Cladribine (Mavenclad, Leustat, Litak) is an immunotherapy from the field of immunosuppressants that is used to treat highly active multiple sclerosis (MS). It belongs to the class of disease-modifying therapies (DMTs), which use depletion to target the immune system in order to prevent the progression of the disease. Find out more about the principle of induction therapies, how cladribine works, how effective it is and the potential risks associated with it. You will learn about the role of cladribine in MS therapy, its different forms and what patients should know when considering this treatment, particularly with regard to pregnancy, breastfeeding and long-term health monitoring.
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 Cladribine (Mavenclad, Leustat, Litak) 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 Cladribine (Mavenclad, Leustat, Litak). 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, Litak)
- B-cell depletion: ocrelizumab (Ocrevus), ofatumumab (Kesimpta, Bonspri), rituximab (Mabthera, Rituxan), ublituximab (Briumvi)
What is Cladribine (Mavenclad, Leustat, Litak) approved for?
Cladribine is approved for the treatment of highly active relapsing forms of MS in adults. A detailed benefit-risk assessment should be carried out, which can be based on the existing pivotal studies CLARITY, CLARITY EXTENSION, ORACLE-MS and ONWARD. Against the background of these study data, cladribine can be used in the following patient groups:
- Patients who have high disease activity during therapy with a disease-modifying drug, i.e.
in the previous year …- … who have suffered at least one relapse during disease-modifying therapy and
- … who have had at least nine T2-hyperintense lesions or at least one
gadolinium-enhancing lesion on brain MRI.
- Patients with two or more relapses in the last year, regardless of whether they were treated with disease-modifying therapy or not..
Different information or recommendations are possible from country to country.
What is the situation for special patient groups?
Children and Teenagers
Due to the risk of cancer, cladribine (Mavenclad, Leustat, Litak) is not recommended in MS patients under 18 years of age. There is no data on safety or efficacy in pediatric patients.
Pregnancy and Breastfeeding: Recommendation of the European (EMA) and American regulatory authorities (FDA)
Women of childbearing age should use effective contraception during treatment with Cladribine (Mavenclad, Leustat, Litak). A negative pregnancy test must be available before each treatment cycle. If possible, contraception should be used with both a contraceptive and a barrier method such as a condom. The interval between the last dose of Cladribine should be at least six months. This also applies to men, as an increased rate of miscarriages and malformations was observed in animal studies, regardless of whether the mothers or fathers were exposed to the active substance.
Should a pregnancy nevertheless occur during treatment or with an interval of less than six months, treatment should be discontinued immediately and intensified diagnostics carried out during pregnancy.
Cladribine should not be taken while breastfeeding.
Recommendation of the DMSKW (German MS Fertility Register)
In the clinical trials of cladribine (Mavenclad®), there were only a few pregnancies, most of which were deliberately terminated. The number of miscarriages was in line with the normal miscarriage rate that occurs in the general population. Three children were born healthy and there were no malformations. The few other children born after the approval of cladribine were also healthy.
Our registry documented 62 pregnancies in which the mothers had taken cladribine at various intervals prior to pregnancy. Of these, 46 babies were born healthy. Two babies had low birth weight (taking cladribine more than six months before pregnancy), and one baby had a heart defect, which is also common in the general population (the mother had taken cladribine 66 days before pregnancy).
Cladribine can pass into breast milk. Initial data from the registry show that in one patient who took cladribine in the first and second week of treatment, only a small amount (about 3% of the dose) passed into breast milk. However, as cladribine is rapidly broken down in the body, no active substance could be detected in breast milk 48 hours after the last dose.
As cladribine remains effective for longer, it could theoretically offer advantages when planning a pregnancy.
However, if you become pregnant during treatment or within 6 months of your last dose of cladribine, please contact your doctor immediately for appropriate advice.
If you become pregnant during a treatment cycle, treatment must be stopped right away.
You must not breastfeed while taking Cladribine. However, as the drug is rapidly broken down, it is safe to resume breastfeeding one week after the last dose. Breastfeeding is not permitted before then.
Who should avoid cladribine (Mavenclad, Leustat, Litak)?
- People with 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.
- Immunodeficient patients.
- Patients with moderate or severe kidney disease.
- Patients with moderate or severe liver disease.
- Vaccination with a live vaccine in the previous four to six weeks, e.g. vaccination against varicella zoster virus (VZV), typhoid, yellow fever, etc.
- Pregnancy or breastfeeding
A relative contraindication exists for …
- Patients with a high susceptibility to infection (e.g. pressure sores on the skin, aspiration tendency, frequent urinary tract infections, respiratory infections).
- Patients with a history of malignant diseases.
- Fructose intolerance, as the Cladribine tablet contains sorbitol.
- Children under 18 years of age. No data are available on safety and efficacy in pediatric MS
How does cladribine (Mavenclad, Leustat, Litak) work?
Cladribine reduces the pro-inflammatory subsets of immune cells and increases the regulatory cells. It specifically reduces certain types of immune cells, known as T and B cells, both dividing and dormant.
The drug works by causing the cells to die. Among other things, it blocks an important enzyme in dividing cells. In resting cells, cladribine causes a rapid loss of energy, which leads to the death of the cell. Cladribine belongs to the induction therapies and is an immunosuppressant, which means that it acts quickly after ingestion and has a long-term effect on the immune system with only a short duration of administration.
A new four-year therapy cycle can be considered from year five onwards. However, real-world data on this is still lacking.
How is it taken?
Mavenclad
Cladribine is administered orally as tablet(s) at a total dose of 3.5 mg/kg body weight in a total of four treatment cycles. A treatment cycle comprises one or two tablets per day for four or five days. The dose must be adjusted according to weight.
The following dosage regimen of cladribine has been approved by the EMA for the treatment of multiple sclerosis: In the first year of treatment, cladribine is administered orally at a dose of 1.75 mg/kg body weight. In the second year, oral administration of cladribine is repeated at a dose of 1.75 mg/kg body weight.
The first two treatments are given in weeks 1 and 5 and the two further treatments in weeks 53 and 57. These four weeks of tablet intake should ideally cover four years of treatment.
The tablet(s) should be taken without chewing at the same time each day of the treatment cycle. You can take the tablets independently of meals. It is recommended that you take them three hours apart from other medicines, as an ingredient in the Cladribine tablets may interact with other active substances.
The amount of Cladribine you need to take is calculated based on your body weight. The manufacturer provides tables to help you determine the dosage quickly and easily. You take either one or two tablets per day. If you need to take two tablets, you should take both at the same time as one dose. The maximum amount that can be taken over two years is 40 tablets of 10 mg each. For some patients a third or fourth course of cladribine may be required.
Leustat and Litak
Leustat and Litak are non-oral forms of cladribine that might be used off-label for treating MS. They are given by infusion or injection. These forms of cladribine are expected to work similarly to the tablets and may have similar side effects, but this hasn’t been fully proven yet.
How effective is cladribine (Mavenclad, Leustat, Litak)?
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 cladribine scores six for preventing relapses and eight for avoiding long-term disability.
In the two-year pivotal study, cladribine was compared to placebo and reduced relapses by 58 percent and slowed disability worsening by 33 percent. In other words, you can also look at 100 patients. 61 of these patients remain relapse-free, even on placebo. In the cladribine group, a further 19 patients remained relapse-free. Looking at the same 100 patients, 79 remained at the same level of disability, as measured by the EDSS (Expanded Disability Status Scale), during the pivotal trial period, including the placebo group. Seven people in the placebo group deteriorated who remained stable on cladribine.
The CLARITY and CLARITY EXT trials showed No Evidence of Disease Activity in three categories (NEDA-3) in years 3 and 4 for 46% of people who first received a placebo and then cladribine, and 48% of those who had taken cladribine from the start. NEDA-3 means there were no relapses, no worsening of disability, and no signs of disease activity on brain MRI scans.
Risks and side effects of cladribine (Mavenclad, Leustat, Litak)
The CLARITY, CLARITY EXTENSION, ORACLE-MS and ONWARD studies formed the basis for the approval of cladribine. The following side effects occur frequently:
- More than 1 in 4 patients experience lymphopenia, a low white blood cell count that may persist for an extended period of time. This can lead to the second cycle of Cladribine having to be postponed in weeks 53 and 57 or sometimes not being given at all.
- The most typical side effects after taking cladribine are skin reactions and, rarely, thinning hair and hair loss.
- There is an increased risk of herpes infections that cause shingles and cold sores.
Safety precautions – lab parameters
Clinical neurological check-up
Clinical neurological check-ups must be carried out quarterly. Before each treatment cycle with cladribine, your doctor should review your medical history and perform a clinical examination to check for any possible reasons why you shouldn’t take the medication.
Basic laboratory program
- Routine laboratory parameters: Blood count plus differential blood count must be checked before each treatment cycle with cladribine. A precise typing of the white blood cells can also be carried out if this appears useful. Checks should then be carried out every two to three months. If the lymphocyte count falls below a critical level, treatment should be suspended in the second year and treatment should only be continued once the values have normalized. If normalization takes longer than six months, Cladribine should no longer be given. If white blood cell counts are low, closer monitoring should be carried out and herpes prophylaxis should be considered if necessary.
- The liver and kidney values must be checked before each treatment cycle with Cladribine and then every two to three months over the entire treatment period.
- An infection must be ruled out before each cladribine treatment cycle. If signs of a clinically relevant infection occur during Cladribine therapy, anti-infective therapy should be initiated. The administration of Cladribine should be interrupted or postponed until the infection is completely cured.
- A negative pregnancy test must be available before each Cladribine treatment cycle.
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.
Cancer screening examinations
Since cladribine can temporarily weaken the immune system, patients should follow standard cancer screening guidelines and go to the recommended check-ups. Additionally, blood tests should be done for at least two years after the last dose of cladribine to monitor your health.
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 two
- Long-term side effects at one
- Cancer risk at five
Cladribine receives the following rating in the MS Selfie Card overview of the effects of therapy:
- Clinic visits: minimal
- Family planning: short-term incompatible
- Vaccinations: good response
Vaccinations
The efficacy of vaccinations may be limited during and after cladribine. If necessary, the success of the vaccination should be checked by means of titer control.
Live vaccines should be avoided and only administered after a thorough risk-benefit assessment. All other vaccinations are permitted during treatment with cladribine.
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
I used the following sources to create the content:
- Lecture on Cladribine by Prof. Dr. Johann Sellner as part of the Master’s program Multiple Sclerosis Management
- Quality manual of the German KKNMS on cladribine (Mavenclad)
- MS-Selfie Infocards by Prof. Dr. Gavin Giovannoni
- German Multiple Sclerosis and Fertility Registry (DMSKW)
- German DECIMS information on cladribine
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
- #076: Alemtuzumab (Lemtrada, Campath) for highly active Multiple Sclerosis
See you soon and try to make the best out of your life,
Nele
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