A recent webinar featuring neurologists Dr Wallace Brownlee and Professor Klaus Schmierer, both from London, provided real-world insights into the use of cladribine (Mavenclad) in relapsing-remitting multiple sclerosis (RRMS).
Dr Brownlee is Consultant Neurologist and Clinical Lead, Multiple Sclerosis Service National Hospital for Neurology and Neurosurgery and MS researcher at Queen Square MS Centre, University College London Institute of Neurology, and Prof Schmierer is Professor of Neurology at The Blizard Institute, Queen Mary University of London, Consultant Neurologist and Research Lead for Neurology at The Royal London Hospital of Barts Health NHS Trust.
Cladribine tablets: real-world experience from London with Dr Brownlee
Dr Brownlee presented his experience with the first 150 patients to be prescribed cladribine at the Queen Square MS Centre in London. He noted that significant lymphopenia was uncommon, but had been seen in both treatment-naïve patients and patients previously treated with lymphocyte depleting disease-modifying therapy (DMT) in both year one and year two of cladribine treatment.1,2
Dr Brownlee explained that experience has taught him to ask his patients about their history of herpes simplex virus (HSV) so that he can take measures to avoid HSV reactivation with declining lymphocyte levels. “Among the first 50 or so patients we treated, we did see quite a lot of HSV reactivation,” he said. He now asks his patients about their history of HSV and offers acyclovir prophylaxis where appropriate, suggesting that prophylaxis is reasonable “at least until you’ve got that first lymphocyte count back after dosing.”
Dr Brownlee noted that “cladribine was generally well-tolerated with a low rate of treatment discontinuation in this real-world cohort. Most patients had a mild or moderate degree of lymphopenia, which is consistent with what we saw in the clinical trials. There is perhaps an influence of age and previous DMT on lymphopenia, which should be investigated in larger real-world cohorts.””
According to the Mavenclad Australian product information, lymphopenia is closely linked to a reduction in lymphocyte count, the effect of which is dose-dependent.3 Lymphocyte counts must be determined before initiating Mavenclad in year 1 and in year 2, and at 2 and 6 months after the start of treatment in each year. If the lymphocyte count is below 500 cells/mm3, it should be actively monitored until values increase again.3
How the Queen Square MS Centre team addresses management issues
Dr Brownlee presented three cases illustrating some of the management issues that he has addressed in his practice: pregnancy and family planning, managing disease activity in the first year of treatment and optimal timing of COVID-19 vaccinations.
The first case was that of a 34-year-old woman with previously active disease, now stable on a sphingosine-1-phosphate receptor modulator but wanting to start a family. Dr Brownlee explained, “At our centre, cladribine would be the first cab off the rank in this situation.” He noted that any change in therapy needs to take into account the potential for rebound disease activity during the washout period.
In the presented case, the patient’s lymphocyte count recovered quite quickly and she was able to initiate cladribine two weeks after discontinuing her previous therapy. She was counselled on the need for contraception during the six months after each dose and the windows in which it would be best to conceive. Dr Brownlee advised, “I prefer women to try and complete both courses of treatment and delay family planning by 18 months after the first dose. ”
The second case was that of a 27-year-old woman who started on cladribine in June 2020. At her baseline scan in August 2020 her disease was stable, but at the April 2021 scan there were a number of new brain lesions. Dr Brownlee noted, “These patients can sometimes be a cause for concern, as some patients can be a bit nervous when there are new lesions.” He described how he manages patient concerns such as this, explaining how he “describes the journey, saying we are halfway down the road and that they’ve only had half of the treatment planned for them. If they are keeping well, we tend to proceed with the second year of treatment.”
The final case was that of a 33-year-old woman who commenced cladribine in late 2019. Year 2, week 1 treatment was given in mid-November 2020 and week 2 treatment was planned for mid-December 2020. However, at the same time her year 2, week 2 treatment was due, she was notified that as a respiratory physician she was eligible for a COVID-19 vaccine, which she was keen to accept given her frontline role in the pandemic. The patient was vaccinated at the end of December 2020 and third week of January 2021, and Dr Brownlee explained, “We waited until four weeks after she received her second dose of the Pfizer vaccine and then [four weeks later] gave the second week of [Year 2] cladribine treatment. We were unsure if this was the best sequence, but in July 2021 she had good levels of COVID-19 IgG spike protein antibody levels and had not had clinical COVID. It was encouraging to see that she’d had a vaccine response even though the dosing with cladribine was given so soon before and after her COVID-19 vaccinations.”
Latest insights and recommendations from Prof Klaus Schmierer
Prof. Schmierer provided a brief overview of MS pathology and how it relates to the mechanism of action of cladribine. He explained, “We know that MS is associated with an ineffectively regulated immune system, which then leads to tissue damage. We are then led to believe that there’s kind of a variety of MS because there’s loads of different mechanisms of action of disease-modifying treatments.”4 Prof. Schmierer described the different immune cell subsets that current therapies target, such as T cells and B cells, noting, “The more effectively you can impact the cell population, the better the impact the treatment appears to have on the disease.”6
Prof. Schmierer explained that cladribine is a small molecule that is also able to penetrate the central nervous system. In its active form, cladribine selectively depletes dividing and non-dividing T and B cells, interrupting the cascade of immune events that lead to tissue damage in MS.3
Prof. Schmierer also presented a case illustrating the use of cladribine in the COVID-19 pandemic. The case described a 36-year-old woman with early active disease where Prof Schmierer noted, “Really, the question is how do you balance this woman’s need for rapid, effective MS treatment against the backdrop of risk for COVID-19?” He offered the latest vaccine advice from Barts Health: “Start the treatment at least four weeks after receiving the vaccine. Based on the evidence we have so far, the vaccine can be given any time after a course of cladribine, though a four-week gap may be beneficial. Although there is no strong evidence to support that specific comment.”7
Prof. Schmierer concluded by reminding the audience that “it’s important to remember MS is progressing from the onset, so early intervention is really important. I think that disease control can be achieved in the majority of patients by selectively depleting immune subsets, and the B-cell memory pool appears to play a key role.”
This article was sponsored by Merck. Any views expressed in the article are those of the experts alone and do not necessarily reflect the views of the sponsor. Before prescribing, please review the Mavenclad product information via the TGA website. Treatment decisions based on these data are the responsibility of the prescribing physician.
- Comi G et al.s. Mult Scler Relat Disord 2019;29:168–174 (Suppl).
- Giovannoni G et al. N Engl J Med 2010;362:416–26 (Suppl).
- Mavenclad (cladribine) Approved Product Information, May 2021.
- Loleit V, et al. Curr Pharm Biotechnol 2014;15:276–96.
- Scannevin R, et al. J Pharmacol Exp Ther 2012;341:274–84.
- Baker D, et al. EBioMedicine 2017;16:41-50.
- Barts Health NHS Trust, BartsMS SARS-CoV2 vaccine advice for people with Multiple Sclerosis, Update September 2021. Available from: https://multiple-sclerosis-research.org/2021/10/booster-vaccinations/ (accessed March 2022).