ProfKs Cohort of Off-label Cladribine users

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There are three main variants of cladribine. there is oral cladribine marketed under the name of Mavenclad, intravenous cladribine, used in hairy cell leukemia marketed under the name leustatin and subcutaneous cladbribine marked under the name litak and is also used for hairy cell leukemia, which is a B cell cancer. When you eat cladribine you get about 40% of the amount given under the skin or infused, but otherwise it is the same active ingredient. So the fact that oral cladribine, which was previously marketed for a short time under the name Movectro, worked in MS meant that the other two variants should work too. So in 2011 we started to see if we could use off-label cladribine and things started to move when ProfK donned his teutonic knight armour outfit as part of the “white Knights” saga and went off on the cladribine crusade. (New to the blog? – Have a read)

Maybe we should have done Marvel rather than Knights. Maybe ProfK could have been “Batman and I’m Robin or is that Dobin:-).

When we thought the company producing Litak could be bought and closed we had a secret supply line up and that was from the Polish Government supported option. They had been supplying drug for the Polish story and this was reported free-online a few weeks ago,

Rejdak K et al. Long-Term Safety and Efficacy of Subcutaneous Cladribine Used in Increased Dosage in Patients with Relapsing Multiple Sclerosis: 20-Year Observational Study. J Clin Med. 2021 Nov 8;10(21):5207. doi: 10.3390/jcm10215207.

In 2014 ProfK started to treat people with off-label Clad and this provides valuable insight of what may happen in peole taking cladribine tablets, which was brought back to life in 2017.

Have a read it is free!

Subcutaneous cladribine to treat multiple sclerosis: experience in 208 patients

Kimberley Allen-Philbey , Stefania De Trane, Zhifeng Mao, Cesar Álvarez-González, Joela Mathews, Amy MacDougall, Andrea Stennett, Xia Zhou, Ozlem Yildiz, Ashok Adams, Lucia Bianchi, Camilla Blain, Christine Chapman, Karen Chung, Cris S Constantinescu, Catherine Dalton, Rachel A Farrell, Leonora Fisniku, Helen Ford, Bruno Gran, Jeremy Hobart, Zhaleh Khaleeli, Miriam Mattoscio, Sue Pavitt, Owen Pearson, Luca Peruzzotti-Jametti, Antonio Scalfari, Basil Sharrack, Eli Silber, Emma C Tallantyre, Stewart Webb, Benjamin P Turner, Monica Marta, Sharmilee Gnanapavan, Gunnar Juliusson, Gavin Giovannoni , David Baker and Klaus Schmierer.

Ther Adv Neurol Disord, 2021, Vol. 14: 1–16. DOI: 10.1177/17562864211057661

Objective: To report on safety and effectiveness of subcutaneous cladribine (Litak®) in multiple
sclerosis (MS) patients.
Methods: Litak® was offered to MS-patients irrespective of disease course. Litak® 10 mg was administered for 3–4 days during week 1. Based on lymphocyte count at week 4, patients received another 0–3 doses at week 5. A second course was administered 11 months later. Follow-up included adverse events, relapses, expanded disability status scale (EDSS), 9-holepeg and Timed-25-foot-walking tests, no-evidence-of-disease-activity (NEDA), no-evidenceof progression-or-active-disease (NEPAD), MRI, cerebrospinal fluid (CSF) neurofilament light chain (NfL), and lymphocyte counts.
Results: In all, 208 patients received at least one course of treatment. Age at baseline was 44 (17–72) years and EDSS 0–8.5. Cladribine was generally well tolerated. One myocardial infarction, one breast cancer, and three severe skin reactions occurred without long-term sequelae. Two patients died (one pneumonia, one encephalitis). Lymphopenia grade 3 occurred in 5% and grade 4 in 0.5%. In 94 out of 116 pwMS with baseline and follow-up (BaFU) data after two treatment courses, EDSS remained stable or improved. At 18 months, 64% of patients with relapsing MS and BaFU data (n = 39) had NEDA. At 19 months, 62% of patients with progressive MS and BaFU data (n = 13) had NEPAD. Of n = 13 patients whose CSF-NfL at baseline was elevated, 77% were normalised within 12 months.
Conclusions: Litak® was well tolerated. Effectiveness in relapsing MS appeared similar to cladribine tablets and was encouraging in progressive MS. Our data suggest cladribine may be safe and effective in MS-patients irrespective of their disease stage.

Some people failed treatment and need a third course.

ChariotMS is using oral cladribine. It is recruiting, so if you fit the criteria, please consider this as an option.

The are sites all round the United Kingdom

wheelchair by the sa shore

Belfast, Birmingham, Brighton, Bristol, Cardiff, Edinburgh, Glasgow – City​, Glasgow – Lanarkshire, Leeds,               Liverpool, Luton, Nottingham, Plymouth, Salford, Sheffield, Swansea, London (Royal London Hospital, Queen’s Hospital Romford, Royal Free Hospital, St George’s Hospital)

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

NCT04695080

Inclusion Criteria:

  1. pwAMS aged 18+ years with an EDSS of 6.5-8.5 (inclusive)
  2. History of bowel cancer screening for men and women and cervical and breast cancer screening for women as per NHS recommended guidelines. https://www.nhs.uk/conditions/nhs-screening/
  3. Ability to complete the 9HPT with either upper limb within 180 seconds. The average score of both attempts for each hand should be used to assess eligibility.
  4. Confirmation of MS diagnosis according to the McDonald Criteria (2017) Thompson et al. 2018)
  5. In the judgement of the investigator, evidence of deterioration of upper limb function during the 2 years running up to the screening date

Exclusion Criteria:

  1. Participants with known hypersensitivity to Cladribine of any grade (as per CTCAE grading system) should be excluded
  2. Any uncontrolled diabetes, arterial hypertension and hypercholesterolaemia as determined by PI or delegated sub-investigator
  3. A history of stroke, deep vein or sinus venous thrombosis and/or myocardial infarction
  4. Moderate to severe renal impairment (creatinine clearance <60 ml/min)
  5. Moderate to severe hepatic impairment (Child-Pugh score >6)
  6. Significant comorbidity, e.g. cardiac failure, renal failure, malignancy, or other health condition that in the view of the PI or delegated sub-investigator precludes participation
  7. Pregnancy including planning to father a child or breastfeeding
  8. Body weight less <40kg
  9. Unwillingness to use effective contraception throughout the trial period until at least six months after the last administration of IMP. This is not applicable for post-menopausal women
  10. Acute infection
  11. Infection with Human Immunodeficiency Virus 1 and/or 2
  12. Active chronic infection (Syphilis, Tuberculosis, Hepatitis)
  13. Precancerous condition or previous diagnosis of cancer
  14. Total lymphocyte count <1.0*109/mL
  15. Seronegativity for varicella zoster IgG, rubella, measles, mumps. Potential participants who fall in this category may undergo vaccination and can be screened (again) once full course has been completed.
  16. Relapse within six months before screening
  17. Inability to complete an MRI (contraindications for MRI, including but not limited to, MRI non- compatible pacemaker, cochlear implants, intracranial vascular clips, surgery within 6 weeks of entry in the study, coronary stent implanted within 8 weeks prior to the time of the intended MRI, severe anxiety or claustrophobia etc.) or contraindication to Gd administration.
  18. Treatment with steroids due to MS relapse/progression within three months of screening.pwAMS who fall in this category may undergo a further screening visit once the three months’ window has expired and may be included if no steroid treatment has been administered in the intervening period.
  19. Treatment with any interferon-beta, glatiramer acetate, teriflunomide or dimethyl-fumarate within three months before screening.
  20. Treatment with natalizumab, fingolimod, siponimod, ponesimod, ozanimod (or other Sphingosine-1-phosphate receptor modulators) within three months of screening.
  21. Treatment with azathioprine, methotrexate, or cyclosporine within six months before screening.
  22. pwAMS treated with teriflunomide will need to undergo accelerated elimination of the compound before being considered (Research and Case Medical Research 2019).
  23. Treatment with haematopoietic stem cell transplantation (HSCT), mitoxantrone, cyclophosphamide, cladribine, alemtuzumab or another B cell depleting compound, such as rituximab, ocrelizumab, ublitiuximab, ofatumumab, or biosimilars, unless the participant concerned has a memory B cell level of ≥20% of the CD19+ population in the peripheral blood. Such a level would normally not be expected earlier than a minimum of six months after the last drug administration. Participants who underwent such treatment will therefore have to be tested for their CD19+/CD27+ memory B cell level at screening.
  24. Treatment with fampridine: If they are already on treatment for at least six months, participants should continue throughout the trial. However, starting continuous fampridine treatment after signing the consent sheet will lead to exclusion from treatment with IMP/placebo.
  25. Concurrent participation or previous participation within the last 6 months in another clinical trial of an IMP or medical device.
  26. Unable to swallow tablets

About the author

MouseDoctor

16 comments

  • Hopefully more drugs will be repurposed and thank you my bretonnian knights! The white knight diaries is an interesting read.

  • I have been accepted for Siponimod treatment , not started yet but soon to be started. My question is, as I fulfill the inclusion criteria for Cladribine, would I be better off on this drug rather than Siponimod. Please give me your honest opinion. Thank you.

    • Siponimod is the licensed option for people with SPMS who have relapses and/or MRI activity. Off-label cladribine is now rarely used due to licensed options being available. For people with EDSS >6.5 there are trials ChariotMS (SP & PPMS), O’HAND (PPMS) and SIZOMUS (currently single centre at Barts Health/The Royal London Hospital).

    • There is really no question that you would be better off on cladribine than siponimod. The problem is finding a doctor who will prescribe it to you off-label. Siponimod barely does anything.

    • The hypothesis is based, firstly, on the evidence that inflammatory activity plays a role throughout the disease process, from the very beginning until people with MS pass away. This is supported by studying large post mortem brain & spinal cord samples. Secondly, cladribine penetrates the blood brain barrier and may thus affect B & T cells and plasma blasts, probably less so plasma cells, directly in the CNS. Thirdly, there is evidence for different vulnerability of long nerve fibre tracts compared to short ones such that immunotherapy may be able to protect areas of the CNS that have not been “lost” to progressive MS. This is why our primary outcome in ChariotMS relates to upper limb function (Nine-hole-peg test time; short tracts) and not on a measure that depends on walking/lower limb function (long tracts). Check out chariotms.com for more.

      • Prof K,

        Happy New Year – for 2022

        “The hypothesis is based, firstly, on the evidence that inflammatory activity plays a role throughout the disease process”

        Why aren’t researchers addressing the real question of why there is inflammatory activity? Surely the inflammation is there because there is an infection or something else damaging the CNS. It would be nice if some research teams moved away from the focus of addressing the immune system response (inflammation) to focus on what is driving the inflammation in the first place. Time to move away from the “autoimmune” mindset and find the real cause of MS. J C virus causes demyelination but isn’t considered an “autoimmune” disease.

        • Your “real question” is being addressed by teams exploring risk factors for MS, including infection, with an emphasis on EBV (check https://multiple-sclerosis-research.org/2021/12/doctorbunny-is-ebv-the-target-in-ms/). However, it is unclear whether, once triggered, MS still requires the presence of the inducing risk factor(s) to continue its CNS damaging activity, or whether the inflammation becomes independent of its inducing cause. We know DMTs can stop inflammatory activity in the CNS, and they are generally effective in pwMS. However, whether effects can be detected in people with *advanced* MS needs to be demonstrated in order to make DMTs available for this population across the NHS. This is what ChariotMS (and O’HAND) are trying to achieve.

      • I have read an article freom 2017 written by Norwegian doctors that ask the question “Is MS a mitochondria mediated disease” where they use as an example what they find from autopsy og MS brains. They say mitochondria cganges and dysfunktions are found in MS brains, and it can be the cause or the consequenses of the disease. Tke outside in hypothesis says it is an autoimmun disease (but does it fullfill the criteria of definition of an autoimmune disease?) and the inside-out hypothesis. As I understand they see attacks on the myelin from within the aksones which indicates another prosess than autoimmun that attack the myelin from outside. I always read that MS is considered autoimmun even though it not fullfill all the criterias to an autoimmune disease, and when i asked a neurologist about this he said “because immunesupressiv medication seems to have an affect”

  • Dear Prof K.

    I had deep vein trombosis for about 2 years, but it is more than 4 yrs ago. Since 2017, after using acenocoumarol all that time, I just suddenly had no deep vein trombosis anymore.

    Is that reason enough to be excluded?

    Thanks

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