Alemtuzumab
Information you need to know about alemtuzumab if you are considering it as a treatment for your MS.
This newsletter is to thank the MS-Selfie subscribers for your subscriptions and donations and to indicate the progress so far. The funds are being used to develop the MS-Selfie Microsite, making navigating and finding information about MS self-management easier. This will make it much easier for newly diagnosed people with MS (pwMS). In addition, the microsite will form the foundation of the MS-Selfie teaching course and book we are designing and writing.
For example, the following is the list of questions I have put together to help people with MS make an informed decision about starting treatment. This newsletter is a draft of the information you need to know about alemtuzumab. I would appreciate feedback to help the medical writing team when converting the information from the Newsletter to the microsite.
How do I want my MS to be treated? What is the difference between a maintenance/escalation DMT and an IRT (immune reconstitution therapy)?
How can I reduce my chances of adverse events on specific DMTs?
What are the attributes of the specific DMTs or treatment strategies?
Alemtuzumab
Cladribine
Fumarates
Anti-CD20
Will I be able to become a parent? What about pregnancy and breastfeeding?
Alemtuzumab
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 recovers back 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 alemtuzumab to other DMTs. In addition to a high rate of no evident disease activity and preventing or slowing down disability worsening, many treated patients 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 partially be explained by using it early and relatively young patients with MS. 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 or evidence of ongoing end-organ damage. Whether these individuals are cured will require much longer follow-up. Alemtuzumab works very 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, you can develop an infusion reaction. Ideally, you should be given steroids, antihistamines and possibly an antipyretic before each infusion to prevent or less 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. Alemtuzumab is an immune reconstitution therapy and hence works by rebooting the immune system.
In addition, to its anti-inflammatory effects, alemtuzumab also 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 people naive to treatment with rapidly evolving severe MS or as a second or third-line therapy for people with highly active MS. In multiple network analyses, alemtuzumab is the most effective MS disease-modifying therapy compared to other licensed therapies. In addition, to its impact on focal inflammatory activity (relapses and MRI activity) and preventing or slowing 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 partially be explained by using it early in relatively young patients with MS. Alemtuzumab is less effective in older patients and patients with more advanced MS.
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 (no accelerated brain volume loss). Whether these individuals are cured will require much longer follow-up. Alemtuzumab works similarly to AHSCT (autologous haemopoietic stem cell transplantation) 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 to 9 months after treatment.
Dosing
Alemtuzumab is given as two annual courses with up to two additional treatment courses if needed. The first course 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, such as a break over the weekend or waiting for an infusion reaction to settle. In year two, the second course consists of three 12 mg doses of alemtuzumab as three daily intravenous infusions (24 mg of alemtuzumab in total).
Up to two additional treatment courses can be given if needed. Additional courses are given if breakthrough activity occurs later on.
Recurrent MS disease activity
If you have recurrent disease activity after the first course in year one, we can bring the second course forward by 3-4 months. The latter occurs in about one in ten patients. This does not necessarily mean alemtuzumab has failed you, but you need the second course to get on top of your MS disease activity. However, rare patients develop severe rebound activity, typically in the 6-9 month window after alemtuzumab. These patients often have multiple Gd-enhancing lesions on MRI and/or tumefactive lesions. In these latter patients, 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 two 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. Please note, 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 why any other MS DMT cannot be started provided all the baseline tests are done for that DMT before starting the treatment.
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 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 intravenously 30-60 minutes before each alemtuzumab infusion
Paracetamol 1g and/or ibuprofen 400mg PRN for pyrexia, myalgias or pain. I have found that alternating paracetamol and ibuprofen effectively control 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.
Co-trimoxazole 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 are common to one or both components.
We have prepared an online tool and guide for our patients for Listeria prophylaxis that you can download.
Subcutaneous alemtuzumab
It is worth pointing out that oncologists have used alemtuzumab for decades to treat leukaemia and lymphoma. They discovered that giving alemtuzumab subcutaneously causes fewer or less severe infusion reactions 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 administered alemtuzumab successfully subcutaneously without steroid cover and have had no significant infusion-like reactions.
Main adverse events
The adverse events related to alemtuzumab can be divided into three classes; i.e. infusion-related adverse events, infectious complications when immunosuppressed and delayed secondary autoimmunity.
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 likely to be due to persistent flu-like side effects into the evening and possibly as a result of the steroids. Rarely anaphylactoid reactions occur with alemtuzumab, which requires overnight hospital admission. In our experience, these tended to occur with the day four infusion (course 1) when steroids were not given. Since administering steroids and antihistamines before each infusion, we have not had a severe anaphylactoid reaction requiring hospital admission.
Please be aware that after alemtuzumab was licensed in the USA by the FDA as a third-line rescue therapy, a new set of adverse events emerged. These included stroke, myocardial ischaemia and 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 subjects with more advanced MS, with frequent comorbidities, i.e. hypertension, obesity, smoking, etc. In Europe, where we were using alemtuzumab to treat very early MS, we didn’t see these complications. Therefore, it is essential to remember that risk:benefit ratio of alemtuzumab changes dramatically in older patients with more advanced MS.
Infections
For the first four 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 above). In addition, the treated patients are asked to start a listeria diet to prevent exposure to the bacteria that causes listeriosis, an uncommon infection. After four weeks, once the monocytes, a white blood cell, have recovered, the antibiotics and antiviral prophylaxis can usually be stopped.
Please be aware that infections can occur after the first four weeks. These can be common community-acquired infections or, more rarely, opportunistic infections. This is why pwMS treated with alemtuzumab must remain vigilant for any infections and seek advice if they develop any symptoms of infection. Common community-acquired infections that can be expected are nasopharyngitis, urinary tract infection, upper respiratory tract infection, sinusitis, oral herpes, influenza, and bronchitis. These infections tend to be mild. However, serious infections occur in approximately 2-3% of treated patients. The 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, has also been reported post-alemtuzumab, so we ask female patients to have an up-to-date cervical smear or vaginal HPV PCR done. Warts are a relative contraindication to alemtuzumab therapy.
Cytomegalovirus infections (CMV), including CMV reactivation, have also been reported post-alemtuzumab. Most cases occurred within two months of alemtuzumab dosing. Similarly, Epstein-Barr virus (EBV) infection reactivation can also 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 the switching guide below).
Delayed secondary autoimmunity
After a course of alemtuzumab, the immune system reconstitutes itself over several months, with the B-cells returning within three to four months and the T-cells returning between months 6 and 9. We think this may result in poor B-cell regulation, which may explain why pwMS 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 it 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 does not cause many problems. A few people with Graves’s disease develop co-morbid 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 the risk post-alemtuzumab will be less than 1 in 500.
The next commonest autoimmune disease is immune thrombocytopenic purpura or ITP. This is when 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 commonest autoimmune disease after 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 can attack the lung and cause damage to the lung that typically presents as a cough and blood in the sputum. The incidence of Goodpasture’s syndrome post-alemtuzumab is approximately 1 in 800.
There are a large number of other much rare autoimmune diseases that have been described in isolated patients post-alemtuzumab. These include acquired haemophilia, TTP ( thrombotic thrombocytopenic purpura), 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 autoimmune diseases typically occur in the first five years after starting treatment with alemtuzumab, and hence 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 will need to continue for four 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 pwMS developing autoimmunity. This is important because if we can work out what happens, we may be able to prevent this complication. There are a lot of theories about what can be done to prevent secondary autoimmunity post-alemtuzumab, but at present, there is no licensed treatment or strategy to do so.
I always tell my patients who are eligible for alemtuzumab that if they are not prepared to sign-up the monthly blood and urine monitoring and the risk of developing a second autoimmune disorder, they should not be treated with alemtuzumab.
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 as these can blunt the therapeutic potential of alemtuzumab.
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
A full-blood count and urine dipstix assessments are done monthly after starting alemtuzumab and up to four 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 autoimmunity and infections early to treat them promptly.
Rebaselining
A rebaseline MRI scan needs to be done after alemtuzumab. I recommend that an MRI is done between 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 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 after they have completed their second course of alemtuzumab. If a woman falls pregnant before the second course, we simply delay the second course until after delivery, and the woman has stopped breastfeeding.
Breastfeeding
We don’t recommend alemtuzumab whilst breastfeeding because concomitant medications are needed to manage infusion reactions and prevent infections that 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, as CD52, which alemtuzumab targets, is present in the testes, it is advisable for males treated with alemtuzumab to wait a few months after treatment with alemtuzumab before attempting to father a child.
Vaccination
It is recommended that alemtuzumab patients are immune to the varicella-zoster virus (VZV) before treatment. In the near future, patients will also be offered the Shingrex component vaccine to boost immunity to VZV before treatment. There is no reason why alemtuzumab patients 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 alemtuzumab and other IRTs.
Travel
People with MS need to be aware that being on alemtuzumab may affect travel; for example, some countries require you to be vaccinated against yellow fever, a live attenuated vaccine. The yellow fever vaccine will therefore have to 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 risk of infection.
Summary of Product Characteristics (SmPC)
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 as soon as possible after the last natalizumab infusion. In patients who are at very high risk of carry-over PML, we offer them a 6-12 month bridge on fingolimod. The bridge on fingolimod, which is reversible, allows one to exclude carry-over PML that typically declares itself within six 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 the total peripheral lymphocyte counts above 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 would be advisable to wait for B-cell counts to recover before starting alemtuzumab. I know that 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.
HSCT
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 alemtuzumab.
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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust. The advice is intended as general and should not be interpreted as personal clinical advice. If you have problems, please tell your own healthcare professional, who will be able to help you.
https://www.nytimes.com/2015/11/15/business/after-merger-two-competing-drugs-and-billion-dollar-questions.html
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Extremely grateful to have had Lem as first DMD at start of my MS when 41. I turned 50 this week and hiking around Iceland - thanks to my HCP’s at Barts ❤️ so thank you! I just wanted to understand if I ever needed a third round - does age play a part in the criteria, how would I know if I transition to SPMS and how would activity be promptly identified now that MRI’s are not yearly?