Off-label Cladribine use has been championed by DrK and this in part led to the re-emergence of the oral variant, which remerged after a 6 year holiday.
During this time we have generated a large cohort (See Stephanias ECTRIMS work below) of people taking this drug and we have defined a new working mechanism for cladribine .
Whilst memory B cell targeting is not uniqure to Cladribine, it has one potential advantage over other highly effective MS drugs.
This is that it enters (about 25% the blood level) and can be active within the CNS (Fingolimod enters the brain but its main mechanism is in the lymph glands) . Therefore it can target elements of disease that are relevant to progressive MS.
However, the centre of off-label cladribine was not the East-End of London, it was the East-End of Europe. Indeed our friends in Poland have been using off-label cladribine for years and they have asked what happens to the oligoclonal bands.
Interested read on.
Background:There has been long-term interest in cladribine as a drug for the treatment of MS. The current study focused on the effect of cladribine on oligoclonal bands (OCB) expression in the CSF in relapsing-remitting MS (RRMS) patients observed over 10 years.
Methods: 29 treatment-naive subjects with RRMS were prospectively enrolled and received induction therapy with subcutaneous parenteral cladribine (at a cumulative dose of 1.8 mg/kg; divided into 6 courses every 5 weeks given for 4–6 days, depending on patients’ body weight). Selected patients received maintenance doses in the follow-up period.
Result: Isoelectric focusing revealed that 55% of patients did not have OCB in CSF after cladribine treatment as compared to baseline testing when 100% of patients were positive for OCB. There were no significant differences in Expanded Disability Status Scale scores at baseline and at the end of treatment cycle between OCB-positive vs. OCB-negative subgroups. At the last follow-up, OCB-negative patients had lower disability compared to OCB-positive patients (p=0.03).
Conclusion: Cladribine-induced immune reconstitution leads to long lasting suppression of intrathecal humoral response, which might be an additional mechanism that enhances the therapeutic effect on disease progression in RRMS patients.
- •Cladribine (2-chloro-2’-deoxyadenosine) is an adenosine deaminase-resistant purine nucleoside analog with preferential lymphocyte reducing properties acting through the mode of pulsed immune reconstitution.
- •We focused on the effect of cladribine on oligoclonal bands (OCB) expression in the CSF in relapsing-remitting MS (RRMS) patients observed over 10 years.
- •Isoelectric focusing revealed that 55% of patients did not have OCB in CSF after cladribine treatment as compared to baseline testing when 100% of patients were positive for OCB.
- •At the last follow-up (Year 10), OCB-negative patients had lower disability compared to OCB-positive patients.
- •Cladribine-induced immune reconstitution leads to long lasting suppression of intrathecal humoral response, which might be an additional mechanism that enhances the therapeutic effect on disease progression in RRMS patients.
So we are starting to hit the oligoclonal bands.
Based on the enzyme distribution of deoxycyctidine kinase I would not expect cladribine to target plasma cells to a major extent but yet this study it shows that oligoclonal bands are disappearing and this may have benefit. So given our recent hypothesis paper it suggests we are on the righ track
This is just the start. The dosing schedule used is not the same as the clinical approach which uses a bigger dose over a shorter period of time meaning that more drug will enter the CNS. So can it be better,
Maybe we can confirm this resut
01 – personalised dosing in people with MS (n>200) – four years experience in clinical care
Introduction: Disease modifying treatment (DMT) is available for early/relapsing MS, however no licensed DMT exists for people with EDSS >6.5. Recently licensed for highly active relapsing MS, Cladribine is also a promising candidate DMT for people with MS (pwMS) at all stages of disability.
Aims & objectives: To report our experience using subcutaneous (s.c.) cladribine personalised dosing (cladribine PD) in pwMS.
Methods: Cladribine PD was offered to pwMS meeting NHS England (NHSE) criteria for licensed DMT, but chose cladribine PD instead, and as a compassionate treatment in pwMS not eligible for NHSE DMT. Disease activity was based on the clinical course and either (i) new lesions on MRI and/or (iii) elevated CSF neurofilament light chain levels. Safety assessments ruled out latent infections, and compliance with regular cervical cancer screening was mandatory. Cladribine 10mg s.c. was administered on three consecutive days (four in pwMS >90kg) during week 1. Based on total lymphocyte count at week 4, patients were given another 0-3 injections in week 5. A second course of treatment was given after 48 weeks. Follow-up included annual MRI head and three monthly blood counts.
Results: Over 200 pwMS (median age: 46 years) were screened; 171 (107 women, 64 men) underwent at least one treatment course; disease duration was 11 (SD=±8) years. At baseline 80/171 pwMS were treatment naive; 91/171 switched from a different DMT; 83/171 did not fulfill NHSE DMT criteria. 128/171 received full dose (60-70mg) at first course; in 43/171 dose was reduced due to lymphopenia (WHO grade ≤2 in 50%; grade 3 in 2%). 75/171 patients completed a second course; 33/75 received full dose; in 42/75 dose was reduced. Cladribine PD was well tolerated. Adverse events included mild injection site reactions (3), skin rash (3), shingles (2), aspiration pneumonia (2), allergic reaction (1), stye (1), dental infection (1), UTIs, and pain (chest, musculo-skeletal, head). Baseline EDSS was 4.7 (SD=±2.2). In 75 pwMS completing two courses of cladribine PD, median EDSS improved in 9 (12%), remained stable in 42 (56%) and worsened in 24 (32%).
Conclusion: Cladribine PD was generally safe and prevented grade 3 lymphopenia in all but 2% of pwMS. It offers an alternative in pwMS eligible for NHSE-funded DMT, and for pwMS not eligible for NHSE-funded DMT with MRI and/or CSF detectable disease activity. Follow-up of this cohort continues to further assess safety and long-term efficacy.Well done to DrK, he didnt sit on his Ass, he got off his bum and has started to offer people an oppertunity to target the damaging biology of MS
UPDATEDThis was a study done in relapsing remitting MS. A lumbar punction and blood sample was taken. A second lumbar puncture was taken about 10 years later.The cladribine was given at a cumulative dose of 1.8 mg/kg subcutaneously (s.c.) (divided into 6 courses every 5 weeks given for 4–6 days, depending on a patient’s body weight. This contrasts to the 3.5mg/kg given over 13 months, remembering that the subcutaneous route will deliver about 60% more and given over a week and one month later and then a year later. In this study they got 0.3mg/kg subsequernt to the first dosing..Some people became negative after getting only one dose cycle, others did not , Others had alot of doses and remained positive.iI you top look back at the people who lots their OCB there was no difference in the EDSS at baseline or 1 year but by 10 years there was a difference in the EDSS so those keeping the OCB continued to worsen