What happens with cladribine in the long-term

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Abstract

Long-term effectiveness in patients previously treated with cladribine tablets: a real-world analysis of the Italian multiple sclerosis registry (CLARINET-MS).Patti F, Visconti A, Capacchione A, Roy S, Trojano M; CLARINET-MS Study Group.Ther Adv Neurol Disord. 2020 Jun 10;13:1756286420922685

Background: The CLARINET-MS study assessed the long-term effectiveness of cladribine tablets by following patients with multiple sclerosis (MS) in Italy, using data from the Italian MS Registry.

Methods: Real-world data (RWD) from Italian MS patients who participated in cladribine tablets randomised clinical trials (RCTs; CLARITY, CLARITY Extension, ONWARD or ORACLE-MS) across 17 MS centres were obtained from the Italian MS Registry. RWD were collected during a set observation period, spanning from the last dose of cladribine tablets during the RCT (defined as baseline) to the last visit date in the registry, treatment switch to other disease-modifying drugs, date of last Expanded Disability Status Scale recording or date of the last relapse (whichever occurred last). Time-to-event analysis was completed using the Kaplan-Meier (KM) method. Median duration and associated 95% confidence intervals (CI) were estimated from the model.

Results: Time span under observation in the Italian MS Registry was 1-137 (median 80.3) months. In the total Italian patient population (n = 80), the KM estimates for the probability of being relapse-free at 12, 36 and 60 months after the last dose of cladribine tablets were 84.8%, 66.2% and 57.2%, respectively. The corresponding probability of being progression-free at 60 months after the last dose was 63.7%. The KM estimate for the probability of not initiating another disease-modifying treatment at 60 months after the last dose of cladribine tablets was 28.1%, and the median time-to-treatment change was 32.1 (95% CI 15.5-39.5) months.

Conclusion: CLARINET-MS provides an indirect measure of the long-term effectiveness of cladribine tablets. Over half of MS patients analysed did not relapse or experience disability progression during 60 months of follow-up from the last dose, suggesting that cladribine tablets remain effective in years 3 and 4 after short courses at the beginning of years 1 and 2.

Keywords: cladribine tablets; clinically isolated syndrome; effectiveness; long-term data; multiple sclerosis; real-world data; real-world evidence; registry; relapsing-remitting MS; secondary progressive MS.

Cladribine is given for 1 year (0-1 and 12-13 months) and then you do nothing for 4 years and the question is then what?

Now I’m not a neurologists so I will keep my mouth shut. But because the CLARITY programme was delay there isn information hole. But what happened in the real world?

The effect didn’t last for ever in about 40% of the people at 5 years and 35% of people at 3 years but at one year only about 15% of people failed. Remember, this could be better than that occurring after anti-CD52 depletion where 50-60% of treatment fails but they get another dose and as you saw recently about 75% of people get long-term treatment benefit

Now if we looked at the alemtuzumab data and there was about 50% failure rate after the first year, but as we heard the other day if you get a third dose then about 75% of people went in to get long-term remission. But in this study the people were switched to something else in about 75% of the time and within about 2-3 years.

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  • Please correct me if I am wrong, but I believe the Alemtuzumab trial patients had MS for 2 years, and the Cladribine tablet trial patients had MS for around 7-9 years, pre trial. In the USA, where I practice, England’s namesake “Reading”, Pennsylvania, I have around 200 out of my 900 patients on Teriflunomide, a cytostatic, not cytotoxic, immunomodulatory, not immunosuppressant, CNS penetrant, broad antiviral drug with continuous emerging data on very good reduction in gray matter atrophy and progressive disability.. Professor G, on his most recent webinar on The Real Smouldering MS, had a slide on how well Teriflunomide performs after failing 2 or more previous DMT’s ( ? antiviral, CNS penetrant, or other central beneficial MOA’s ). I do not know if Nice, and your National Health Service, provides Teriflunomide to your population, so I apologize if I am touting a favored MS DMT of mine for the long haul, after Cladribine, if needed, for breakthrough disease, as a relief pitcher, who may go as long as 6 innings to finish out the baseball game to the end of one’s life, safely.

    • Teriflunomide is indeed available, but because of its failings as a first line, I suspect it often gets over-looked as a second line. We asked for some phenotyping data first verses second line it never arrived, but there is some interestign luflunomode data in arthritis. It could be a used after a induction therapy people would buy into it as they have the re-assurance on maintianing treatment but you have to ask why not cladribine after cladribine.

    • Dr. Reed, Thank you for sharing. I find your insights to be very reassuring! There is not much data out on pwMS who had to stop taking an anti-CD20 drug and then switched to drug x, drug, y, or drug, z. That leaves the few patients in this small percent, with an uncertain path forward.

      Being told to just switch to another “big gun” is unacceptable, particularly when they are unwilling to provide the necessary data/tests to ensure a safe de-risking treatment plan can be developed. I always find it frustrating that when an individual is diagnosed with MS, they are told to educate themselves and handed fifteen drug brochures. Then, once you get educated and start to advocate for yourself, they tell you to stop googling or you are misinterpreting the data……just listen to me, I am the doctor.

      No, all we want is some compassion and collaboration. We want the neurologist to treat the patient as if they themselves had MS. I bet then, they would read every paper, watch every video, and try to get access to the best medicine, and most up-to-date information.

      Your willingness to share your insights is refreshing and I wanted to just say thank you!

  • Thanks for the update. It feels like cladribine has been left at the side of the road. From being a game changer to a “oh ya that” … 57.2,% were relapse free 60 months (5 years) after the last dose, so 7 years after the first dose. Meaning 57.2% were relapse free in years 3, 4, 5, 6 and 7. Obviously a higher percentage would be great but surely that’s good isn’t it? Then again I suppose how was their disability? Is it worth doing a third and fourth year of treatment to push it out further? A maintenance dose?

    • Cladribine has so much promise and if you did a trial on cladribine straight after diadgnosis I bet it would match anyuthing out their, however most people have no clue how it works, the Sh1 has stuck and people stay clear as a result and as it is tarred with the same brush as alemtuzumab you may as well cover it in feathers

      • I was diagnosed in May 2018, took 6 weeks to make my decision after reading til my eyes bled. Alemtizumab was the front runner til I came upon cladribine which hadn’t even been approved here yet, so I held out 3 months til it was approved , then 10 more weeks for vaccines etc. Took my first dose 6 months exactly from diagnosis…. but of course, the big question is, how long have I had MS? So is it really only 6 months since the start 🤷‍♀️. First MRI pre year two, no new lesions, stable. Happy with that so far and I feel “normal”, my normal, cos everyone’s normal is different right? 🙂

  • Are those odds good enough for MSers I wonder?
    Is Dr A. on this case?
    Or can profiling be done otherwise?

    Neuros need to up their game in 2020. Giving someone facing guaranteed disability a pill with 50/50 hit rate is not good enough.

  • I assume that these observations are all useful arguments in an effort to approve the provision of a third Mavenclad treatment cycle. So the question is, who will drive this effort forward and by when is it reasonable to expect a decision from EMA?
    You are well aware that the first cohort of Mavenclad patients is already in their third year and rapidly approaching the point where they likely would be candidates for an additional cycle. As you always write: “Time is brain”..

    • Good questino. Sadly I dont know what happens here…Maybe ProfG/K can answer…My concern is because the cladribine patent expires in the next few years then unless the sponsors can do a Teva (Copaxone was discovered in the 1970s and the patents didnt go until 2014), they will not have done and will not do the necessary studies to make the regulators agree to more cycles.

      • My 2nd reply to MD and others:
        I’ve had about 35 long standing MS progressive Mavenclad pts here in the US, having completed only their first cycle. None have continued to progress, having previously failed several other MS DMT’s over the years, as per smoldering progression. Several have had modestly improved motor function in the LE’s( one would think there was no hope and their multiple sclerotic plaques in the cord made them too far gone )—-anecdotally, as just said, not so!
        What really impressed me was Dr Rejdak’s 29 MS patients, all 100% Oligoclonal band + ( OCB ) at baseline of study, and 55% were Oligoclonal Band negative, 10 years later, with less progression. My take on OCB’s is that they are an epiphenomen, responding to the progressive epitope spreading diffuse brain and cord MS tissue damage percolating into the CSF, throughout the entire life of the MS patient, including the years of pre dx prodrome. So yes, more Cladribine, if regulatory approved, after 4 years, even in the aging, immune senescent, MS patient, since Cladribine is not continuously immunosuppressant.
        Clifford Reed

        • “. My take on OCB’s is that they are an epiphenomen, responding to the progressive epitope spreading diffuse brain and cord MS tissue damage percolating into the CSF, throughout the entire life of the MS patient, including the years of pre dx prodrome.”

          🙂

          Thats a blasphemy to the “colective cyborg”

          🙂

          Obrigado

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