Last updated on February 7th, 2024 at 11:30 pm

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

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 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 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 lung 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 occurs 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.

Adverse events in older patients with MS

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.

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.