions. Alemtuzumab is not teratogenic, i.e. it does not cause birth defects. However, we don’t advise patients to fall pregnant whilst significantly immunosuppressed. Ideally, patients should delay falling pregnant until they have completed their second course of alemtuzumab. If a woman falls pregnant before this, we simply delay the second course until after delivery and once breastfeeding has stopped.

Breastfeeding

We don’t recommend alemtuzumab whilst breastfeeding because concomitant medications are needed to manage infusion reactions and prevent infections, and these drugs can cross over into the breast milk. Breastfeeding is also a risk factor for breast infections.

Fertility

There is no evidence that alemtuzumab affects either male or female fertility. In men treated with alemtuzumab, there is no evidence of aspermia, azoospermia, consistently depressed sperm count, motility disorders or increased sperm abnormalities. However, men should ideally wait a few months after alemtuzumab treatment before attempting to father a child because the drug targets the surface molecule CD52, which is present in the testes.

Vaccination

Patients should be immune to the varicella-zoster virus (VZV) before alemtuzumab treatment. In the UK, we anticipate that the component or inactive VZV vaccine (Shingrex) will soon be available on the NHS for people with MS to boost immunity to VZV before treatment. There is no reason why patients on alemtuzumab 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. Once patients have reconstituted their immune function, they can receive live vaccines safely. The latter is one of the advantages of alemtuzumab and other IRTs over DMTs that are continuous immunosuppressive therapies.

Travel

Being on alemtuzumab may affect travel for people with MS; for example, some countries require you to be vaccinated against yellow fever, a live attenuated vaccine. The yellow fever vaccine must therefore be given before starting alemtuzumab or after immune reconstitution. Travelling whilst significantly immunosuppressed, i.e., within the first 3 ̶ 4 months of treatment, is not advisable because of the infection risk.

Summary of Product Characteristics (SmPC)

Lemtrada.

Switching-2-alemtuzumab

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

DMTsDetail

Fumarates

31/08/2023 Gavin Giovannoni

Summary

Fumarates (dimethyl fumarate and diroximel fumarate) are moderate- to high-efficacy platform therapies for treating active MS; they reduce the relapse rate by ~45 ̶ 50% and slow the acquisition of disability. They reduce magnetic resonance imaging (MRI) activity by over 80% but have little effect on brain volume loss in the first 2 years of treatment.

The fumarates are licensed as first-line therapies in the UK but are not recommended for second-line use unless they are being prescribed because another DMT is not tolerated. After the first 7 days, they are taken twice daily; this dosing regimen can lead to poor adherence in some people with MS. Fumarates have a complex and interesting dual mode of action. Firstly, they activate antioxidant and cell survival pathways; secondly, they are anti-inflammatory medications targeting a critical pathway in the inflammatory cascade inside cells. They reduce the circulating lymphocyte count by about 30%, which is not a problem for most people with MS. However, about 5% of people with MS develop grade 3 (<500/mm³) lymphopaenia and 15% develop grade 2 (<800/mm³); if prolonged (>6 months) this can increase their risk of opportunistic infections. Progressive multifocal leukoencephalopathy (PML) and other opportunistic infections are rare on fumarates. However, extra vigilance is recommended in patients who are lymphopaenic.

The most common side effects of fumarates are flushing and gastrointestinal events, i.e. diarrhoea, nausea and abdominal pain, all of which tend to begin early (primarily during the first month) and may continue intermittently, particularly the flushing. About one in 10 people with MS discontinues a fumarate due to side effects. Diroximel fumarate is better tolerated than dimethyl fumarate regarding gastrointestinal side effects and flushing.

Blood and urine monitoring is done 3-monthly for the first 12 months; if there are no problems, we switch to 6-monthly monitoring. Fumarates have no known potential to cause foetal abnormalities when women fall pregnant on the drug or during pregnancy; however, they are not recommended in women of childbearing potential not using appropriate contraception. The decision to stop the drug to fall pregnant or to continue during pregnancy is based on a personal benefit ̶ risk assessment.

Trade names

Tecfidera (dimethyl fumarate), Vumerity (diroximel fumarate).

Mode of action

Fumarates are fat soluble, but we don’t know for certain if they enter the brain and spinal cord. Dimethyl fumarate and diroximel fumarate are rapidly broken down in the body to monomethyl fumarate (MMF), which enters cells and activates a cell transcription factor called Nrf2. This pathway stimulates the cell to make antioxidant molecules as part of the programmed cell survival pathway. MMF also inhibits NF-kappa B, the master inflammatory transcription factor. Finally, MMF binds to and activates the nicotinic acid receptor, responsible for the flushing side effect. Apart from these well-known molecular effects on cells, we don’t know exactly how fumarates work in MS.

Efficacy

Moderate to high; fumarates are licensed in the UK as first-line therapy for people with active MS. They are not intended for second-line treatment unless there is intolerance to the first DMT.

Class

Maintenance, immunosuppressive.

Immunosuppression

Yes, but only high-risk if there is persistent lymphopaenia.

Dosing

Dimethyl fumarate dosing

The starting dose of dimethyl fumarate is 120 mg twice a day for 7 days; if tolerated, the dose is increased to the recommended maintenance dose of 240 mg twice a day. If you miss a dose, do not take two tablets together. You may take a missed dose late, providing you do so at least 4 hours before the next dose; otherwise, wait until the next scheduled dose. A temporary dose reduction to 120 mg twice a day may reduce the occurrence of flushing and gastrointestinal symptoms. However, the recommended maintenance dose of 240 mg twice a day should be resumed within the next 4 weeks. Dimethyl fumarate should ideally be taken with food; fatty foods improve its tolerability.

Diroximel fumarate dosing

The starting dose of diroximel fumarate is 231 mg twice a day. After 7 days, the dose should be increased to the recommended maintenance dose of 462 mg twice a day. Temporary dose reductions to 231 mg twice a day may reduce the occurrence of flushing and gastrointestinal adverse reactions. Within one month, the recommended dose of 462 mg twice a day should be resumed. If you miss a dose, a double dose should not be taken. You may take the missed dose only if it leaves 4 hours between doses. Otherwise, you should wait until the next scheduled dose.

Main adverse events

Gastrointestinal events

Most people with MS who start taking a fumarate develop gastrointestinal side effects such as cramps, abdominal pain and occasional diarrhoea. These can be reduced by titrating the dose upwards when starting treatment, taking the drug with fatty foods, and using simple over-the-counter symptomatic therapies such as antispasmodics. Diroximel fumarate is better tolerated than dimethyl fumarate in terms of gastrointestinal side effects.

Flushing

Another common side effect is flushing, or redness of the face and upper body, which typically comes on 20 ̶ 30 minutes after administration and persists for about an hour. All these side effects are transient, improve with time and usually stop after 8 ̶ 12 weeks. Diroximel fumarate is better tolerated than dimethyl fumarate in terms of flushing.

PML and opportunistic infections

Older people with MS who have had prolonged lymphopaenia are at increased risk of progressive multifocal leukoencephalopathy (PML) if they are JC virus (JCV) seropositive. We therefore stop fumarates in patients who become persistently lymphopaenic (i.e. with counts <800/mm³).

Around 1 in 10 people treated with diroximel fumarate get side effects of a cold or chest infection.

Neutralizing antibodies (NAbs)

NAbs are not a problem with this DMT class; fumarates are small molecules or metabolites that do not induce an immune response.

Pharmacovigilance monitoring requirements

Baseline

Full blood count, urea and electrolytes, liver function tests (LFTs), thyroid function tests, urine protein, pregnancy test.

Follow-up

FBC and urine protein after 3 and 6 months of treatment, every 6 to 12 months thereafter or as clinically indicated.

Rebaselining

A rebaselining MRI needs to be done after a fumarate has had sufficient time to work. I recommend performing an MRI 6 months after starting treatment and including Gd-enhancement as part of the rebaselining.

Women of childbearing potential and pregnancy

Although there is no evidence that fumarates have any reproductive toxicity, they are not recommended during pregnancy or in women of childbearing potential not using appropriate contraception. A fumarate should only be used during pregnancy if needed because the potential treatment benefit justifies the potential undefined risk to the foetus. Most neurologists allow their patients to fall pregnant on fumarates, stop the medication once the patient knows they are pregnant, and reinitiate the medication post-partum.

Breastfeeding

It is unknown whether dimethyl fumarate, MMF or diroximel fumarate is excreted in human milk; if so, it is likely to be in very small amounts. We therefore advise women with MS that it is safe to breastfeed when taking a fumarate.

Fertility

There is no evidence that fumarates affect either male or female fertility.

Vaccination

Clinical studies have shown that vaccinations of component or inactivated vaccines were safe and effective whilst on fumarates. However, live attenuated vaccines may carry a risk of infection, so the current recommendation is to avoid them unless the risk of not being vaccinated is likely to outweigh the potential risk of infection.

Travel

Being on a fumarate may affect travel; for example, some countries require vaccination against yellow fever, a live attenuated vaccine that is not recommended while taking a fumarate.

Summaries of Product Characteristics (SmPC)

Tecfidera, Vumerity.

Switching-2-fumarates

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 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.

DMTsDetail

HSCT (haematopoietic stem cell transplant)

08/08/2023 Gavin Giovannoni

Summary

HSCT (haematopoietic stem cell transplant) is not a drug, it is a procedure that involves harvesting of stem cells that first need to be mobilised from the bone marrow using a ‘conditioning’ regimen of low-dose chemotherapy and growth factors. The stem cells are harvested from the blood and frozen down or stored. People with MS undergoing HSCT then have their immune system depleted with chemotherapy to a greater (myeloablative HSCT) or lesser extent (non-myeloablative HSCT). The stem cells are re-infused to allow more rapid recovery of bone marrow and immune function. HSCT is not a ‘licensed therapy’ for MS, but it is offered as a treatment for more active disease in many countries – typically for MS that has not responded to standard DMTs. HSCT is on the list of essential off-label DMTs because it is a generic procedure available in many countries. In other words, it can also be used for treating MS where access to high-cost licensed DMTs is limited.

What is HSCT?

HSCT is simply a ‘rebranding’ of bone marrow transplantation (BMT). BMT refers to the harvesting of stem cells using a bone marrow aspirate, whereby a thick needle is inserted into the bone and the marrow is sucked out under pressure. This procedure is painful and is done under sedation. Haematologists have now developed an effective way of mobilising and harvesting stem cells from the blood without tapping the bone marrow. A small dose of chemotherapy is given, followed by growth factors so the stem cells spill over from the bone marrow into the blood. These stem cells are harvested and frozen and can then be given after chemotherapy (immunoablation therapy) has depleted your immune cells.

The introduction of the harvested stem cells speeds up bone marrow recovery after immune system ablation (depletion). More rapid bone marrow recovery makes BMT safer because you have less chance of getting a life-threatening infection or bleeding.

The stem cells in HSCT don’t go to the brain and spinal cord to repair the damage. This is a common misconception. Recovery of neurological function seen after HSCT is spontaneous endogenous repair, which we see with all the DMTs, particularly the highly effective treatments. Like other DMTs, HSCT is most effective when used early, before MS causes too much damage, or in younger people with MS (as we age, the nervous system’s ability to repair itself decreases).

Types of HSCT

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.

Many in the field maintain that if you treat MS with HSCT you should use the more toxic and riskier myeloablative–HSCT. They argue that non-myeloablative–HSCT is no better than the high-efficacy drugs we already use, such as alemtuzumab, natalizumab and/or ocrelizumab. Trials are currently ongoing to compare alemtuzumab with non-myeloablative–HSCT and see if the potential benefits of non-myeloablative–HSCT warrant the risks.^1,2,3

Non-myeloablative HSCT – risks

The chance of dying from non-myeloablative–HSCT is in the order of 0.3% ̶ 2%; i.e., a 1-in-330 risk 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. It seems that the more disabled you are, the worse the neurotoxicity. If you have lost a lot of nerve fibres and have reduced brain reserve, the chemotherapy worsens neurological function. This is why many BMT units stopped using this therapy in people with more advanced MS and why most units have an upper Expanded Disability Status Scale (EDSS) score limit as part of their inclusion and exclusion criteria.

Does your immune system return to normal post-HSCT? There is evidence that HSCT may rejuvenate the immune system and change the so-called ‘repertoire’ (memory) of your B and T cells. We don’t yet know what it means for MS, but we do know that HSCT may destroy memory cells from your previous vaccinations. So, you may need to be revaccinated with all your childhood vaccines at ~2 years after HSCT to restore your immune responses to these common infections.

What about secondary autoimmunity?

There are data to suggest that people with MS treated with both myeloablative–HSCT and non-myeloablative–HSCT are at risk of developing secondary autoimmune diseases similar to those that occur after alemtuzumab treatment. This risk is lower than that seen with alemtuzumab, but there is a definite signal. At present I find it challenging to recommend non-myeloablative–HSCT over alemtuzumab, unless it is part of a controlled trial or the patient has already failed alemtuzumab.

Myeloablative HSCT – risks

The short-term risks from the intense chemotherapy needed to ablate the immune system with myeloablative–HSCT are much worse than with non-myeloablative–HSCT. Everything is worse: the diarrhoea tends to be bloody and protracted; mucositis is the norm (the lining of your mouth, throat and intestine slough); infections are more severe and are potentially life-threatening; there is the potential for solid organ toxicity (liver, lungs, kidneys and heart); your bone marrow takes longer to recover, and as a result you are more likely to need platelet and blood transfusions. Myeloablative–HSCT is not for the faint-hearted. Many HSCT enthusiasts in the autoimmune field assert that myeloablative–HSCT is the way to go; the failure rate from non-myeloablative–HSCT is too high. They argue that if you are going to take the risk of having HSCT, you might as well go for maximum efficacy with myeloablative–HSCT.

The Lazarus effect

The seemingly miraculous treatment effects of people with MS in wheelchairs getting up and walking are not unique to HSCT. We see these ‘Lazarus effects’ with other highly effective DMTs. Provided you have sufficient reserve capacity in the brain (brain reserve) and spinal cord (neurological reserve) you will see spontaneous recovery from relapse-related disability once inflammation is switched off and recovery mechanisms can proceed. Tragically these Lazarus-like examples create unrealistic expectations for people with more advanced disease. Once you have a fixed or progressive disability, you have most likely lost your neurological reserve. Even if you switch off inflammation with HSCT or another anti-inflammatory DMT, any significant recovery of function is unlikely. Many progressive MS trials have failed because the benefit:risk ratio changes with more advanced disease. This is why most HSCT or BMT units have age and disability cut-offs for people with MS.

Would I refer patients for HSCT?

Yes, I do. HSCT is indicated as part of routine clinical care in the small number of patients with malignant MS who has already failed licensed treatment options. In such patients, the benefits of HSCT outweigh the risks of the disease. In practice, however, people with MS are concerned chiefly about the infertility risk from HSCT. The risk of premature ovarian failure, or early menopause, following chemotherapy is over 40%; this dissuades many women. Similarly, for men, cyclophosphamide (the chemotherapy) hits the testes hard, so if you want to start or extend your family after HSCT you will need to bank sperm.

Weighing the risks

Please remember the human brain is hard-wired to be optimistic. I like the analogy of the gambler’s dilemma. No gambler places a bet or goes into a casino to lose money; they believe they will win. 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. In the same way, I warn my patients who sign up for alemtuzumab treatment that they should expect to develop a secondary autoimmune complication; if they don’t, they should count themselves lucky. If they are not prepared to develop a second autoimmune disease, they shouldn’t be treated with alemtuzumab.

Mode of action

HSCT is an immune reconstitution therapy (IRT). It works by depleting your immune system and allowing it to reconstitute. The hope is that when the immune system has reconstituted, the autoimmune cells that cause MS are absent.

Efficacy

Very high.

Class

Non-selective IRT, short-term immunosuppression.

Immunosuppression

Yes, short-term, whilst the immune system is depleted. Once it reconstitutes itself, the immune system is competent.

Protocols

The following are some examples of HSCT protocols used to treat MS.

Low intensity (non-myeloablative)

Cyclophosphamide plus anti-thymocyte globulin.
Cyclophosphamide plus fludarabine phosphate.

Intermediate intensity (non-myeloablative)

BEAM – a combination of BiCNU/carmustine, etoposide, Ara-C/cytarabine and melphalan.
BEAM plus anti-thymocyte globulin.
Cyclophosphamide plus thiotepa.
Total lymphoid irradiation plus melphalan.
Carmustine plus cyclophosphamide plus anti-thymocyte globulin.

High intensity (myeloablative)

Cyclophosphamide plus total body irradiation plus anti-thymocyte globulin.
Busulfan plus cyclophosphamide plus anti-thymocyte globulin.
Busulfan plus anti-thymocyte globulin.

Adverse events and events of special interest

This is not a complete list of adverse events associated with HSCT. Please note some of the complications can be life-threatening.

Infection

During the first 6 weeks after HSCT, until the new stem cells start making white blood cells (engraftment), you can easily develop serious infections. Bacterial infections are most common, but viral infections that were controlled by your immune system can become active again. For example, cytomegalovirus (CMV) is a common cause of pneumonia in people who have had transplants and in people with MS who were already infected with CMV. Fungal infections can also be an issue. Even infections that cause only mild symptoms in people with normal immune systems can pose a danger. For instance, pneumocystis pneumonia (often called PCP) is easy to catch and can cause fever, cough, and serious breathing problems if your immune system is compromised. Antibiotics are often used to keep HSCT patients from getting this. You may be given antibiotics to try to prevent other infections until your blood counts reach a certain level.

While in the hospital, everyone who enters your room must wash their hands well. They may also wear gowns, shoe coverings, gloves, and masks. Since flowers and plants can carry bacteria and fungi, they are not allowed in your room. After engraftment, the risk of infection is lower, but it still can happen. It takes 3 months to one year after transplant for the immune system of most patients to work as well as it should. Because of the increased risk, you will continue to be watched closely for signs of infection, such as fever, cough, shortness of breath, or diarrhoea. Your doctor may check your blood often, and extra precautions will be needed to avoid exposure to germs. For the same reason, you may be told not to eat certain fresh fruits and vegetables. All your food must be well cooked and handled very carefully by you and family members. Certain foods may need to be avoided for a while. You will also be told to avoid contact with soil, faeces (both human and animal), aquariums, reptiles, and exotic pets. Your team may tell you to avoid being near disturbed soil, bird droppings, or mould. You need to wash your hands after touching pets. If you have a cat, you may need to remove the cat’s litter tray from where you eat or spend time.

Your transplant team will tell you and your family about the precautions you need to follow. Despite all these precautions, many patients develop fevers, one of the first signs of infection. If you do get a fever or other signs of infection, contact your doctor right away. Tests will be done to determine the cause of the infection (chest X-rays, urine tests, and blood cultures), and antibiotics will be started.

Nausea and vomiting

A common side effect from the chemotherapy given with HSCT, nausea and vomiting, is treated with antiemetics. No one drug can fully prevent or control chemotherapy-related nausea and vomiting; hence, combination therapies are often required.

Mouth and throat pain

Mucositis (inflammation or sores in the mouth) is a short-term side effect that happens with high-intensity chemotherapy. It usually gets better within a few weeks of treatment, but it can make eating and drinking painful.

Hair loss

Hair loss is likely during HSCT, typically beginning within 2 ̶ 3 weeks of treatment. However, hair growth will return to normal once the treatment is finished.

Bleeding and transfusions

After HSCT, you are at risk for bleeding because the conditioning treatment destroys your body’s ability to make platelets (the blood cells that help blood to clot.) While you wait for your transplanted stem cells to start working, you must take special precautions to avoid injury and bleeding. Platelet counts are typically low for at least 3 weeks after HSCT. During this time, you might notice easy bruising and bleeding, such as nosebleeds and bleeding gums. A platelet transfusion may be required if your platelet count drops below a certain level. It also takes time for your bone marrow to start making red blood cells. If you become too anaemic, you might require red blood cell transfusions.

Cardiotoxicity

High doses of chemotherapy used as part of HSCT can cause cardiotoxicity. This is most common in older people with MS and people who have received prior cardiotoxic drugs, for example, mitoxantrone.

Neurotoxicity

Both the central and peripheral nervous systems are susceptible to the toxic effects of chemotherapy used as part of the conditioning regimen in HSCT. People with more advanced MS and significant disability are particularly sensitive to chemotherapy-induced worsening of disability. The effects on the peripheral nervous system are mainly due to length-dependent neuropathy, with loss of feeling in the ends of the extremities. Neurotoxicity is rarely a problem with low- and intermediate-intensity chemotherapy regimens.

Interstitial pneumonitis and other lung problems

Pneumonitis is a type of lung inflammation most common in the first 100 days after HSCT. Pneumonia caused by infection happens more often, but pneumonitis may be caused by chemotherapy rather than germs. It results from damage to the areas between the cells of the lungs (the so-called interstitial spaces). Pneumonitis tends to occur only with more intensive conditioning regimens.

Hepatic veno-occlusive disease

Hepatic veno-occlusive disease is a serious problem in which tiny veins and other blood vessels inside the liver become blocked. It is very uncommon, and only happens in individuals who received the drugs busulfan or melphalan as part of their conditioning regimen and as part of allogeneic HSCT (from a donor) rather than autologous HSCT (AHSCT, i.e. from the patient).

Infertility

Many people with MS who have HSCT become infertile and cannot have children. This is not caused by the transplanted stem cells but rather by the high doses of chemotherapy and/or radiation therapy used to ablate the immune system. These treatments affect normal and abnormal cells and damage the reproductive organs. If having children is important to you, or if it might be important in the future, there are ways to protect your fertility. If indicated, women should be offered GnRH agonists as ovarian protection throughout therapy or the possibility of egg harvesting and storage. The risk of infertility depends on the specific conditioning regimen. After chemotherapy, women find their menstrual periods become irregular or stop completely (amenorrhea). This doesn’t always mean you cannot get pregnant, so birth control should still be used before and after HSCT.

The drugs used during HSCT can also damage sperm, so men should use birth control to avoid starting a pregnancy during and for some time after the HSCT process. HSCT may cause temporary or permanent infertility for men as well; it is worth considering storing sperm before having a transplant (this process can take several days). Fertility returns in some men, but the timing is unpredictable.

Secondary autoimmunity

People with MS treated with HSCT are at risk of developing secondary autoimmune diseases similar to those that occur after alemtuzumab treatment. The risk of secondary autoimmunity after HSCT is about 10%, which is lower than after alemtuzumab. Does this mean that you must participate in the same type of pharmacovigilance required by patients treated with alemtuzumab? I am not sure about this, but all the patients I have referred for HSCT who have come through the procedure successfully are not enrolled in an intensive pharmacovigilance programme. All study subjects in our current trial of alemtuzumab versus non-myeloablative–HSCT are undergoing monthly blood and urine monitoring, which should allow us to assess the current pharmacovigilance requirement.

Graft-versus-host disease (GVHD)

This adverse event is commonly reported on HSCT and BMT unit websites. It typically happens with allogeneic (donor) transplants when the immune cells from the donor see your body as foreign. Allogeneic transplants are not used to treat MS. Despite this, GVHD may occur with autologous HSCT if you receive a blood transfusion that contains live lymphocytes from the donor. The latter is prevented by irradiating all fresh blood products before administering them to HSCT patients.

HSCT graft failure

Grafts fail when you have too few stem cells, either because the body does not accept them or they did not survive the mobilisation and storage procedure. In this case, we must wait for your bone marrow to recover spontaneously. Depending on the intensity of the conditioning regimen, this can take many weeks. During this period, you are very susceptible to infections and bleeding. Grafts rarely fail, but graft failure can result in death.

Secondary cancers caused by HSCT

There is a small chance of developing a secondary cancer after HSCT, which is caused by the chemotherapy damaging your cell’s DNA or the associated immunosuppression.

Lymphomas are most often associated with HSCT, especially the B cell types, which tend to be caused by Epstein-Barr virus (EBV). When the immune system is suppressed after HSCT, EBV may result in proliferation of B cells and post-transplant lymphoproliferative disease (typically in patients receiving allogeneic HSCT).
Acute leukaemia is a type of cancer that can develop a few years after HSCT.
Myelodysplasia or myelodysplastic syndrome is a bone marrow disorder that may develop a few years after HSCT in which the bone marrow makes defective blood cells.
Solid tumours that develop many years later may include the skin, mouth, brain, liver, cervix, thyroid, breast or bone.

Risk factors for developing a secondary cancer include:

total lymphoid irradiation (though it is seldom used as part of HSCT regimens for MS)
the type of high-dose chemotherapy used in the conditioning treatment
age (older than 40 years at the time of transplant)
infection with certain viruses, i.e. EBV, CMV, hepatitis B or hepatitis C.

Pharmacovigilance monitoring requirements and derisking strategies

Baseline

Full blood count, urea and electrolytes, liver function tests, thyroid function tests, serum protein electrophoresis, serum immunoglobulin levels, serology (varicella zoster virus [VZV], human immunodeficiency virus-1 and -2, hepatitis B and C, syphilis, EBV and CMV), tuberculosis enzyme-linked immune absorbent spot (TB ELISpot), up-to-date cervical smear and/or human papillomavirus testing and a pregnancy test. If indicated, some centres may assess the baseline function of the heart (ECG and cardiac ejection fraction) and lungs (lung function tests).

Follow-up

During HSCT, blood tests are frequently done to monitor for bone marrow recovery. If indicated, most units monitor peripheral blood EBV and CMV viral loads for EBV and CMV reactivation.
Once bone marrow function has recovered, blood tests are typically done 3 monthly for the first 2 years.
Endocrine work-up for women with persistent amenorrhea.

Infection prophylaxis

If you are VZV seronegative, you should receive the VZV vaccine at least 6 weeks before treatment with HSCT to allow sufficient time to develop immunity and protective antibodies.
To reduce your risk of developing listeriosis, which is a rare infection transmitted via food, you should receive advice about starting a listeriosis diet and a behavioural programme to minimise your chances of exposure to the infectious agent.

Depending on where you have your HSCT, you may also be offered antibiotic prophylaxis to reduce your chances of developing bacterial, fungal and parasitic infections.

Rebaselining

A rebaseline MRI needs to be done after HSCT. Most units do this after bone marrow recovery once patients have had time to recover from the HSCT procedure – typically at around 6 months.

Pregnancy

Pregnancy is contraindicated during HSCT as some chemotherapies are teratogenic and may harm the developing foetus. While having HSCT, women who might become pregnant should use effective birth control.

Breastfeeding

Some chemotherapy agents are excreted in human milk; therefore, breastfeeding should be discontinued before starting HSCT.

Vaccination

Immunisation is likely to be ineffective when given during or after HSCT. Immunisation with live virus vaccines is generally not recommended until after the immune system has reconstituted. Some units recommend a routine revaccination programme approximately 2 years after HSCT. The need for revaccination depends on the intensity of the chemotherapy regimen used during conditioning; the more intensive the regimen, the more likely you are to be revaccinated.

Switching-2-HSCT

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.

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.

References

RCT comparing autologous hematopoietic stem cell transplantation versus alemtuzumab, cladribine or ocrelizumab in MS (RAM-MS). ClinicalTrials.gov ID NCT03477500.
Best available therapy versus autologous hematopoetic stem cell transplant for multiple sclerosis (BEAT-MS). ClinicalTrials.gov ID NCT04047628.
StarMS HSCT trial opening at hospitals around the UK. MS Society, UK, October 2022.

DMTsDetail

Teriflunomide

11/07/2023 Gavin Giovannoni

Summary

Teriflunomide is a moderately effective platform therapy for treating active MS; it reduces the relapse rate by ~30% and slows the acquisition of disability to a similar degree. It reduces magnetic resonance imaging (MRI) activity by ~70% and slows down brain volume loss, but not to the same degree as highly effective DMTs. Teriflunomide is licensed as a first-line therapy in the UK. It is taken as a daily 14 mg tablet. Although teriflunomide inhibits cell proliferation, it is not an immunosuppressive agent and is classified as an ‘immunomodulatory therapy’.

Teriflunomide has not been associated with opportunistic infections, secondary malignancies, a blunted antibody response to vaccines or lymphopaenia (low lymphocyte counts). Low lymphocyte counts occur in only a small minority of people with MS. In general, teriflunomide is well tolerated, with only a small number of people with MS (< 5%) developing abnormal liver function tests or gastrointestinal symptoms (mainly diarrhoea) that result in them having to stop the therapy. Teriflunomide can cause mild hair thinning that is transient; please note this is not alopecia or baldness and, in my experience, is not a problem for people with MS taking the drug.

Teriflunomide is considered to be potentially teratogenic, i.e. it has the potential to cause foetal abnormalities when women fall pregnant on the drug, which makes it unsuitable for women of childbearing age who are planning to start, or extend, their families. Teriflunomide has a long half-life and hence stays in the body for months. There is a rapid elimination procedure that can remove teriflunomide from the body within days. When teriflunomide is started, the European Medicines Agency (EMA) requires blood monitoring every 4 weeks for 6 months and 2 monthly thereafter. I think these requirements are excessive; many neurologists use the American guidelines, which stipulate monthly tests for 6 months and regularly after that.

It has been difficult to use teriflunomide in the UK, on the NHS, because of its monitoring requirements and associated costs. In clinical practice, teriflunomide seems to be much more effective than suggested by the clinical trial results, which may explain its popularity in other countries. Interestingly, people who start teriflunomide as a second-line or third-line DMT do better than those using it first-line. I have no idea why teriflunomide is more effective after people with MS have failed other DMTs; it may have something to do with its alternative modes of action, for example, its antiviral effects.

Trade name

Aubagio.

Mode of action

Teriflunomide probably has several modes of action but mainly works by inhibiting an enzyme called dihydroorotate dehydrogenase (DHODH) which affects pyrimidine metabolism in cells. This inhibits cell division, so it is called an antiproliferative agent. It is thought to work in a similar way in MS, by reducing the proliferation of activated lymphocytes. Teriflunomide also has broad-spectrum activity against many viruses.

Efficacy

Moderate. It is licensed in the UK as a platform or first-line therapy for people with active MS.

Class

Maintenance, immunomodulatory.

Immunosuppression

No.

Dosing

The recommended dose of teriflunomide is 14 mg once daily, but 7 mg/day has also been shown to be effective. In the USA, both the 7 mg and the 14 mg doses of teriflunomide are licensed. Outside the USA, only the 14 mg dose is licensed.

The 14 mg dose was superior to the 7 mg dose on several outcomes in the phase 3 trials. In general, 7 mg is prescribed to people with MS who can’t tolerate the higher 14 mg dose because of gastrointestinal symptoms or other blood abnormalities. Outside the USA, where the 7 mg tablet is unavailable, you can take the 14 mg tablet on alternate days. Splitting the tablet is not easy because it is not scored, and doing so breaks the enteric coating.

The half-life of teriflunomide is very long, so alternate-day dosing is fine. Teriflunomide can be taken with or without food.

Main adverse events

Liver

Elevations of liver enzymes have been observed on teriflunomide. These are seen within the first 6 months of treatment. People with MS 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.

Blood pressure

High blood pressure may occur during treatment with teriflunomide.

Infections

No increase in serious infections has been observed with teriflunomide. The safety of teriflunomide in people with MS with latent tuberculosis (TB) is unknown, which is why I recommend screening for TB infection before starting teriflunomide.

Lung

Interstitial lung disease has been rarely reported in people with MS on teriflunomide. Therefore, any new onset or worsening breathing or chest problems, such as persistent cough and shortness of breath, need to be investigated.

Blood

Teriflunomide causes a small (~15% ) drop in the number of circulating white blood cells, but not sufficient to cause any problems. In a few people with MS (<5%) the drop may be more profound and require them to stop taking the medication.

Skin

A few cases of severe hypersensitivity skin reactions have been reported on teriflunomide, including Stevens-Johnson syndrome, toxic epidermal necrolysis and a condition called DRESS (drug reaction with eosinophilia and systemic symptoms). Please look out for any skin rash.

Neuropathy

Rare cases of peripheral neuropathy have been reported in people with MS on teriflunomide. Please watch out for tingling sensations and/or loss of feeling in the toes and fingers; these adverse events tend to be symmetrical, which helps differentiate them from MS symptoms.

Neutralizing antibodies (NAbs)

NAbs are not a problem on teriflunomide because it is a small molecule and not a biological (protein) therapy.

Pharmacovigilance monitoring requirements

Baseline

Full blood count, urea and electrolytes, liver function tests, thyroid function tests, serum immunoglobulin levels, serology (varicella zoster virus, 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

Liver enzymes should be assessed every 4 weeks during the first 6 months of treatment and regularly thereafter or as indicated by clinical signs and symptoms such as unexplained nausea, vomiting, abdominal pain, fatigue, loss of appetite, or jaundice and/or dark urine. Full blood cell counts need only be performed every 6 months or if you develop an infection on treatment.

Rebaselining

A rebaseline MRI scan needs to be done after teriflunomide has had sufficient time to work. I recommend that an MRI is done 6 months after starting treatment and that Gd-enhancement is included as part of the rebaselining MRI.

Women of childbearing potential and pregnancy

If you are a woman of childbearing age, before starting teriflunomide treatment I would recommend a negative pregnancy test result. Teriflunomide is potentially teratogenic, i.e. it can cause birth defects; therefore, you must have effective contraception whilst on treatment. It takes many months to eliminate teriflunomide from the body. Therefore, on stopping treatment the potential risk to the foetus may persist, and contraception should be continued during the drug elimination period, or you should undergo the rapid elimination procedure. If there is any delay in the onset of your period (menses) or any other reason for suspecting pregnancy, you must notify your nurse or doctor immediately and undergo pregnancy testing. If pregnant, it is possible to rapidly lower the blood level of teriflunomide by instituting the accelerated elimination procedure. If you do fall pregnant whilst on teriflunomide, we would not automatically recommend termination of pregnancy but, rather, refer you to a high-risk antenatal clinic for counselling and foetal screening. Many babies exposed to teriflunomide in the womb have been born without overt problems.

Breastfeeding

Teriflunomide is excreted into the breast milk of lactating women and has the potential for adverse reactions in nursing infants, so women on teriflunomide should not breastfeed.

Fertility

There is no evidence that teriflunomide affects either male or female fertility.

Male fertility

The risk of toxicity to the embryo through teriflunomide affecting the sperm is low. Animal studies have shown no evidence that teriflunomide adversely affects male fertility or damages sperm. Despite this, some regulatory authorities have recommended that men wishing to father a child discontinue teriflunomide treatment and undergo the accelerated elimination procedure. However, the EMA does not recommend this. Based on the data, I don’t recommend that men with MS wanting to start or extend a family stop teriflunomide or take any specific precautions.

Vaccination

Two clinical studies have shown that vaccination with component or inactivated vaccines was safe and effective whilst on teriflunomide. However, the use of live attenuated vaccines may carry a risk of infections and – based on the current recommendation – should be avoided.

Travel

People with MS need to be aware that being on teriflunomide may affect travel; for example, some countries require you to be vaccinated against yellow fever, which is a live attenuated vaccine and hence contraindicated.

Summary of Product Characteristics (SmPC)

Aubagio.

Accelerated elimination

An accelerated elimination procedure may be needed to eliminate teriflunomide from the body very quickly. This is typically done for women of childbearing age who want to fall pregnant or have fallen pregnant. It may also be done when switching treatments.

After stopping treatment with teriflunomide:

Cholestyramine 8 g is administered three times daily for 11 days; alternatively, cholestyramine 4 g three times daily can be used but only if cholestyramine 8 g three times a day is not well tolerated.
Alternatively, 50 g of activated powdered charcoal is administered every 12 hours for 11 days.

For women wanting to fall pregnant, the effectiveness of the accelerated elimination procedure can be verified by two tests at least 14 days apart to determine the plasma concentration of teriflunomide. Once this falls below 0.02 mg/l, a waiting period of one-and-a-half months is required before fertilisation can be advised.

Please note that cholestyramine and activated powdered charcoal may influence the absorption of oestrogens and progestogens. Since the oral contraceptive pill cannot be guaranteed reliable during the accelerated elimination procedure, an alternative contraceptive method is recommended.

Switching-2-teriflunomide

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

DMTsDetail

Natalizumab

28/06/2023 Gavin Giovannoni

Summary

Natalizumab is a first-in-class selective adhesion molecule blocker that reduces the trafficking of lymphocytes into the central nervous system (CNS). It 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, average annual brain volume loss for patients treated with natalizumab is within the expected range for age-matched people without MS. Natalizumab has a rapid onset of action; when it is used early in the disease course, many people with MS report a reduction in symptoms of disability and fatigue.

One result of reduced lymphocyte trafficking in the brain is reduced immune surveillance. This puts patients receiving natalizumab at high risk of progressive multifocal leukoencephalopathy (PML) if infected with the JC virus that causes it. The risk of PML is variable and can be reduced by using extended interval dosing (EID), whereby natalizumab is given as a 6-weekly infusion and is very well tolerated. (Normally natalizumab is given every 4 weeks.) A small number of people with MS (<5%) may develop infusion reactions, which can be serious. Infusion reactions typically come on with the second, third or fourth natalizumab infusion and are associated with developing so-called neutralising antibodies (NAbs).

Trade names

Tysabri.

Mode of action

Natalizumab is immunosuppressive, and it is associated with opportunistic infections, including PML, and possibly secondary malignancies of the CNS. Natalizumab is a monoclonal antibody that targets VLA-4 or α4β1 integrin on lymphocytes, preventing them from crossing the blood ̶̶ brain barrier. A lymphocyte must stick to the wall of a blood vessel before it can cross – like two surfaces of Velcro sticking together. Natalizumab blocks one of the surfaces so the lymphocytes cannot cross the blood vessel wall. People with MS on natalizumab treatment have more circulating white blood cells in their blood than normal. This is because the cells that normally adhere temporarily to blood vessel walls (marginating cells) are now found in the blood.

Efficacy

Very high, particularly in people with rapidly evolving severe MS.

Class

Maintenance, immunosuppressive.

Immunosuppression

Yes, but limited to the CNS.

Dosing

Tysabri 300 mg and Tyruko 300 mg are both administered by intravenous infusion once every 4 weeks. Tysabri is also available as a subcutaneous injection, given once every 4 weeks.
There is evidence that extended interval dosing (EID) of natalizumab – increasing the gap between infusions from 4 weeks to 5 or 6 weeks – may dramatically reduce the risk of PML.

Main adverse events of special interest

Infusion reactions

These tend to be mild and occur in about 20% of patients; they may be associated with headache, dizziness, nausea, urticaria and rigors.

Hypersensitivity reactions

These occur in approximately 5% of patients. In about a quarter of this 5% they can be anaphylactoid in nature and typically occur during the infusion or within an hour of completing the infusion. Hypersensitivity reactions are characterised by either a low or high blood pressure, chest pain, chest discomfort, shortness of breath, swelling of the throat, rash, urticaria, rigors, nausea, vomiting and flushing. Most hypersensitivity reactions occur on the second, third or fourth infusion and are associated with the development of anti-drug antibodies, i.e. your own body rejects natalizumab by making antibodies against it. Persistent anti-natalizumab antibodies develop in approximately 5 ̶ 6% of people with MS on natalizumab; they decrease the drug’s effectiveness and cause hypersensitivity reactions.

Infections

In general, natalizumab is not associated with systemic infections. As an immunosuppressive therapy, natalizumab has been associated with opportunistic infections, particularly PML. Other opportunistic infections include cryptosporidium diarrhoea and cryptococcal meningitis. Herpes infections (varicella zoster virus, herpes simplex virus) have occurred more frequently in patients receiving natalizumab than in those receiving a placebo. Serious life-threatening encephalitis and meningitis caused by herpes simplex or varicella zoster can occur on natalizumab. The presentation of these infections is atypical because reduced trafficking of cells into the CNS reduces the intensity of the inflammation. Rarely, these viruses may infect the retinae and lead to acute retinal necrosis and loss of vision.

PML and granule cell neuronopathy

JCV is the commonest opportunistic infection in seropositive natalizumab-treated people with MS. JCV can cause PML and granule cell neuronopathy (GCN). PML is the commonest complication of JCV, and its management is described separately. GCN is characterised by lytic infection of the cerebellar granule cell layer and presents with a cerebellar ataxia and cerebellar atrophy and white matter changes in the cerebellum and brainstem on magnetic resonance imaging (MRI). Many cases of GCN also have white matter changes elsewhere, suggesting an overlap between GCN and PML. There is evidence that increasing the time interval between natalizumab doses – extended interval dosing – may dramatically reduce the risk of PML.

Abnormal liver function

Autoimmune hepatitis, increased liver enzymes and hyperbilirubinaemia rarely occur with natalizumab.

Anaemia

Rare cases of anaemia and haemolytic anaemia have been reported in natalizumab-treated people with MS.

Malignancies

Several cases of CNS lymphoma have been reported in natalizumab-treated people with MS. The risk of CNS lymphoma is likely to be increased based on the mode of action of natalizumab, i.e. it blocks immune surveillance of the CNS and hence there will be an increased risk of CNS tumours.

Neutralising antibodies (NAbs)

Yes, in approximately 5% of natalizumab-treated patients.

Pharmacovigilance monitoring requirements

Baseline

Full blood count, urea and electrolytes, liver function tests, JC virus-serology and pregnancy test.

Follow-up

LFTs 3-monthly for one year, NAbs at 12 months and JCV–serology every 6 months. In people with MS at high risk of PML, 3 ̶ 4-monthly MRI; otherwise, annual MRI for disease activity monitoring.

Self-monitoring

All people with MS should be warned about opportunistic infections and informed to look out for symptoms suggestive of infections. Women should be reminded to self-examine their breasts monthly and should have cervical smears and/or human papillomavirus testing every 3 years.

Rebaselining

I recommend a rebaseline MRI 3 ̶ 6 months after starting treatment with natalizumab and including gadolinium enhancement as part of this.

Pregnancy

Animal studies have shown no toxicity from natalizumab, and data from clinical trials and post-marketing studies in humans suggest natalizumab exposure has no adverse effect on pregnancy outcomes. Babies born to people with MS on natalizumab have a transient mild-to-moderate low platelet count and anaemia, which typically disappear within weeks. Most neurologists now allow their female patients to fall pregnant whilst on natalizumab and then offer to stop it after they have become pregnant. Some neurologists are letting patients continue natalizumab throughout pregnancy. The decision to do this is based on the emerging safety profile of natalizumab in pregnancy and the risk of rebound MS activity when natalizumab washes out.

Breastfeeding

The amount of natalizumab that crosses over into the breast milk is very small and is likely to be digested by the baby’s digestive enzymes; therefore, it is safe to breastfeed on natalizumab.

Male fertility

Safe.

Vaccination

Safe for component or inactivated vaccines. Live vaccines are contraindicated. Live viruses, particularly ones that can infect the CNS, are potentially dangerous.

Summary of Product Characteristics (SmPC)

Tysabri, Tyruko.

Extended interval dosing

Reducing the risk of PML

At present, several factors can help us assess the risk of PML: JC virus testing (negative and positive), level of JCV antibodies (antibody index), previous exposure to immunosuppression, and treatment duration. We also have frequent MRI monitoring (3 ̶ 4-monthly) to detect PML early and plasma exchange to remove natalizumab as a backup option if a patient develops PML. Another option to reduce the risk of PML may be extended interval dosing (EID).

I have several patients who, despite being JCV-seropositive, insist on staying on natalizumab rather than trying an alternative treatment. A few patients, even after switching to another DMT to prevent getting PML, have opted to go back onto natalizumab. The reason typically relates to the return of MS fatigue, or brain fog, after stopping natalizumab. After restarting natalizumab, patients come back and say, ‘I feel well, my fatigue has gone, and my thinking is clear’. This is why anything that decreases the risk of PML for patients on natalizumab is good.

Rationale for extended interval dosing

The theory behind EID is that some cells are less sensitive than others to the effects of natalizumab; if you delay the next natalizumab infusion by 1 or 2 weeks, the saturation of the surface receptors drops below a threshold and allows those cells to traffic into the CNS. If these cells with lower sensitivity to natalizumab are the antiviral T cells and/or the natural killer cells that fight viruses, this could allow immune surveillance of the CNS to occur and prevent PML from developing. By achieving the correct EID, the saturation of the immune cells that cause MS (possibly the memory B cells) is sufficient not to allow MS to reactivate. Clearly, not all cells are equal when it comes to the effect of natalizumab. Importantly, several other adhesion molecules impact the adhesion (stickiness) of immune cells to the blood vessels in the CNS. A delicate balance between the availability of different accessory adhesion molecules could also make the difference.

When these principles were adopted by several neurologists in the USA, the data emerging from their centres suggested they were correct in hypothesising that the risk of developing PML was reduced when JCV-seropositive people with MS received EID natalizumab.

Comparison of extended and standard interval dosing

Biogen, the manufacturer of Tysabri, sponsored some large studies to explore this theory.^1,2 Using the so-called TOUCH program (Tysabri Outreach: Unified Commitment to Health), which is a mandatory database of all people with MS receiving Tysabri in the USA, statisticians identified more than 35,000 anti-JC virus antibody-positive patients on Tysabri; they compared those on EID with those on standard interval dosing (SID) for PML risk.¹ The TOUCH programme is real-life data, not a clinical trial database, so the periods of EID are variable. To deal with this, the statisticians defined three types of EID with increasing stringency. The remarkable finding was that EID was seen to reduce the risk of PML significantly compared with SID in two of the analyses; in the most stringently defined cohort of EID there were rare cases of PML.

Clinical implications

I have acted on this finding and have offered EID to my patients taking natalizumab who are at risk of PML. It is advisable to transition to 6-weekly EID over several months so as not to precipitate pre-infusion worsening of symptoms. I am now recommending three infusions at 5-weekly intervals before moving to 6-weekly infusions.

The question to consider is whether EID will be associated with some loss of natalizumab effectiveness. A recent study showed no loss of efficacy with EID.² In addition, the study was not clear on finding a personalised dose. Therefore, all patients on EID received it every 6 weeks.

I personally am thrilled by these results. Why? Because anything that derisks PML for people with MS on natalizumab is good, particularly for people with more advanced MS. This is important because natalizumab is effective in more advanced MS, particularly in slowing down or preventing worsening of hand and arm function.

Switching-2-natalizumab

Natalizumab

Recent data have shown that increasing the dosing interval between natalizumab infusions (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.

References

Ryerson LZ, et al. Risk of natalizumab-associated PML in patients with MS is reduced with extended interval dosing. Neurology 2019;93:e1452 ̶ 62.
Foley JF, et al. NOVA study investigators. Comparison of switching to 6-week dosing of natalizumab versus continuing with 4-week dosing in patients with relapsing-remitting multiple sclerosis (NOVA): a randomised, controlled, open-label, phase 3b trial. Lancet Neurol 2022;21:608 ̶ 19.

DMTsDetail

S1P modulators

30/05/2023 Gavin Giovannoni

Summary

‘S1P modulators’ is the ‘short-hand’ we use to describe a group of drugs called sphingosine 1-phosphate receptor modulators (see Mode of action below). Fingolimod was the first of the S1P modulators to be licensed in MS (in 2010) and the first oral tablet approved for use in MS. Since then, three more S1P modulators have been licensed: siponimod, ozanimod and ponesimod. These are highly effective drugs, decreasing the relapse rate by over 50%, reducing worsening disability and the development of new lesions on magnetic resonance imaging (MRI), and slowing the loss of brain volume. S1P modulators work by trapping lymphocytes in lymph nodes and causing a low lymphocyte count in virtually all people with MS on the drugs. These drugs are maintenance therapies taken continuously and hence cause systemic immunosuppression. As a result, S1P modulators are associated with rare opportunistic infections and secondary malignancies, for example, lymphomas and skin cancers. They are anti-trafficking drugs, i.e. they block lymphocytes migrating into the CNS of people with MS, so when they are stopped, they are associated with rebound disease activity. Rebound typically occurs at around 6 ̶ 8 weeks after stopping fingolimod and siponimod and may also occur with ozanimod and ponesimod. S1P modulators have off-target side effects; for example, they slow the heart rate down and may need to be started in a hospital or under observation.

Trade names

Gilenya (fingolimod), Mayzent (siponimod), Zeposia (ozanimod), Ponvory (ponesimod).

Mode of action

Fingolimod is a sphingosine 1-phosphate (S1P) receptor modulator. Fingolimod is converted to an active drug, fingolimod phosphate, in the body. Fingolimod phosphate binds to its receptor (the S1P receptor) subtype 1 located on lymphocytes, which causes the receptors to be internalised and removed from the surface of the cells. By preventing S1P receptors from recirculating onto the surface of lymphocytes, fingolimod blocks the capacity of lymphocytes to leave lymph nodes, causing their redistribution rather than depletion. Siponimod, ozanimod and ponesimod are active drugs and do not need to be phosphorylated, but they work in the same way as fingolimod.

Efficacy

High; fingolimod is licensed in the UK and Europe as a second-line therapy for people with highly active MS. In other countries, fingolimod can be used first-line. Siponimod is licensed for people with MS with active secondary progressive MS. Ozanimod and ponesimod are licensed as first-line treatments for people with active MS.

Class

Maintenance, immunosuppressive.

Immunosuppression

Yes, systemic.

Dosing

Fingolimod dosing

In adults, the recommended dose of fingolimod is one 0.5 mg capsule taken orally once daily. In children with MS (10 years of age and above), the recommended dose is dependent on body weight:

body weight ≤40 kg: one 0.25 mg capsule taken orally once daily
body weight >40 kg: one 0.5 mg capsule taken orally once daily.

When people with MS start on 0.25 mg capsules and reach a stable body weight above 40 kg, they should be switched to 0.5 mg capsules. Fingolimod can be taken with or without food. Fingolimod capsules should always be swallowed intact without opening them.

Although the Gilenya SmPC states that when switching from a 0.25 mg to a 0.5 mg daily dose it is recommended to repeat the same first dose monitoring as for treatment initiation, we have not done this. The following text is from the Gilenya SmPC:

The same first dose monitoring as for treatment initiation is recommended when treatment is interrupted for:

1 day or more during the first 2 weeks of treatment
more than 7 days during weeks 3 and 4 of treatment
more than 2 weeks after one month of treatment.

If the treatment interruption is of a shorter duration than the above, the treatment should be continued with the next dose as planned.

Siponimod dosing

The dose of siponimod depends on how rapidly you can metabolise the drug. Before starting treatment, people with MS must be genotyped to determine their metaboliser status. In people with MS who metabolise the drug slowly and have the so-called 3-3 genotype, siponimod should not be used. In intermediate metabolisers (genotype 2-3 or 1-3), the recommended maintenance dose is 1 mg taken once daily (four tablets of 0.25 mg). In people with all other genotypes who are rapid metabolisers, the dose of siponimod is 2 mg per day.

To reduce off-target side effects, siponimod treatment is started with a titration pack that lasts for 5 days, as follows:

days 1 and 2: 0.25 mg once daily
day 3: 0.5 mg once daily
day 4: 0.75 mg once daily
day 5: 1.25 mg once daily
day 6: increase to the patient’s prescribed maintenance dose of siponimod.

During the first 6 days of treatment initiation, the recommended once-daily dose should be taken in the morning with or without food (see SmPC for more details).

Ozanimod dosing

The recommended dose is 0.92 mg of ozanimod once daily. To reduce off-target side effects, an initial dose titration is required over the first 7 days (see SmPC for more details):

days 1 ̶ 4: 0.23 mg once daily
days 5 ̶ 7: 0.46 mg once daily
day 8 onwards: 0.92 mg once daily.

Ponesimod dosing

The recommended dose is 20 mg of ponesimod once daily. To reduce off-target side effects, an initial dose titration is required over the first 14 days. The dose starts at 2 mg per day and builds up over 14 days to the maintenance dose of 20 mg per day (see SmPC for specific details).

Dose reduction

The European Medicines Agency recommends that if someone with MS has a persistent lymphopaenia of below 200/mm³ (grade 4), then S1P modulators should be stopped until the lymphocyte counts recover. It is our practice to put these patients on alternate-day dosing or to reduce the daily dose and to rechallenge them with the full dose once the counts have recovered to above 200/mm³. Now that fingolimod has been licensed for treating children with MS, with a dose based on weight, a 0.25 mg tablet is available. So instead of taking 0.5 mg on alternate days, there is also the possibility of taking 0.25 mg daily.

As the response to fingolimod or other S1P modulators and the risk of opportunistic infections are unrelated to the lymphocyte counts, the US Food and Drug Administration has not recommended routine monitoring of lymphocyte counts. Because of this, I am not unduly concerned about lymphocyte counts in patients on fingolimod and other S1P modulators and tend only to respond to counts of less than 100/mm³.

Main adverse events of special interest

Cardiac

The main adverse event of S1P modulators is a transient slowing of the heart rate that can, rarely, be associated with a heart block. This is why fingolimod is started in hospital with cardiac monitoring. With the newer generation S1P modulators, this is managed by a dose titration. Cardiac conduction abnormalities are usually transient and asymptomatic. Owing to the cardiac side effects, concurrent therapy with beta-blockers, heart-rate-lowering calcium channel blockers (such as verapamil or diltiazem), or other substances which may decrease heart rate (e.g. ivabradine, digoxin, anticholinesterase inhibitors or pilocarpine) is not recommended. The effects on heart rate and cardiac conduction may recur on the reintroduction of S1P modulator treatment, depending on the duration of the interruption and the time since the start of treatment. S1P modulators may prolong the so-called QT interval on your ECG, so they are best avoided in individuals with relevant risk factors, for example, low potassium or congenital QT prolongation.

Immunosuppressive effects

S1P modulators predispose people with MS to an infection risk, including opportunistic infections, and increase the risk of developing lymphomas and other malignancies, particularly those of the skin. Potential opportunistic infections include fungal infections, for example, cryptococcal meningitis and progressive multifocal leukoencephalopathy (PML). Before initiating treatment with S1P modulators, it is important to do a baseline infection screen and to check the full blood count. You must have antibodies or immunity to varicella (chickenpox) prior to starting treatment. If you are varicella negative, it is recommended that you receive a full course of one of the varicella vaccines. Similarly, you must have a full vaccine review before starting this class of treatment. Human papillomavirus (HPV) infection, including papilloma, dysplasia, warts and HPV-related cancers, has been reported in people with MS on S1P modulators, which is why we recommend cervical smears or HPV testing at baseline before starting treatment.

Macular oedema

Swelling of the macula, the central part of the retina, occurs in ~ 1 in 200 people with MS treated with fingolimod or another S1P modulator. This can cause symptoms and can be detected using the so-called Amsler grid (see below). You must be assessed at an eye clinic 3 ̶ 4 months after initiating an S1P modulator to screen for this complication. Some clinicians do baseline testing of the eye before initiating S1P modulators; in fact, this is in the SmPC for ponesimod. Please note that if you have a history of uveitis (inflammation in the eye) or have diabetes mellitus, you are at increased risk of developing macular oedema. I tend to avoid prescribing S1P modulators to patients with diabetes.

The Amsler grid (left) is a simple square containing a grid pattern and a dot in the middle. If there are problem spots in your field of vision, areas of the grid may appear blank or distorted (right, example).

Liver

Increased liver enzymes have been reported in people with MS on S1P modulators such as fingolimod. This is why your LFTs (liver function tests) are monitored after starting fingolimod and other S1P modulators, and if they exceed five times the upper limit of normal fingolimod needs to be stopped. LFTs are recommended at 1, 3, 6, 9 and 12 months after therapy and then 6 monthly after that. Please be aware that if you develop any symptoms suggestive of liver problems, such as unexplained nausea, vomiting, abdominal pain, fatigue, loss of appetite, or jaundice and/or dark urine, you should have liver enzymes checked. If you have pre-existing liver disease, most neurologists will avoid using this class of therapy.

High blood pressure

S1P modulators increase your blood pressure by a small amount. If you develop hypertension, you may need to start antihypertensive medications; hypertension occurs in ~ 1 in 20 people with MS treated with fingolimod and is less common with the newer generation S1P modulators.

Respiratory effects

S1P modulators cause a minor reduction in lung function, so neurologists tend to avoid using fingolimod and other S1P modulators in people with MS with pre-existing lung disease.

Vascular effects

Rare cases of posterior reversible encephalopathy syndrome (PRES) have been reported on S1P modulators. Symptoms can include sudden onset of severe headache, nausea, vomiting, altered mental status, visual disturbances and seizures. If you suspect you have PRES, you should contact your doctor urgently.

Cutaneous neoplasms

Basal cell carcinoma (BCC) and other cutaneous neoplasms, including malignant melanoma, squamous cell carcinoma, Kaposi’s sarcoma and Merkel cell carcinoma, have all been reported in people with MS on fingolimod, and there is the potential for these conditions to occur with the other S1P modulators. Please be vigilant for any new skin lesions and bring them to the attention of your doctor, who may need to refer you to a dermatologist. In our centre, we encourage our patients to take pictures of lesions with their smartphone camera and email them to us. We often get back a dermatology opinion very quickly this way. In people with MS at high risk, i.e. those with a dysplastic naevus syndrome, severe sun damage and/or prior history of skin cancer, we refer to dermatology for regular (annual) skin cancer screening. At present, annual skin screening is not justified in low-risk patients. Owing to the potential risk of malignant skin lesions, you need to be careful with excessive sunlight exposure or phototherapy with UV-B-radiation or PUVA-photochemotherapy.

Rebound disease activity

Severe exacerbation of disease has been observed in people with MS stopping fingolimod and siponimod treatment and may also occur with ozanimod and ponesimod. The possibility of recurrence of exceptionally high disease activity needs to be carefully considered when deciding on the sequence of treatments. Rebound typically occurs 6 ̶ 8 weeks after stopping fingolimod, siponimod and ozanimod. If it occurs with ponesimod, it will likely happen much earlier because ponesimod washes out more rapidly than the other S1P modulators.

Neutralising antibodies (NAbs)

NAbs are not a problem with S1P modulators because these DMTs are all small molecules and not a biological (protein) therapy.

Pharmacovigilance monitoring requirements

Baseline

Full blood count, urea and electrolytes, liver function tests, thyroid function tests, serum immunoglobulin levels, serology (varicella zoster virus, human immunodeficiency virus 1 and 2, hepatitis B and C, syphilis), tuberculosis enzyme-linked immune absorbent spot (TB ELISpot), up-to-date cervical smear and/or human papillomavirus testing, pregnancy test, blood pressure and electrocardiogram. Lung function tests are recommended for anyone with a history of asthma or lung disease.

Follow-up

FBC, LFTs and blood pressure should be monitored at months 1, 3, 6, 9 and 12 on therapy and 6-monthly thereafter.

Visual function

Macular oedema screening should be done 3 ̶ 4 months after treatment start in an eye clinic. The SmPC for ponesimod recommends a baseline eye scan, but this may not be necessary in people with low-risk MS.

Self-monitoring

All people with MS should be warned about opportunistic infections and informed to look out for symptoms suggestive of infections, suspicious skin lesions and symptoms of liver dysfunction. Women should be reminded to self-examine their breasts monthly and should have cervical smears and/or HPV testing done every 3 years. People with MS need to be aware of visual symptoms and can self-assess their macular function with an Amsler grid. There are several Amsler grid apps available for smartphones. Routine blood pressures also need to be taken.

Rebaselining

A rebaseline MRI scan needs to be done after the S1P modulator has had sufficient time to work. As S1P modulators work quite rapidly, I would recommend that an MRI is done 3 ̶ 6 months after starting treatment and that Gd-enhancement is included as part of the rebaselining MRI.

Women of childbearing potential and pregnancy

If you are a woman of childbearing age, before starting S1P modulator treatment, I would recommend a negative pregnancy test result. S1P modulators are potentially teratogenic, i.e. they can cause birth defects, therefore, you must have effective contraception whilst on treatment. It takes approximately 2 months to eliminate fingolimod from the body and 3 months to eliminate ozanimod; for ponesimod and siponimod, the elimination times are 1 week and 10 days, respectively. Therefore, on stopping treatment the potential risk to the foetus may persist and contraception should be continued during the drug elimination period. If you do fall pregnant whilst on an S1P modulator, we would not automatically recommend termination of pregnancy but, rather, refer you to a high-risk antenatal clinic for counselling and foetal screening. Many babies exposed to S1P modulators in the uterus have been born without any overt problems.

Breastfeeding

S1P modulators are excreted in the breast milk of lactating women and have the potential for serious adverse reactions in nursing infants, so women on these drugs should not breastfeed.

Fertility

I am not aware of any data to suggest that S1P modulators are associated with reduced female fertility.

Male fertility

S1P modulators have not been shown to affect sperm counts or sperm motility. There is no need for men with MS to stop fingolimod if they want to father a child.

Vaccination

It is safe to receive component or inactivated vaccines, but the antibody responses may be blunted. Live vaccines are contraindicated in people with MS on S1P modulators. Live viruses, particularly ones that can infect the central nervous system, are potentially dangerous.

Travel

People with MS need to be aware that being on an S1P modulator may affect travel; for example, some countries require you to be vaccinated against yellow fever, which involves a live attenuated vaccine and is hence contraindicated. If you travel to places associated with exotic infections, for example, dengue fever, you may be at risk of complications from these infections because S1P modulators are immunosuppressive.

Summaries of Product Characteristics (SmPC)

Gilenya, Mayzent, Zeposia, Ponvory.

Switching to an S1P modulator

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.

SIP 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.

DMTsDetail

Mitoxantrone

02/05/2023 Gavin Giovannoni

Summary

Mitoxantrone is licensed to treat MS in a few countries (though not in the UK). It is typically used to treat active secondary progressive, progressive relapsing, or worsening relapsing ̶ remitting MS. It is a repurposed chemotherapy agent and is given as an intravenous infusion. It is either given as a monthly infusion for 6 months, or every 3 months for up to 2 years or as a combination of these two protocols. Mitoxantrone is associated with quite severe toxicity (infections, cardiotoxicity, premature ovarian failure and secondary leukaemia) which is why it is not used often now. In some countries it is used as a true induction therapy and is followed by a maintenance DMT, typically interferon-beta or glatiramer acetate. Because mitoxantrone is toxic to the heart there is a limited cumulative dose that can be given safely over a lifetime. I have kept mitoxantrone on the list of essential DMTs because it is generic and hence is available for treating MS in resource-poor settings.

Trade names

Novantrone.

Mode of action

Mitoxantrone is an immune reconstitution therapy. It works by inhibiting the enzyme topoisomerase II which unwinds DNA. As a result of its actions on this enzyme it disrupts DNA synthesis and DNA repair in cells and causes them to die. White blood cells are particularly sensitive to its actions. Mitoxantrone is derived from a group of chemicals called anthracenediones that are toxic to the heart in high doses.

Efficacy

High to very high.

Class

Non-selective immune reconstitution therapy (IRT), short-term immunosuppression.

Immunosuppression

Yes, short-term.

Infusion protocols

Edan protocol: Mitoxantrone 20 mg intravenous infusion (ivi) monthly in combination with 1 g methylprednisolone x 6 months (6 doses).
Hartung protocol: Mitoxantrone 12 mg/m² ivi 3-monthly x 2 years (8 doses).
Gonsette protocol: Mitoxantrone 12 mg/m² ivi monthly x 3 months followed by mitoxantrone 12 mg/m² ivi 3- monthly up to 2 years (10 doses). Please note the Gonsette protocol includes an algorithm to adjust the next dose depending on the recovery of the peripheral blood cell counts.

Additional courses of mitoxantrone can be given beyond what is stated in these protocols provided the total lifetime dose of mitoxantrone does not exceed 140 mg/m² and that cardiac monitoring (echocardiogram [ECG] and ejection fraction) does not show signs of a cardiomyopathy.

Adverse events and events of special interest

Infection

Mitoxantrone causes a low white cell count that may result in an increased susceptibility to infection. Therefore, it is important that all infections are identified early and treated. The presence of an active infection may delay the next infusion. Chest infections and urinary tract infections are common after mitoxantrone. Maintenance of skin integrity is also important because broken skin or ingrown toenails may become areas harbouring infection. People with MS and their families and/or carers should be educated about how to assess and detect infection so that potential problems are recognised early. Please note that individuals treated with mitoxantrone may develop neutropenia and are hence susceptible to neutropenic sepsis, including infection with Listeria monocytogenes.

Nausea and vomiting

Nausea may occur during treatment and the next day. Antiemetic drugs are usually prescribed to help manage this. The doses of mitoxantrone used to treat MS are much lower than those used in cancer, therefore these side effects are milder than those generally experienced by people with cancer.

Hair loss

Hair may become temporally thinner during mitoxantrone treatment but will return to normal once the treatment is finished. Hair loss is uncommon and happens in fewer than 3% of people with MS who receive mitoxantrone. If it does occur, it usually begins 3 ̶ 4 weeks after the first dose has been administered.

Cardiotoxicity

High doses of mitoxantrone have been associated with cardiotoxicity. So a baseline heart scan must be performed before commencing the first dose of treatment. This scan can either be a MUGA scan or an ECG. These routine tests measure the contractility of the heart. The MUGA scan requires the injection of a very low dose of a radionuclide tracer, which is then detected using a machine similar to an x-ray machine. An ECG is a form of ultrasound done using a probe that is applied to the chest. Neither of these tests is painful. The MUGA scan or ECG should be completed at baseline and then 3-monthly before the administration of the next dose of mitoxantrone. Mitoxantrone treatment may have to be stopped if the tests show a significant decrease in cardiac function, i.e. a decrease in ejection fraction below 50%. These problems generally happen in people who receive a total lifetime dose of more than 140 mg/m².

Extravasation

Mitoxantrone is an irritant that can produce pain and inflammation along the path of a vein through which it is administered. Extravasation occurs when the drug accidentally infiltrates the tissue outside the vein. To avoid extravasation, the cannula must be sited in the non-dominant arm and away from areas of joint flexion. The site should not be obscured and should be checked at regular intervals. An extravasation kit should beavailable at the bedside for medical staff to use in case of emergency.

Therapy-related leukaemia

Secondary acute myelogenous leukaemia (or acute myeloid leukaemia, AML) has been reported in people with MS or with cancer treated with mitoxantrone. Therapy-related leukaemia associated with topoisomerease II inhibitors such as mitoxantrone typically develops within 2 ̶ 4 years after chemotherapy has started. Based on the current data, the risk of leukaemia in subjects with MS treated with mitoxantrone is ~1 in 200–400 subjects.

Infertility

Amenorrhea (lack of periods) may occur during treatment and should be investigated because it may respond to treatment with hormonal replacement therapy. A less common complication is the induction of menopause, which should be fully investigated should it occur. Transient amenorrhea occurs in ~12% of patients and persistent amenorrhea, or premature menopause, in ~10% of patients. The risk of persistent amenorrhoea is higher in women older than 35 years (14%) and lower in women less than 35 years of age (6.5%). If indicated, women should either be offered GnRH agonists as ovarian protection throughout therapy or the option of egg harvesting and storage.

Pharmacovigilance monitoring requirements and de-risking strategies

Baseline

Full blood count, urea and electrolytes, liver function tests, thyroid function tests, serum protein electrophoresis, serum immunoglobulin levels, serology (varicella zoster virus, human immunodeficiency virus 1 and 2, hepatitis B and C, syphilis), tuberculosis enzyme-linked immune absorbent spot (TB ELISpot), up-to-date cervical smear and/or human papillomavirus testing, pregnancy test, ECG and cardiac ejection fraction (echocardiography or MUGA scan).

Follow-up

1- to 3-monthly (predosing): FBC, U&E and LFTs and in women a pregnancy test
3-monthly: ECG and cardiac ejection fraction (echocardiography or MUGA scan)
12-monthly: TFTs
Endocrine work-up for women with MS with persistent amenorrhea.

Infection prophylaxis

Varicella zoster virus (VZV): if found to be VZV seronegative you will need to receive the VZV vaccine at least 6 weeks before being treated with mitoxantrone to allow sufficient time to develop immunity and protective antibodies against the virus.
Urinary tract infections (UTIs): if you have a history of recurrent UTIs you should be taught to self-monitor your urine using home dipstix, given a supply of urine specimen bottles for laboratory testing and possibly an unfilled prescription for a standard first-line antibiotic. Then, if you do develop a UTI and self-diagnose it, you can take your urine specimen for microscopy, culture and antibiotic sensitivity testing (MCS) at your GP surgery or the laboratory and then collect your prescription and start your antibiotics. Once the culture and antibiotic sensitivities come back from the laboratory this may prompt your doctor to change the antibiotics. Please note, however, that not all GPs and family practitioners support self-monitoring and self-management of your MS.
Listeriosis: you are at risk of developing listeriosis after mitoxantrone. To decrease this risk, you should receive advice about starting a listeriosis diet and a behavioural programme to reduce your likelihood of exposure to the infection. You may also be offered antibiotic prophylaxis. For example, the Association of British Neurologists gives the following summary advice for people with MS receiving alemtuzumab (also a risk for listeriosis): ‘We recommend several preventative measures, of which the most straightforward is co-trimoxazole 960 mg three times a week for one month after each cycle of alemtuzumab’. Here too is a link to a short online web application on this topic (Alemtuzumab safety advice).

Rebaselining

A rebaseline MRI needs to be done after completing the course of mitoxantrone. Depending on which protocol you have been treated with, this could be performed at 6 or 24 months.

Pregnancy

Pregnancy is contraindicated when using mitoxantrone as it may harm the developing foetus. While taking mitoxantrone, women who might become pregnant should use effective birth control and should be sure, before each dose, that they are not pregnant. If unsure, a pregnancy test should be performed.

Breastfeeding

Mitoxantrone is excreted in human milk, and significant concentrations (18 ng/ml) have been reported for up to 28 days after the last administration. Because of the potential for serious adverse reactions in infants from mitoxantrone, breast-feeding should be discontinued before starting treatment.

Male fertility

Although mitoxantrone causes transient oligospermia, male infertility has not been a problem. In contrast to other chemotherapy agents (e.g., alkylating agents such as cyclophosphamide), after cessation of mitoxantrone therapy there is complete recovery of sperm production without morphological changes in vitro or genotoxic effects on germinal cells in vivo. In view of this, it is not necessary to offer male patients the option of routine sperm banking.

Vaccination

Immunisation may be ineffective when given during mitoxantrone therapy. Immunisation with live virus vaccines is generally not recommended until after the immune system has reconstituted.

Summary of Product Characteristics (SmPC)

Novantrone (USA)

Switching-2-mitoxantrone

Mitoxantrone repeat course

As mitoxantrone is an Immune Reconstitution Therapy (IRT), breakthrough activity may trigger the need for additional courses to be given, provided the total lifetime dose of mitoxantrone does not exceed 140 mg/m² and that cardiac monitoring (ECG and echo/MUGA) does not show signs of underlying cardiomyopathy.

Other DMTs

Provided the baseline screening tests are acceptable and there are no specific contraindications, it is feasible (from a clinical perspective) to use mitoxantrone after another licensed DMT; please check the licensing regulations in your country.

Interferon-beta and glatiramer acetate

There are no specific cautions.

S1P modulators (fingolimod, siponimod, ozanimod and ponesimod)

The development of mitoxantrone-related cardiomyopathy and/or cardiac arrhythmia is a contraindication for using fingolimod and other S1P modulators (siponimod, ozanimod and ponesimod) after mitoxantrone. It is important to be extra-vigilant when doing the routine baseline cardiac checks post-mitoxantrone. If it has been some time since mitoxantrone’s last dose, I recommend checking a cardiac ejection fraction with echocardiography or a MUGA scan.

Alemtuzumab and HSCT (non-selective cell depleting DMTs)

A persistently low peripheral white cell count post-alemtuzumab, HSCT or other DMT, i.e. a neutrophil count <1000/mm³ or a total lymphocyte count <800/mm³ is a relative contraindication to using mitoxantrone. Another hit on the bone marrow and primary and secondary lymphoid organs may render an individual more immunosuppressed and worsen their leukopaenia. The decision to use mitoxantrone in this situation has to be based on the potential benefits versus the risks of these treatments and the risks of untreated active MS.

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 using mitoxantrone. The effect of mitoxantrone on primary and secondary lymphoid organs may worsen the lymphopaenia and is a risk factor for developing grade 3 or grade 4 lymphopaenia, i.e. <500/mm³ or <200/mm³, respectively. However, the decision to use mitoxantrone in this situation has to be based on the potential benefits of the treatment versus the risks of lymphopaenia and the risks of untreated active MS.

Anti-CD20 therapies (selective cell depleting DMTs)

Anti-CD20 therapies (ocrelizumab, ofatumumab and others) are selective B-cell depleting agents, so mitoxantrone is theoretically much safer than the other less selective and non-selective agents post-ocrelizumab.

Natalizumab

As mitoxantrone is an IRT that can’t be rapidly reversed, it is critical to ensure that there is no asymptomatic PML. Carry-over PML from natalizumab to mitoxantrone is potentially fatal. Therefore, a baseline MRI scan and possibly a CSF examination is essential to exclude the possibility of PML before starting mitoxantrone.

Dimethyl fumarate

DMF reduces the lymphocyte count by approximately 30% and in some people with MS by more than this. Therefore, individuals with lymphopaenia on DMF may be more susceptible to developing clinically significant prolonged lymphopaenia post-mitoxantrone.

Teriflunomide

Because teriflunomide is an antiproliferative agent, it may delay or prevent the recovery of the peripheral white cell count post-mitoxantrone. 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. I, therefore, don’t think an accelerated washout is necessary.

Special circumstances

The presence of other specific comorbidities and adverse events may make it difficult to start mitoxantrone after another DMT.