Cladribine failures after fingolimod

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Fingolimod traps lymphocytes in the bone marrow and lymph glands and causes depletion in some individuals. The problem is that when you come off fingolimod, how long do you wait before starting the next treatment? Wait too long and you get disease rebound, as occurs with natalizumab also, which is a mega relapse. Here are three individuals swapped onto cladribine. However, don’t wait long enough and it may hide the lymphocytes in tissues not reached effectively by antibodies such as alemtuzumab.

In these cases cladribine was not good enough to stop MS after fingolimod.

Although it is suggested that cladribine depletes lymphocytes after 4 weeks, which appears to be the case for B cells in the blood, for the T cells to be fully depleted takes 8 weeks and it takes some time to become effective based on the ORACLE optic neuritis trial.

In all these three individuals disease had become active by the end of the wash-out 8-12.

Patient#1 initiated fingolimod after a relapse while on interferon beta-1a. After one year of treatment, she experienced a polysymptomatic relapse with evidence of multiple brain gadolinium-enhancing lesions and fingolimod was dis-continued. Cladribine was started after a 12-weeks wash-outAt cladribine start, brain MRI still exhibited ongoing disease activity.In the 6 following months, she experienced 3 relapses with incomplete recovery and persistent MRI activity. Given the aggressive course of the disease, she discontinued cladribine and underwent autologous hematopoietic stem cell transplantation (aHSCT). 
Patient#2 initiated fingolimod after a relapse under treatment with dimethyl-fumarate. After 6 months of treatment, one silent gadolinium-enhancing lesion was detected on brain MRI. After three years, a further lesion appeared on brain MRI and fingolimod was discontinued. After 8 weeks of wash-out, she received the first course of cladribine. Although her neurological exam remained stable, brain MRI scans at cladribine start, after 3 and 6 months showed new widespread active lesions. Given the sustained radiological inflammatory activity they switched to ocrelizumab therapy. 
Patient#3 initiated fingolimod because of suboptimal disease control while on interferon beta-1a. After 2 years of treatment, she experienced a spinal relapse with evidence of new active lesions and fingolimod was discontinued. After 10 weeks of wash-outcladribine was administered. In the following 10 months, she presented with 2 relapses and her follow-up brain MRI scans revealed several tumefactive lesions. She discontinued cladribine and underwent aHSCT.

“We cannot rule out that a shorter wash-out before starting treatment with cladribine would have yielded a better control of the disease. Although evidence is limited, we suggest that cladribine should be used with caution as a rescue strategy for MS patients with persistent disease activity during fingolimod treatment. Further studies are needed to characterize the best therapeutic strategy after fingolimod discontinuation”.

I will leave it to ProfG and ProfK to explain what they would do to transition to cladribine from fingolimod and it can get complicated if fingolimod has caused persistent lymphopenia (low levels of lymphocytes) it makes the point that when ever you start a therapy, you should always consider where next if the treatment fails.

Hello MD, ProfK here: As you say time is of the essence, and the problem, of course, is the ‘mandatory’ lymphocyte level of 1.0 x 109/L before starting oral cladribine treatment. Since pwMS on S1P modulators, such as fingolimod, can develop severe rebound disease despite subnormal lymphocyte counts, it is key not to delay starting follow-on treatment. However, all of the above cases were well within the “rebound-window” prior to starting cladribine treatment. Based on the immune cell kinetics, we expect the effect of cladribine to kick in from month 2, and this is probably fully developed from month 3 after treatment initiation. During this period, pwMS remain at risk of rebound disease, which is why at BartsMS we have moved to a different strategy when switching from S1P modulators to cladribine. We wait until a clear upward trend of the total lymphocyte count is established, which could be, for example, from 0.1 to 0.5 x 109/L four weeks after stopping fingolimod, and then start cladribine. Using this individualized approach, we have not experienced any rebound disease so far.

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8 comments

    • “So what can we do if Cladribine failed?”

      Lose your Neuros phone number..and call your travel agent to book a flight to
      Russia/Mexico..or if you’re feeling lucky you can try India..less safe record but cheaper hsct cost. Mexico has the best food so they get the edge over Russian meat stews and porridge.

      Patient #1 “In the 6 following months, she experienced 3 relapses with incomplete recovery and persistent MRI activity. Given the aggressive course of the disease, she discontinued cladribine and underwent autologous hematopoietic stem cell transplantation (aHSCT).”

      Patient #3 “She discontinued cladribine and underwent aHSCT.”

      There was already Alemtuz/HSCT…maybe there were other reasons nobody
      else dared to pull Cladribine out of the pharma trash bin.

  • This is my concern it’s a good question but there’s not always an answer. For people on ocrelizumab who have failed on a few other therapies where next? Is there and equal or higher efficacy drug? aHSCt seems only real option of if fails but not avail in USA.

    • Completely agree with the comments. I was told aHSCT was the best option after Ocrevus failed. However, aHSCT is not available in U.S. Very frustrating to be told…..one more large cervical lesion and you could be paralyzed. Good to know there is a treatment that could possibly help me, but oh wait, you can’t get that treatment. Wonderful (heavy sarcasm added!) I think I may be ready to join SID in the kingdom of the frustration.

      • The many factors preventing HSCT in The USA per my research, the reasons are bogus imho.

        Firstly, the Legality risk problem looms large in the USA in most states, especially if a dangerous HSCT procedure. Dependent on which state you practice the malpractice award could be in the millions of dollars plus the high insurance premiums yearly, except in Texas. In Texas the Malpractice was capped at $250,000 per award, therefore the legality awards are lowered to affordable levels if worse case occurs, thus low malpractice insurance as well. The malpractice was capped in Texas to attract more Medical Dr’s to help reduce the Dr shortages in the largest State (lower 48) around 10 years ago, Texas (2020 pop. 29 million plus souls) is the second most populous state behind California as most know. Texas is Pro Business FIRST, Citizen second, Thus Texas is ripe for several brave investors, courageous Dr’s, Pharmacists, Nurses, and Patients to start a HSCT clinic. The barriers are less and less, I am stumped why an American investor has not started HSCT Clinic. I only read and hear excuses. Excuses stating Not Safe, more studies are needed to prove safety/efficacy, I call BS, HSCT has been given and studied since the 1990’s and available in most Modern countries, except for the most Capitalistic country in the world, the USA. Nothing is stopping HSCT, but the expertise, the courage and a big cash investments. Anyone interested? I am obviously.

        Secondly I believe another large hurdle to overcome is the MS Pharma lobby groups, including the PHD influences at the Universities who conduct many of the studies. No, disrespect, but the PHD’s will receive their countless millions to study HSCT for another X number of years, ensuring their tenure, future studies and banks accounts full of cash. All I see is delay’s for the young MS victims who could benefit the most from HSCT like Prof G written and others say repeatedly. Why not provide the young MS victims the most effective treatment to date preventing future MS damages.

        Thirdly, the Insurance would be aware of the HIGH COST OF EACH HSCT treatment if all went well, and if HSCT created new issues the costs could escalate quickly. Thus Insurance is against HSCT or HSCT would already be a choice imo.

        For fun let us do a wag (wild ass guess) calculation for HSCT costs if available in the USA. If 100,000 young MS patients were given the HSCT in the USA, I am guessing the cost would be about $150,000 per HSCT patient/treatment (I probably under guessed cost in the USA). The total cost would equal * 1.5 Billion dollars per year *, every year or until everyone is allowed to be treated. Remember 100’s are diagnosed weekly in the USA, with many more in denial.
        Many more would chose Texas vs Mexico if cost was comparable, the higher level of care would be in the USA typically.

        Lastly, how many billions of dollars would be lost if HSCT was the DRUG OF CHOICE or Tier 1 option vs the other 20 billion dollar per year for the MS market of drugs Pharma is cashing in these days. They are against HSCT from a business competition stand point, obviously.

        Any risk takers, I can help?

        I have to man reasons not to be involved.
        Thanks for reading. Take care and stay safe, the firestorm is approaching us as the colder temps rise, the Virus is driving the bus and the destination is unknown.

    • “Is there and equal or higher efficacy drug ?”

      No drug..ATA 188 is infusion of EBV reactive t cells. Better than hsct because you need at least one lesion in the past year for hsct to work for progressive ms. Try to just get in the trial..later most likely they will help with travel/hotel cost..though they won’t offer it upfront as they are cheap bastards. Always iffy thing to get trial acceptance…but other than loans/mortages/flights to Mexico for hsct it’s a legit option.

      https://www.nationalmssociety.org/About-the-Society/News/MS-Trial-Alert-Testing-ATA188-in-Progressive-MS

      Edss 3-6.5 age cutoff age is 55 for part 2.
      Previous treatment with alemtuzumab, hsct and cladribine for Part 2 not eligible.

      https://clinicaltrials.gov/ct2/show/NCT03283826

      So unfortunate the cladribine non responders are not even trial eligible.
      Talk about adding insult to injury.
      But that’s what you get with diseases. First ms hsct trial in u.s. was at Scripps institute in 1999…20 years later still no hematologist/hospital will perform it in the u.s.

      This blog has for the most part ignored it except when G writes a post on hsct “Fake News” or wants to call people “HSCT Zealots”. No not a cure… but if you have progressive ms and lesions..pretty much your best/only option.

      • I suspect you would only be satisfied if the blog was entirely dedicated to HSCT. As it is, it has been covered pretty extensively, as a quick use of the search function will reveal. On a final note, if you have progressive MS, HSCT is clearly not going to do anything for you.

  • Thank you very much, that’s exactly what I was looking for. What is meant here is that if the washing period is kept for 4 weeks, there is no possibility of rebound, I got it right? The 3 patients who had the transition waited long weeks.

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