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).

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.

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

1. 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.
2. Giovannoni G, et al.  A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med 2010;362:416 ̶ 26.
3. Pakpoor J, et al. No evidence for higher risk of cancer in patients with multiple sclerosis taking cladribine. Neurol Neuroimmunol Neuroinflamm 2015;2:e158.
4. Cheson BD, et al. Second malignancies as a consequence of nucleoside analog therapy for chronic lymphoid leukemias. J Clin Oncol 1999;17:2454-60.