This post explains why I have started to refer to cladribine as a small molecule anti-CD20/CD19 therapy and why oral cladribine should be part of the exit strategy to treat MS during the tail of the COVID-19 pandemic.
Although we use cladribine as an immune reconstitution therapy and often compare it to alemtuzumab it is, in fact, closer to anti-CD20 therapies in terms of its immunodepletion profile. This distinction is particularly important during the COVID-19 pandemic because it has allowed us to classify cladribine in an intermediate risk DMT, which allows us to treat MS with an IRT when we can’t use alemtuzumab.
Cladribine’s pros:
Cladribine is an oral therapy; hence no visits to COVID-HOT hospitals or institutions.
It kills cells gradually by a process called apoptosis. Cells dying from apoptosis are phagocytosed or swallowed by macrophages and as a result, there is no cell lysis or bursting open of the cells and the release of their contents that causes a cytokine release syndrome. This means there is no need to pre-treat patients with steroids, which we are trying to avoid at present.
Cladribine does not deplete monocytes and neutrophils and has a moderate impact on so-called NK cells. As the innate immune system is left intact there is a low risk of bacterial and other infections during the depletion phase and the innate cells can help fight viral infections, such as SARS-CoV-2.
T lymphocytes are in general depleted by about 40%-50% and most patients don’t drop their counts below 500/mm3. In the phase 3 programme about a quarter of patients had a 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 had not recovered to above 800/mm3. We have used the trial data to model grade 3 and 4 lymphopaenia. I.e. less than 500/mm3, and estimate that less 5% of cladribine treated subjects will develop lymphocyte counts less than 500/mm3 if we stick to the redosing guidelines. This is very important as lymphopaenia is probably the most important risk factor for viral and severe viral infections.
In the T-cell compartment, the CD8+ T-cells were less effected than CD4+ T-cells. This is important because CD8+ T-cells are the cells responsible for fighting viral infections. This probably 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. The viral infections that did occur tended to be non-specific upper respiratory tract infections and were mild to moderate. In fact, the infection profile on cladribine, including the zoster signal, was much more similar to that which we see with ocrelizumab compared to alemtuzumab.
Cladribine is a remarkably good depleter of B-cells. B-cells number drop quicker than T-cells numbers; i.e. within days to weeks. In addition, B-cells are depleted by about 90% and importantly memory B-cells are severely depleted and to a similar level that we see with alemtuzumab. Importantly, when the B-cell numbers return these are so-called naive B-cells, which come from the bone marrow and are not memory B-cells. Interestingly, when you stop an anti-CD20 therapy such as ocrelizumab or rituximab and allow B-cell reconstitution they are also naive and are not memory B-cells that return in the short-term. In other words cladribine, alemtuzumab and ocrelizumab have similar effects on B-cells.
Please note that because 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. This 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. What this means during the COVID-19 pandemic is that if you are treated with oral cladribine and at 3 months your lymphocyte counts is above 500/mm3, which will be the vast majority of treated patients, you don’t need to self-isolate. In the 3-4% who have a lymphocyte count below 500/mm3 at month three, you will need to continue to self-isolate until your counts go above 500/mm3. To find out the latter you could wait another three months for the next blood test our you could ask your GP or MS team for an earlier test.
When you look at how cladribine works, i.e. it needs to be activated by an enzyme call DCK (deoxycytidine kinase) and broken down by an enzyme called ADA (adenosine deaminase), the profile of cells expressing the correct ratio of these enzymes matches the B-cell population that expresses CD19 and CD20 and explains why B-cells are more susceptible to the effects of cladribine than T-cells.
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.
In a similar way to ocrelizumab, I think cladribine has been hard done by COVID-19 guidelines that have stated not starting or not redosing cladribine during the COVID-19 pandemic. Why? Where is the science to support this position?
Now that we can see the pandemic is not going to end anytime soon and with a vaccine 18 or 24 months away I think we should reconsider using oral cladribine as it 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 and/or anti-CD20 therapies are safe. They have well-defined risk-benefit profiles that are less risky than what has been proposed by many people in terms of developing severe COVID-19. These risk-benefit profiles simply allow you to counsel patients with active MS about their treatment options during the COVID-19 pandemic.
I personally think both anti-CD20 therapies and cladribine are two highly effective therapies that allow a treatment exit strategy during the long tail of the SARS-CoV-2 pandemic.
Do you agree?
CoI: multiple
Do you prefer cladribine to ocrelizumab?
No, it is horses for courses. In England, fingolimod, cladribine and natalizumab are only licensed for highly active or rapidly evolving MS. If you have someone with active MS who has a poor prognostic profile or wants a high-efficacy therapy first-line ocrelizumab is needed. It is a great pity we can’t use licensed DMTs as they do in Australia, i.e. they are all licensed for treating active MS and its up to the neurologist and the patient to decide how and in which order.
Horses for courses! You just helped this PwMS laugh out loud…thank you for that & for your response to the question. I’ve got my neuro clinic appt this week (telemedicine) & Ocrevus infusion scheduled week following. A bit nervous … but reading your blog and tweets has taken the edge off… mercí!
This pandemic is going to be with us for years and your MS for life. We can’t not treat MS or delay treating MS until after the pandemic. Anyway there are infections apart from SARS-CoV-2 that you have to deal with.
Do you think BTK inhibitors will upset the apple cart and make all these current licenced drugs redundant? Or will they be used as add on therapy? If latter then it’s truly sad state of affairs. If pharma used the same amount of money on finding a cure as spent on clinical trials then we would have a cure. Imagine 1 billion dollars to find a cure. The amount required for 3 phase clinical trials.
I suspect that are not quite as active…but they target microglia/macrophage but do you want a daily treatment or a give and try to forget one..
Absolutely not! The real MS is smouldering MS and BTKi only deal with a small component of what is smouldering MS. Can I also suggest waiting for phase 3 data, which may not be that good?
Thanks MD and Prof G. You’d think with all the talented scientists pharma have at their disposal. They will not pour so much money down the drain chasing half a solution like btk.
Do you know how long one might be covered for following the first year of cladribine? I was supposed to start year 2 in March but that has been suspended. My neurologist wants to put me on copaxone, but I think I’d rather just go with the cladribine.
Had the pills been popped in the post you would have been 2 months into lock down . How long…sorry I don’t know
Fully agree, personally given the infancy of this outbreak and an ability to delay year 2 treatment it must be stated that if one was due to take this treatment soon ( circa 3 to 6 months ) utilising the 6 month delay window may be of benefit to allow a Covid treatment to emerge. As time passes if no treatment proves effacacious then treating you’re Ms may be a better option as a covid would likely not arrive pre-vaccine anyway. As always the situation will be current for everyone…
Very interesting – thank you! Would you tend to consider transitioning stable patients off of fingolimod and onto cladribine so that they are vaccine ready? Any wash out period to fingolimod?
No the logistics of switching therapies at present are not easy. They will get easier in a month or two. However, fingolimod only blunts vaccine responses it does not inhibit them and I am sure there will be antibody tests available to test who has seroconverted post-vaccine.
The only issue is if the vaccine that gets licensed uses a live viral vector to deliver the immunogen. Live vaccines are contraindicated on fingolimod.
Professor G!, in this time, we have to learn to live with COVID and start to think how to treat the patients because COVID-19 live with us and the only that I have to say that thanks for help to us to comprehend more about the treatments. And of course I agree with you.
Reassuring to read this as I started year 2 cladribine last weekend, albeit in Australia where community viraemia is very low, although staying safe not able to totally self isolate.
Gavin
I’m not sure why Merck have hesitated to register Cladribine in NZ – they were exploring this – at least a year ago. Market size perhaps.
Are you suggesting any self-isolation is advisable pre Cladribine lymphocyte nadir? Of course this is dependent on prevalence of community viraemia- now a handful of cases/ day in NZ, which of itself has encouraged use of anti CD 20 treatments – including Ocrelizumab.
Regards,
Re: “Are you suggesting any self-isolation is advisable pre Cladribine lymphocyte nadir? ”
Yes, because a small number of people treated with cladribine (<5%) will develop a grade 3 lymphopaenia. Saying this it is more likely to occur in year 2 than year 1. It is a small risk.
In the pre-COVID-19 era, we didn't recommend self-isolation and patients do well despite being exposed to other viruses etc. Maybe we are being too conservative.
I finished year 2 in January and had bloods done in February at neurologists request. They were 0.25, have risen to 0.43 now but if anything like last year they’ll be up and down til the end of the year. Will be interesting to see where they are in December. I take it as it’s working, stable MRI no new lesions. I would retake it if needed in the future as a maintenance if that was recommended
If you are young and have no comorbidities and your lymphocyte counts are above 500/mm3 you should be fine, i.e. there is no need to self-isolate.
Good morning. Thank you for all your posts, they are really helpful for me, particularly at this time. I stopped fingolimod at the start of the year and was due to start cladribine, and then COVID19 hit. My neuro took the decision to delay the treatment until it is deemed safer and instead put me on tysabri in the interim (SID for first couple of months, started 2 weeks ago) . When would be a good time to explore starting cladribine treatment? Does this have a better outlook Covid-wise? Thank you
Natalizumab is an excellent DMT and if you do well on it you may want to stay on it. We are switching all our patients who have been on natalizumab longer than 6 months to EID to reduce the risk of SARS-CoV-2 encephalitis.
Interesting. Are you collecting data on relapse rate during the transition?
What about people due for year to alemtuzumab this year? Could they switch to Cladribine instead of receiving se one round Alemtuzumab? Or, is delaying alemtuzumab a better option?
The NHS England treatment guidelines for alemtuzumab and cladribine are not identical. But yes, I see no reason why patients treated in the past with alemtuzumab cannot switch to cladribine. That is assuming all the baseline checks are done. There is little doubt that in the short term cladribine is the safer drug.
Do we yet know how safe Cladribine really is in the long term and can it leave some patients with persistently low lymphocytes for years?
Alemtuzumab does the same. My wife finished year 1 treatment last July. Her lymphocyte count is 0.43. So, still below normal range. Hence we are now questioning year 2 treatment. We are now weighing up the risk / benefits of delaying or switching to a different DMT. All decisions carry risk. We are lucky in a way as Australia’s COVID-19 infection rate is comparably low and testing rate high. Nevertheless, receiving alemtuzumab in a pandemic is a scary proposition.
Thanks. I’ll need to look at Australia’s guidelines. I expect they don’t restrict any treatment to first, second, or third line but other clinical features will need to be evaluated and considered. Nothing is ever predictable or straight forward with this insidious disease. More and more, patients are having to make big treatment decisions with little guidance from physicians.
Could Cladribine be an exit strategy affter several years of rituximab? (infusions given with gaps of between 6 and 12 months)
With or without the added Covid-19 factor, is the change feasible, is it worth exploring?
There is no biological reason wht this couldnt happen
Thank you very well explained. I started cladrbine october 2020, when can i take the covid vaccine