ProfK for Number 10


No this is not a call for ProfK to become the next Prime Minister,but I am sure he would have done a better job. However, as German with a knowledge of oral Cladribine what are his Expert Thoughts?

You will note there are nine german neurologists….PofK can be the tenth one

Stangel M, Becker V, Elias-Hamp B, Havla J, Grothe C, Pul R, Rau D, Richter S, Schmidt S. Oral pulsed therapy of relapsing multiple sclerosis with cladribine tablets – expert opinion on issues in clinical practice. Mult Scler Relat Disord. 2021 Jun 7;54:103075. doi: 10.1016/j.msard.2021.103075. Epub ahead of print. PMID: 34261026.

Q1 Should oral cladribine be used early in the course of MS to increase the likelihood of a maximum therapeutic benefit?.…….Duh

Clinical studies indicate that oral cladribine is effective in the early phase of MS. However, there is insufficient evidence to decide whether long-term efficacy is improved if oral cladribine is used early, as suggested by data available for other highly effective treatment options. (Consensus 70%)

Q2 Is oral cladribine an effective treatment after a first demyelinating event (i.e. at clinical onset of MS)?….Duh

Oral cladribine is highly effective in patients presenting with a first demyelinating event according to the ORACLE trial. (Consensus 100%)

Q3 Is oral cladribine an effective treatment option for RMS patients in transition to SPMS (i.e. secondary progression with relapses and/or MRI activity)?

Oral cladribine is an effective treatment option for patients in the transition phase from RRMS to SPMS (i.e. secondary progression with relapses and/or MRI activity) (Consensus 80%)

Q4 Is oral cladribine a suitable treatment option for RMS patients requiring a rapid onset of the disease-modifying effect?

The treatment effect of cladribine tablets starts within the first 24 weeks after initiating treatment. Available evidence is insufficient to further narrow down the exact time of onset (Consensus 89%). Em I think the MAGNIFY shows it start to work within 8 weeks.

Q5 Is the second cycle of cladribine tablets in year 2 important for long-term efficacy?

There is good evidence for the long-term efficacy of oral cladribine after completing the two licensed treatment cycles (Consensus 100%). There is insufficient evidence for adequate long-term efficacy after completing only one treatment cycle of oral cladribine (100%).

Q6 Will patients with disease activity in year 1 benefit from a second course of cladribine tablets in year 2?

There is low-grade evidence for a benefit of the second oral cladribine treatment cycle in terms of disease activity in patients with a relapse during the first year after treatment initiation (Consensus 67%).

Q7 How should patients be managed after completing the 2-year treatment period with oral cladribine?

If there is evidence of breakthrough disease after the second year of treatment with oral cladribine, all disease-modifying drugs licensed for RMS patients may be used, in accordance with an individualized risk-benefit analysis including the lymphocyte status. (Consensus 40%)

Q8 What is the risk of infection in patients treated with oral cladribine, which infections have been observed and how are they managed?

With the exception of a moderately increased risk of herpes zoster episodes, the overall risk of infections is not increased on treatment with oral cladribine (Consensus 78%).

Q9 What is the approach to vaccination in RMS patients before and on treatment with oral cladribine?

Immunizations with live-attenuated vaccines are possible 4 to 6 weeks before starting therapy with cladribine tablets. Vaccinations with live-attenuated vaccines should be avoided during the active treatment phase and afterwards until the lymphocyte counts have returned to the normal range. (Consensus 89%),

Q10 Is there a relevant risk of malignancies associated with oral cladribine?

There is currently no evidence of an increased risk of malignant disease in MS patients treated with oral cladribine. (Consensus 100%) – Comment ProfK: This is quite remarkable given a key reason for rejecting cladribine by the EMA in 2010/11 was the perceived cancer risk. Our meta-analysis had a significant impact on the EMA’s positive decision the second time around nearly seven years later.

Q11. At which time after treatment initiation with oral cladribine can female patients envisage a pregnancy?

Women can become pregnant 6 months after the last dose in the second year of therapy with cladribine tablets. Consensus : 89%.)

Q12 What are the monitoring requirements in patients before and on therapy with oral cladribine?

The monitoring requirements for patients treated with oral cladribine are low. Consensus 67%.

Q13 Does oral cladribine reduce the burden of therapy in RMS patients versus other highly effective treatment options?

Pulsed therapy with cladribine tablets is associated with a low treatment burden on RMS patients (Consensus 78%).

Q14. What is the impact of treatment with oral cladribine on the quality of life in RMS patients?

The quality of life of patients treated with cladribine tablets is improved as compared to placebo (Consensus: 89%) Comment ProfK: Fortunately, we decided to publish the respective data from the CLARITY data vault.

If you have any questions about cladribine we will try to answer but please read CHARIOTMS (NCT04695080)

ChariotMS – Cladribine to Halt Deterioration in People With Advanced Multiple Sclerosis (ChariotMS)

COI: Multiple

Disclaimer: Please note that the opinions expressed here are those of the author and do not reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust or Queen Mary Univeristy of London.

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  • Thanks MD for posting this, it’s answered many questions I had re Mavenclad. I start my 2nd week of my 2nd year today – so far all going well, hope it stays this way🤞

  • Nice post. The info on cladrabine seams abit lacking online compared to the other DMT around. And with more people getting offered it now on the NHS for various reasons it’s good to get abit more info

      • Also, let’s not forget that Prof G used to say that if he had MS he would want alemtuzumab, and has recently started saying that he would want HSCT. And Prof G has been massively involved with cladribine for a long time. So he’s very familiar with cladribine and clearly he doesn’t think it’s better. I’m inclined to trust his judgment.

        • ProfG keeps the discussion rolling, which is appreciated. What he would do in the real situation is hypothetical since anticipation of such decisions is notoriously difficult. The efficacy data of alemtuzumab, particularly the atrophy data, is very good. No other drug or intervention can currently compete with the length of systematically collected brain volume data. However, there are well-rehearsed issues. HSCT is yet another kettle of fish. 1:100-1:200 risk of malignancy is higher than Mitoxantrone (1:400 risk of TRAL), which has been all but abandoned in spite of its high efficacy.

        • Well you are entitled to your opinion, but when I was given the option, I chose cladribine.

          My research and support for this decision is well documented in the comment sections of this blog.

          Maybe you could share some of your reasons with the group…….

    • Poor man’s Alemtuzumab?

      Depends if the rich man wants more chance of serious side effects, and a good chance of another auto immune disease

      • Yeah I hear what your saying. But what’s worse than Active MS. Given the choice I will gladly trade another aut immune for MS. Even if its ulcerative colitis.

  • “Q3 Is oral cladribine an effective treatment option for RMS patients in transition to SPMS (i.e. secondary progression with relapses and/or MRI activity)?

    Oral cladribine is an effective treatment option for patients in the transition phase from RRMS to SPMS (i.e. secondary progression with relapses and/or MRI activity) (Consensus 80%)”

    Not sure what this means…?…
    Does it stop their progression..?

  • Brain atrophy data?
    What are chances of persistent lymphopenia?
    Why was there an initial signal for malignancy?

    • ORACLE suggested a strong effect on atrophy, but this was short term and not properly followed up. The next batch of quality atrophy data will emerge from MAGNIFY-MS; though limited by lack of a comparator (single arm study) this will be valuable data. Next placebo-controlled dataset is going to emerge from ChariotMS (FIRST PARTICIPANT CONSENTED TODAY!). It will be interesting to see whether in advanced MS and effect on brain or spinal cord volume can be detected. Risk of ‘persistent’ lymphopenia is extremely low. IMO the malignancy risk was overemphasized due to the zero events in the placebo-arm of CLARITY, as we described here:

  • Grat list, but it fails to answer (and question) what to do after completing the two years/ four cycles of cladribine. Is it just a wait-and-see game? To me this is the same as the «escalation» approach, with the only difference being that one is starting off with a heavier hitter than CRAB drugs etc. Why is no one talking about a strategy for either a maintenance track or re-treatment IRT track? Prof G have mentioned it a couple of times, but I do not see this reflected in any clinical trials.

    There is enough anecdotal evidence out there on social media etc suggesting that (for most) the effect from cladribine finally wears off. Then what? I am not planning on going untreated after the licenced 4 years are up. But I wish someone could point me and my neuro in some direction(s).

    • Yep, I would really love to know the answer to this as well. Currently, at 1.2 years after second year dose. To be fair, at this point things like fatigue and brain fog still improving, but would like to have an idea of what the next step will be if necessary. Although, I would be happy to have another round of cladribine if it was available.

    • IMO there’s a degree of hype attached to Alemtuzumab. We accept that ~50% will need a third course because of re-emerging disease activity. There is no trial data exploring the same concept for cladribine, however since you are quoting anecdotal evidence, the Australian follow-up of pwMS receiving a single course of Mavenclad (or Movectro as it was called back then) showed about 80% of patients were free of progression and 65% free of relapses 2 years after receiving *a single course* of the compound. Of note, this was based on n=90 people with a mean age of 47 years, a 13-year history of MS and a median baseline EDSS of >5. For comparison, CARE MS II (alemtuzumab as a 2nd-line DMT) was tested in pwMS aged 35 years, median EDSS of 2.5 and disease duration of <4 years. I would expect cladribine to match this performance given the same patient population; the ORACLE study suggests that. This is why we designed a cladribine vs alemtuzumab trial (CLEAR:MS, see my comment above) as a non-inferiority trial. Unfortunately, it wasn't funded.

    • “There is enough anecdotal evidence out there on social media etc suggesting that (for most) the effect from cladribine finally wears off. ”

      Am sure it does…just as hsct seems to wear off after 4-5 years…so many in FB group post
      “symptoms returmning at 4 year post hsct”..Still the first treated in u.s. were in year 2000 and
      some of them still have no progression.

      “The transplant saved my life–I was, and still am, beyond fortunate. For four years it helped me feel almost normal again. And I purposefully took every advantage, living life with my right foot firmly on the accelerator, figuratively and literally. It allowed me to drive again, travel the world again, and even snowboard again. But I knew that I might have to write this post one day.

      As evidenced by the just released 3-year update of HALT-MS in JAMA Neurology, the success rate of the trial has been unprecedented in MS, with nearly 80% of patients showing no evidence of disease activity after three years, and with some patients seeing a marked reversal in disability, myself included (2.5 EDSS points!). Unfortunately, it appears that with time the treatment’s durability is tested, as early numbers suggest fewer than 70% exhibit zero disease activity (relapse, new lesions or EDSS increase) at year four, a figure that drops below 60% at year five. Still powerful results, but far from across-the-board remission.”

  • I’ve been offered cladrabine and think I’m going to take it.
    Just a couple of concerns like the person above states. Is what’s after your course of treatment. Other effective treatments are given for years where as cladrabine isn’t.
    Is waiting a great option as an attack may come or underlying damage maybe happening and it is not being addressed. Abit of under the radar progression. Which may catch up with you over time. Cladrabine such a great drug as it crosses the BBB however future treatments seams the issue.

    • The reason cladribine is given only in short courses is the same as with alemtuzumab or HSCT (and I suspect to an extent with ocrelizumab, rituximab, ofatumumab, …): They delete lymphocyte populations that harbour the cells driving MS, and these cells (i) take a very long time to repopulate and if they do (ii) are – ideally – not of the same auto-aggressive phenotype as those deleted. Prediction about who needs more drug is difficult. Currently we use annual MRI & clinical review, but neurofilament levels also help, in the future probably both combined with lymphocyte subsets. Clinical testing is also becoming more sensitive to change, for example app-based, and this will help further define who needs re-treatment or indeed a switch.

  • Before starting cladribine should a patient have a baseline lymphocyte count and subsequent counts performed to check for efficacy?

    • Checking your lymphocyte count before starting is mandatory, as is follow-up testing at month 3. If there is *no* drop at all in your lymphocyte count after treatment, there is a risk that for some reason the drug doesn’t work. With monoclonals (alemtuzumab, rituximab, etc) you sometime get anti-drug antibodies, with cladribine it may be a specific phenotype of the enzymes that ‘switch’ the drug on in the body. Routine blood monitoring currently focusses on safety, not effectiveness.


    Read Stuart Allen’s story. With the re-release of Mavenclad he was also featured in an article as a patient receiving cladribine. Now I don’t know how many cycles of Litak he took after the one written about in the Memo, but with the initial Movectro dosage, Litak and now Mavenclad he has at least completed three treatments over a 10+ year period. Note that the reason he took Litak was that the initial treatment with cladribine «wore off». Also note that he has taken a lot of other (maintenance) drugs also before and after, which, as he reports, had little effect.

    Now, every patient is different, especially when it comes to MS. But it would be could to have some trials testing out different strategies for immune reconstitution therapies (IRTs). I am not keen on «wait and watch» until I get more end organ (brain) damage.

    • Thanks for sharing this, Sondre. Stuart’s testimony is quite powerful, as is Merran’s . Re Litak, we have just submitted for peer review an update of our off-label cohort – 208 pwMS we’ve treated with claribine starting 3 years before the tablets were licensed.

    • I read Stuart’s and Merren’s stories just after I was diagnosed. They made me decide to wait until Mavenclad was available on PBS in Australia to start treatment, only about 4 months. I still have no regrets about my decision.

  • Thank you for this post MD.

    Also, big thank you to Prof. K for proving some clarity and reason to the conversion.

    It is very disheartening when individuals, in the comments section, start trashing a DMT. Many pwms would love to have access to cladribine. Those of us who have chosen clad as their DMT, do so with the HOPE it will provide some slowing of our progression.

    Making a DMT decision is a very emotionally draining process, particularly when previous DMTs have failed.

    So thank you for all your work in this space.

  • I’ve been thinking about a strategy to mitigate the effects of CD20 depleting treatments on vaccine responses: is it worth moving patients to Cladribine, given evidence that it does not interfere with the Covid vaccine response, and therefore, buy a few years during which we will hopefully manufacture robust treatments for Covid-19?

    The way I see it, patients spend a couple of years on Cladribine and they are either i)NEDA, in which case they will stay the course, or ii) not NEDA, in which case they can move back to CD20, or take a further course of Cladribine.

    Assuming that the patients are stable on Rituximab, or Ocrelizumab, what are some reasons against my proposed strategy?

    • There is a number of options worth considering, including the one you suggest. The pandemic has raised the profile of vaccination not only against COVID-19, but more generally. The issues around vaccination response(s) haven’t been fully addressed yet, but I expect by the end of the year we will know far more about the risk associated with DMTs including the ‘pure’ CD20 depleters; I expect this to impact not only on DMT selection, but also on treatment schedules of current anti-CD20 therapies.

    • if you give cladribine after ocrelizumab you are still going to haveto wait for the ocrelizumab effects to wash out this couldbe years

      • “if you give cladribine after ocrelizumab you are still going to have to wait for the ocrelizumab effects to wash out and this could be years”..……MD, if possible, could you be more specific? Do you mean until CD19 B-cell repopulate? Thanks

        • What MD means is that in order to achieve higher likelihood of antibody generation you will have to wait until your B cells have recovered. This can take vastly different amounts of time (up to years), and so a simple “switch” from OCR to cladribine is not going to solve your problem, certainly not in the short term.

        • The median time for ocrleizumab induced B cell depletion to reverse back to normal takes from 5 months to three and a quarter years the average time after three does was 62 weeks and 72 weeks after 4 doses. Once the B cells repopulate to a certain level you will make antibody responses but not until then

  • Does cladrabine lower certain groups of white blood cells in the long run? Or do they always come back to normal levels

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