Because cladribine and alemtuzumab are classified as immune reconstitution therapies (IRTs), and probably work in a similar way, they are tarnished with the same brush. However, cladribine’s immune depletion and reconstitution, and adverse event profile are very different to alemtuzumab’s and therefore cladribine should be considered on its own when weighing up the risks and benefits of treating highly-active MS during the COVID-19 pandemic. For example, the advice that pwMS need to shield after cladribine treatment is a very harsh call and in my opinion unnecessary. Why?
The following are the points concerning cladribine in the latest version (19-May-2020) of the ABN GUIDANCE ON THE USE OF DISEASE-MODIFYING THERAPIES IN MULTIPLE SCLEROSIS IN RESPONSE TO THE COVID 19 PANDEMIC
5. The effect of DMTS on the risk of SARS-CoV2 infection and COVID 19 disease remains uncertain and we commend pwMS and MS teams to continue to submit data to the UK MS Register study of COVID 19. We recommend that patients are counselled on the effect of a DMT on their individualised risk of COVID 19 disease, taking into account its duration of action; any comorbidities; and also the DMT’s impact on the efficacy of any future SARS-CoV2 vaccine. Patients should be informed if their treatment choice requires shielding [especially cladribine and alemtuzumab].
11. Cladribine should be started cautiously on a case-by-case basis when the risk of SARS-CoV2 is very high. Re-treatment should be delayed until the risk of infection is level 3 or below.
14. pwMS with mild symptoms of COVID-19 should not stop first-line DMTs, but infusions [and cladribine administration] should be delayed until symptoms resolve.
C. THE RISK OF COVID-19 IN PEOPLE WITH MS [PWMS] ON DISEASE MODIFYING THERAPIES [DMTS]
11. There is very limited experience4 of pwMS on cladribine becoming infected with SARS-CoV2 and the SmPC warns of herpetic viral infections being “common”. However, it may be considered on a case-by-case basis. When and where the rate of SARS-CoV2 infection is very high, the risks of increased infection for three months after cladribine administration, and the advice to shield, may outweigh its benefits.
D. DMTS IN PwMS WITH ACTIVE COVID 19 INFECTION
14. pwMS with mild symptoms of COVID-19 should not stop a first line DMT, but infusions [and cladribine administration] should be delayed until symptoms resolve.
We know that anti-SARS-CoV-2 immunity requires innate immune responses (neutrophils and macrophages) and T-cell responses (predominantly CD8+ responses) to clear the virus. Cladribine does not deplete monocytes and neutrophils and has a modest impact on CD8+ve T-cells. Therefore t is unlikely to have a major impact on anti-SARS-CoV-2 immunity.
On cladribine, T lymphocytes are in general depleted by about 40% and the vast majority of patients don’t drop their counts below 500/mm3. In the T-cell compartment, the CD8+ T-cells are much less affected than CD4+ T-cells. This is important because CD8+ T-cells are the cells responsible for fighting viral infections and explains, apart from a small risk of herpes zoster reactivation, why we didn’t see an increase in viral infections compared to placebo in cladribine treated subjects in the phase 3 trial programme.
In the phase 3 programme about a quarter of patients had a transient grade 3 or 4 lymphopaenia, but this tended to occur after the second course in year 2 in subjects who were redosed when their lymphocyte counts in year 1 had not yet recovered to above 800/mm3 (per-protocol dosing). We have used the trial data to model grade 3 and 4 lymphopaenia (<500/mm3), and estimate that less 7% of cladribine treated subjects will develop lymphocyte counts less than 500/mm3 if we stick to the cladribine redosing guidelines. This is important because most of the cases of zoster were in subjects who developed grade 3 or 4 lymphopaenia, which implies the risk of getting herpes zoster in real-life (post-marketing) is likely to be much lower than what we saw in the clinical trials.
Should we be so hung up about the lymphocyte count? When we explore the safety data of oral cladribine, from both the trial programme and post-marketing surveillance, we really don’t see a significant viral infection signal in cladribine-treated subjects. The viral infections that did occur tended to be non-specific upper respiratory tract infections and were mild to moderate. The following presentation is data that we recently presented at the AAN and EAN meetings and illustrates how uncommon viral infections are in pwMS treated with cladribine.
Based on these data I really don’t think it is necessary to for pwMS to shield during the current pandemic. All they need to do is maintain social distancing, practice good personal hygiene and avoid contact with potentially infectious people. This means that pwMS working in high-risk professions (healthcare and care sector workers with direct patient contact) who are treated with cladribine should not have direct patient-facing activities until they have recovered their lymphocyte counts to a safe level (>500/mm3 in people less than 60 years of age and >800/mm3 in those older than 60 years).
Although, cladribine is a remarkably good depleter of B-cells the B-cell numbers return quite quickly. The reconstituted B-cells are initially naive B-cells, which come from the bone marrow and are not memory B-cells. This is important for vaccine-readiness if a SARS-CoV-2 vaccine does emerge.
In comparison to cladribine, ocrelizumab and rituximab are given as maintenance or continuous therapy there is a small increase in the incidence of serious infections over with time and the development of hypogammaglobulinaemia, which is not seen with cladribine. Once the immune system reconstitutes post-cladribine it can fight infections, immune survey the body for cancers and mount immune responses to new viral infections, such as SARS-CoV-2, and vaccines. In relation to vaccines both live and inactivated component vaccines can be given after cladribine.
The other important thing about cladribine is the monitoring requirements are low. Once you have had a course you only need a full blood count to be done 3 and 7 months after starting treatment. The rationale for this is that the 3-month time-point is where the nadir occurs and the 7-month time point is to check for recovery of lymphocyte counts.
Another advantage of cladribine is that as a small molecule it penetrates the CNS; cerebrospinal fluid (CSF) levels are about 25% of what is found the peripheral blood and at a level that would target B- and T-cells within the brain and spinal cord. I think this property of cladribine is very important and is one of the reasons why we are exploring cladribine as a treatment for progressive MS in the CHARIOT-MS trial.
I think cladribine is a very misunderstood DMT and has been hard done by in the COVID-19 treatment guidelines which in general are not evidence-based nor are they necessarily based on basic immunological principles.
As the COVID-19 pandemic is likely to have a long tail with a vaccine 18 to 24 months away I think we the MS community should reconsider our position on oral cladribine as cladribine addresses many of the issues of treating highly active MS in these troubling times and it has the added advantage of leaving people with MS with a reconstituted vaccine-ready immune system if and when a SARS-CoV-2 vaccine arrives.
Please note that I am not saying cladribine is safe; no DMT is safe. However, cladribine has a very well-defined risk-benefit profile that is less risky than what is been suggested in the ABN guidelines. The risk-benefit profile of cladribine simply allows you to counsel patients with highly-active MS about their treatment options during the COVID-19 pandemic and cladribine deserves to be part of that discussion.
CoI: multiple, but in particular I was the principal investigator on the oral cladribine phase 3 trial and have been involved with the development of oral cladribine as a treatment for MS since 2002.