This time the focus is on alemtuzumab (Lemtrada, Campath). It is one of the highly effective immunotherapies and, in a subgroup of patients with highly active MS, even enables disease activity to be halted for more than five years. Due to its long-lasting effects on the immune system and sometimes severe side effects, it is used relatively sparingly.
It is used as a disease-modifying therapy for active multiple sclerosis, both in relapsing forms and, following FDA approval, also in active SPMS.
Due to its mechanism of action, alemtuzumab leads to immediate immune cell depletion of CD52-positive immune cells (primarily T cells and B cells). It is therefore used, for example, in patients with massive inflammatory activity who are at risk of a rapid increase in disability.
Please remember that I can only provide an overview here. Your neurologist and your MS nurse should advise you in detail about the right therapy for you. This is because they know your general state of health and you should also talk about your goals, wishes, fears and preferences so that these can be taken into account.
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Table of Contents
General Information
To get a good overview of the major topic of therapy decisions, I recommend that you first listen to episode 58: Immunotherapy in MS. A guide to efficacy and choice with Prof. Tjalf Ziemssen. There you will find out why:
- You can only compare the various disease-modifying drugs to a limited extent.
- It is important to start an effective therapy quickly.
- MRI and other examinations are important for assessing progression and provide information about effectiveness.
- Therapies should be changed as little as possible, but of course if they are not effective enough.
- In most cases, it is better to start with a highly effective therapy and only switch to a lower category at an advanced age.
- In the case of highly active MS, it may be more important to start immunotherapy quickly and tackle rehabilitation as a second step.
- Generics and biosimilars are being used more and more and which approval requirements they have to fulfill.
- The risks and side effects of a therapy must be differentiated into unpleasant side effects at the start of therapy and rare possible risks. And these must be set in relation to the usually irreversible effects of untreated MS in the long term.
- It is important to honestly discuss your opinion, wishes, goals and fears with your neurologist in order to make treatment decisions together that both sides can agree on.
- It is advantageous to be cared for by MS specialists and to stay informed yourself in order to benefit from new findings and treatment options.
- Contribute to a favorable prognosis with your own healthy lifestyle.
Another general note
The approval studies for the individual drugs were carried out at very different times. Thirty years ago, you had to be more severely affected or more advanced in the course of the disease to receive a reliable diagnosis of multiple sclerosis. Less severely affected people were probably not diagnosed or not diagnosed at first. With ever-improving examination methods, such as MRI, even small lesions in the central nervous system can now be seen better. Furthermore, 30 years ago it was not yet known that neuromyelitis optica spectrum diseases, NMOSD for short and MOGAD, are separate diseases that require their own therapies and sometimes even react negatively to MS medication. They were previously thought to be multiple sclerosis and MS therapies did not alleviate the disease activity.
How is Alemtuzumab (Lemtrada, Campath) classified in immunotherapies?
There are currently three different therapeutic approaches for the preventive, i.e. disease-modifying therapy (DMT) of multiple sclerosis. The most unspecific is immunomodulation. Migration inhibition already narrows the pathway. And the most specific is the depletion of immune cells, which also includes alemtuzumab (Lemtrada, Campath). The DMTs are listed in alphabetical order:
- Immunomodulation – the therapies weaken the immune system. They have a very broad effect via various factors (e.g. on Th1/T17 – Th2/Treg, antigen presentation) as well as on different signaling pathways and possibly via other mechanisms: they attempt to shift the milieu from inflammatory to non-inflammatory:
- Dimethyl fumarate (Tecfidera and generics) & diroximel fumarate (Vumerity),
- Glatiramer acetate (Copaxone, Clift, Brabio),
- Interferon-beta: interferon beta-1a (Avonex, Rebif), interferon beta-1b (Betaferon, Extavia), peginterferon beta-1a (Plegridy)
- Teriflunomide (Aubagio)
- Migration inhibition – the migration of certain immune cells is inhibited:
- Natalizumab (Tysabri, Tyruko)
- S1P modulators: Fingolimod (Gilenya), Ozanimod (Zeposia), Ponesimod (Ponvory), Siponimod (Mayzent)
- Cell depletion – developing immune cells die off
- Depletion of T-cells, B-cells, NK-cells and monocytes: Alemtuzumab (Lemtrada, Campath)
- T- and B-cell depletion: Cladribine (Mavenclad, Leustat, Litakin)
- B-cell depletion: ocrelizumab (Ocrevus), ofatumumab (Kesimpta, Bonspri), rituximab (Mabthera, Rituxan), ublituximab (Briumvi)
What is Alemtuzumab (Lemtrada, Campath) approved for?
Due to reports of severe immune-mediated and cardiovascular side effects, including several deaths, the use of alemtuzumab was first restricted, then reviewed and finally adjusted by the European Medicines Agency (EMA).
Alemtuzumab is approved for the treatment of highly active relapsing forms of MS in:
- Patients who continue to have high disease activity despite complete and adequate treatment with at least one disease-modifying therapy, or
- in patients who have two or more relapses with disability progression in one year, and one or more gadolinium-enhancing lesions on MRI of the brain or show a significant increase in T2 lesions compared to a recent MRI.
In other words, where there is evidence of high existing inflammatory activity.
The FDA has also approved alemtuzumab for use in active SPMS. But it should generally be reserved for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS.
Both the FDA and the EMA strongly advise against the use of alemtuzumab in clinically isolated syndrome (CIS) due to the possible side effects. This is stated differently on Prof. Giovanonni’s MS selfie card.
Different information or recommendations are possible from country to country.
What is the situation for special patient groups?
Children and Teenagers
Due to the strong intervention and the uncontrollable possible side effects and because there are enough alternative immunotherapies with high efficacy, there is no need to use alemtuzumab in children and adolescents.
Pregnancy and Breastfeeding: Recommendation of the European (EMA) and American regulatory authorities (FDA)
Women of childbearing age should use effective contraception during alemtuzumab (Lemtrada, Campath) therapy. If there is a desire to have children, contraceptive measures should be continued for at least 4 months after the last alemtuzumab infusion. Women treated with alemtuzumab should not breastfeed during the administration of a cycle and for up to four months thereafter, unless the potential benefit of the therapy for the mother outweighs the potential risk to the newborn.
Recommendation of the DMSKW (German MS Fertility Register)
Recommendation based on the current data situation and experience of the DMSKW:
As alemtuzumab crosses the placental barrier from the 2nd trimester and increasingly as the pregnancy progresses, a negative pregnancy test should be available at the beginning of each alemtuzumab cycle.
Effective contraceptive measures should be used for up to 4 months after the last cycle, but the drug is no longer detectable in the blood after 30 days.
If a pregnancy does occur during alemtuzumab therapy, a complete blood count and lymphocyte count should be performed on the newborn immediately after birth. Anyone participating in the German Pregnancy Registry (DMSKW) who was still being treated with alemtuzumab (Lemtrada, Campath) at the start of pregnancy will receive a letter from the DMSKW, which can be taken to the maternity clinic to inform all doctors involved. A persistently reduced lymphocyte count would mean that vaccinations would have to be postponed.
In order to achieve the best possible therapeutic effect, both therapy cycles should be completed before a pregnancy is planned.
Thyroid function must be checked regularly during the pregnancy planning phase and during pregnancy (every 4 weeks during pregnancy in the case of known thyroid disorders). Hyperthyroidism and hypothyroidism that may occur as a result of treatment should be well controlled. In the case of so-called antibody-mediated secondary autoimmune diseases, which can develop after treatment with alemtuzumab, pathogenic antibodies could also be transferred to the fetus. This does not mean that the baby will suffer from a secondary autoimmune disease, but that symptoms of the disease may be observed in the newborn in the first few weeks after birth. The gynecologist and, if necessary, the pediatrician should be aware of all concomitant diseases of the mother.
According to the information for healthcare professionals, women treated with alemtuzumab (Lemtrada, Campath) should not breastfeed during the administration of a cycle and for up to four months afterwards. However, it is known that alemtuzumab is excreted from the body after 30 days and can therefore no longer be present in breast milk. If treatment with alemtuzumab was administered some time ago, there are no restrictions on breastfeeding.
Who should avoid alemtuzumab (Lemtrada, Campath)?
- Hypersensitivity to the substance or one of the other ingredients.
- acute and chronically active infections, such as HIV infection, tuberculosis, hepatitis B and hepatitis C, parasitic or systemic fungal infections.
- Blood coagulation disorders treated with antiplatelet agents or anticoagulants.
- Liver diseases, especially autoimmune diseases.
- Cardiovascular diseases (previous heart attacks, strokes).
- previous vascular rupture or hereditary predisposition to vascular rupture (e.g. Marfan / Ehlers-Danlos syndrome).
- uncontrolled high blood pressure.
- Diseases of the gallbladder, especially autoimmune diseases.
- other concomitant autoimmune diseases.
- Decreased neutrophil count in the blood.
- Pregnancy
A relative contraindication exists for …
- Women who are breastfeeding.
- a known blood coagulation disorder or under drug-induced blood coagulation inhibition.
- Patients with a high susceptibility to infection (e.g. pressure ulcers of the skin, aspiration tendency, frequent urinary tract infections, opportunistic infections).
- Patients with clinically relevant, uncontrolled autoimmune diseases (e.g. thyroid autoimmune diseases, immune cytopenias including idiopathic thrombocytopenic purpura, rheumatoid arthritis, lupus erythematosus, vasculitis, severe psoriasis, Goodpasture’s syndrome, chronic inflammatory bowel disease, autoimmune hepatitis).
- Patients with a history of malignant diseases that have not healed.
- Patients with a low platelet count.
- Patients without antibodies against varicella-zoster.
- Patients with severe hepatic or renal insufficiency. Alemtuzumab should only be used if the disease activity justifies the increased treatment risk.
- Children under 18 years of age. No data are available on safety and efficacy in pediatric MS.
How does alemtuzumab (Lemtrada, Campath) work?
Alemtuzumab leads to immediate immune cell depletion of CD52-positive immune cells (mainly T cells and B cells). After the acute depletion, B cells recover to the initial level (or sometimes significantly more) within four to six months. In rare cases, reactivations of MS in the form of severe relapses have been described during this phase. It usually takes several years for the T cells to recover to near the individual baseline range; in many cases, the T cells remain below the limit where they can work and function normally for a longer period of time.
How is it taken?
Alemtuzumab is administered as an intravenous infusion in two consecutive annual treatment phases. In the first year from day one to five, twelve milligrams each time, which corresponds to a total dose of 60 milligrams. And in the second year on days one to three, twelve milligrams each, which corresponds to 36 milligrams in total.
If there is still or renewed clear clinical and MRI-detectable disease activity after completion of the two treatment phases, up to two further treatment phases with 12 mg alemtuzumab each on three consecutive days can be carried out according to the updated approval. The interval to the previous treatment phase should be at least one year.
How effective is alemtuzumab (Lemtrada, Campath)?
Gavin Giovannoni, an MS expert from the UK, has graded his MS selfie cards on a scale of one to ten, with one being low efficacy and ten being maximum efficacy. In his estimation alemtuzumab scores ten for preventing relapses and ten for avoiding long-term disability.
In the pivotal study, alemtuzumab was compared to beta interferons and reduced relapses by over 50 percent and slowed disability worsening by 42 percent. In other words, you can also look at 100 patients. 47 of these patients remain relapse-free, even on beta interferons. In the alemtuzumab group, a further 18 patients remained relapse-free. Looking at the same 100 patients, 80 remained at the same level of disability, as measured by the EDSS (Expanded Disability Status Scale), during the pivotal trial period, including the beta interferon group. Seven people in the beta interferon group deteriorated who remained stable on alemtuzumab.
The results of the Care-MS I and II subsequent registry studies showed a sustained effect over 5 years in more than half of the patients, but 32 and 41% required a third, 10 and 12% a fourth and 1.5 and 1.6% a fifth cycle of therapy (Arnold et al. 2017; Coles et al. 2017). A long-term halt in disease activity can therefore be achieved in a subgroup of patients.
Risks and side effects of alemtuzumab (Lemtrada, Campath)
One of the reasons why alemtuzumab is rarely administered is because it has a very long-term effect on the immune system.
The most important side effects are
- Infusion reactions that occur during or within 24 hours of alemtuzumab infusion. These include headache, rash, fever, nausea, hives, itching, insomnia, chills, feeling hot, fatigue, shortness of breath, taste disturbance, chest tightness, generalized rash, palpitations, upper abdominal discomfort, dizziness and pain.
- Infections. A special diet must be followed for one month after administration of alemtuzumab due to the risk of listeriosis.
- Secondary autoimmune diseases, e.g. autoimmune thyroid diseases, can be triggered by alemtuzumab. 40 percent of all patients develop autoimmune thyroid disease, which is easily treatable but also requires lifelong treatment. This can also occur long after treatment, so that certain blood and urine tests must be carried out every four weeks for four years after the last administration.
- Severe reactions, which occurred in 3% of patients in the pivotal trials, include fever, hives, atrial fibrillation, nausea, chest tightness and low blood pressure. Individual cases of slowed heartbeat have been described, sometimes with heart rates below 30 beats per minute.
- Very few cases of acute coronary syndromes have been described to date during treatment with alemtuzumab, some of which occurred a short time after the infusion, others at longer intervals. It is unclear whether there is a connection with serious cardiovascular events.
Safety precautions – lab parameters
Clinical neurological check-up
Clinical neurological check-ups must be carried out quarterly to check for the presence of infections and autoimmune diseases. If such symptoms are present, appropriate specialists (e.g. hematologists, endocrinologists, nephrologists) should be involved in the treatment as soon as possible.
MS disease activity must also be monitored in order to better assess the individual risk-benefit ratio. There is an increased risk of infection, particularly in the first few months after alemtuzumab administration. Patients should be regularly informed of corresponding symptoms (fever, deterioration in general condition, headaches, neurological symptoms). Information should be provided on where patients can go in emergency situations, including outside normal working hours.
Basic laboratory program
- Routine laboratory parameters: A differential blood count and urine status must be performed monthly for at least 48 months after the last alemtuzumab infusion. If the platelet count falls below a certain value, a weekly check must be carried out and if it falls below a particularly low limit, a hematological presentation must be made.
- The TSH value must be determined every three months for at least four years after the last alemtuzumab infusion in order to be able to identify thyroid dysfunction promptly. In the event of pathologically altered thyroid hormone levels, a referral must be made to an endocrinology specialist.
Radiological monitoring
An MRI of the brain, and possibly also of the spinal cord, should be performed once a year to assess the success of the treatment and to detect possible complications of the therapy that are relevant for the differential diagnosis. Contrast agents are only necessary if there are indications of a worsening of the disease or if there is no standardized initial MRI.
You do not need to worry about this. It will be checked for you. However, please take the tests seriously and make up for them if you are unable to keep an appointment, and don’t skip them altogether.
On the MS selfie card mentioned earlier, the side effects are rated on a scale from one for few or rare to ten for many or frequent as follows:
- Regular side effects at four
- Long-term side effects at nine
- Cancer risk at five
Alemtuzumab receives the following rating in the MS Selfie Card overview of the effects of therapy:
- Clinic visits: many
- Family planning: short-term incompatible
- Vaccinations: moderate response
Vaccinations
The efficacy of vaccinations may be limited during and after alemtuzumab. If necessary, the success of the vaccination should be checked by means of titer control.
Before starting treatment with alemtuzumab, patients should be tested for varicella-zoster (VZV). VZV-seronegative patients should be vaccinated against VZV before starting treatment. Other recommended vaccinations should also be carried out before treatment with alemtuzumab and the first infusion should not be started until four to six weeks after vaccination.
Live vaccines should be avoided and only administered after a thorough risk-benefit assessment. All other vaccinations are permitted during treatment with alemtuzumab.
Vaccination against herpes zoster, which leads to shingles, is recommended for patients with immunotherapy from the age of 50. In this case, vaccination with the inactivated Shingrix vaccine is recommended.
Sources
Final note
Please remember, there is no one great medication that helps everyone, but it must always be weighed up what suits a particular person best. Other illnesses, personal goals and preferences must also be taken into account. Your neurologist and MS nurse are the right persons to talk to and can make individual recommendations. This article is for information purposes only and does not constitute a recommendation. What helps one person may not help another.
I hope that, together with your neurologist and MS nurse, you will quickly find the right immunotherapy for you. And that you can lead a fulfilled, happy and self-determined life with MS, supported by a healthy lifestyle and a dose of fortune.
You may also want to look at the posts on the other DMTs:
- #061: Dimethyl fumarate (Tecfidera) and diroximel fumarate (Vumerity)
- #065: Glatiramer acetate (Copaxone, Brabio)
- #068: Interferon-beta (Avonex, Betaferon, Extavia, Plegridy, Rebif)
- #070: Teriflunomide (Aubagio)
- #072: Natalizumab (Tysabri, Tyruko) for active relapsing remitting MS
- #074: S1P Modulators – Fingolimod (Gilenya), Ozanimod (Zeposia), Ponesimod (Ponvory), Siponimod (Mayzent) for active RRMS & SPMS
See you soon and try to make the best out of your life,
Nele
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