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.
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.
Konrad Rejdak, Zbigniew Stelmasiak, Paweł GriebCladribine induces long lasting oligoclonal bands disappearance in relapsing multiple sclerosis patients: 10-year observational study Mult Sclero Rel Disord DOI: https://doi.org/10.1016/j.msard.2018.10.006
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.
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
Baker D, Pryce G, Amor S, Giovannoni G, Schmierer K. Learning from other autoimmunities to understand targeting of B cells to control multiple sclerosis. Brain. 2018 Oct 1;141(10):2834-2847. doi: 10.1093/brain/awy239.
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
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
Thanks MD. A few questions:
Oligoclonal banding, as I thought, is not specific to MS? It is only specific for damage done to the CNS and is present in other diseases or damage of the CNS. Would Cladribine also get rid of oligoclonal banding in things like CVA?
Also, it seems like there is no significant difference between EDSS scores between the OCB+ vs OCB- groups in the Rejdak study above at baseline and at end of treatment. Maybe I am missing something but who cares if Cladribine makes a person with MS OCB- if it has no effect on EDSS?
Not sure what CVA is is is cardiovascular accident.
I guess this is saying oligoclonal bands are affected. Oligoclonal bands are produced by B cells and this indicates that cladribine effects such B cells and so probably it would target this is other conditios
If you have been reading the blog you will remember that it may be that EDSS does not respond as it is too late to get a response, but other outcomes can. This is why it is important in the study Prof Rejdak says "At the last follow-up, OCB-negative patients had lower disability compared to OCB-positive patients (p=0.03)".
Thanks. CVA is cerebrovascular accident or stroke and has oligoclonal bands as well. Wouldn't that indicate oligoclonal bands are a downstream or cleanup by B-cells to damage already done and not necessarily driving MS?
How do they define lower disability if it does not include EDSS?
Maybe, it says inflammatory cells have arrived and a B cell niche has been formed that allows their long term survival.
As to driving MS, the OCB are not the drivers I think these are the new lesions forming they light the fuse the microglia kep it burning
Lower disability…I dont define it and yes EDSS is part of the lower disability. Once I have access to the paper I can be more specific about what was found.
Once I can get full access I will comment more and perhaps we can get a quest post from Prof Rejdak.
Have send you
Obrigado
Obrigado..
"OCB are not the drivers I think these are the new lesions forming they light the fuse the microglia kep it burning"
Interesting..first time ever they found EBV in microglia and astrocytes.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0192109
Great news
Also for the "black swan"
But you have confliting results
Cladribine in treatment of chronic progressive multiple sclerosis7
https://www.ncbi.nlm.nih.gov/pubmed/7912347
In this study they treat only ppms patients
Could this be related to the fact that ocbs did not disappear?
Obrigado
Sipe says cladribine benefits progressive MS. What's the conflict?
I am sure they treat more than ppMS, but maybe they are restricting their claims.
.
At the last follow-up, OCB-negative patients had lower disability
compared to OCB-positive patients (p=0.03)
What does this mean?????
They dont report the Edss of the patients in the beginning of the study
nor in final notes..:(
So if they are better than the ocb positive patients i would like to
by know how much? (Edss)
Obrigado
I dont have paper to hand sorry, when I get back from Lisbon I will have a look
Obrigado
Are you in Lisbon?
CSF examination
The number of oligoclonal bands did not change in any
patient. For the cladribine group, relative oligoclonal
concentrations at baseline and at 6 months and 12 months
averaged 29-9 (4-2), 26.5 (3-4), and 25-0 (3-3) a significant
decline (Fg = 5-17, P < 0 -02). Corresponding values for the
placebo group were 26-2 (3-8), 29-9 (3-8), and 29-9 (4-7), a
modest but non-significant increase (Fg =181,p=0-18).
Among the matched pairs, the placebo patients tended to
have higher values than their counterparts on cladribine:
The mean paired difference (placebo minus matched
cladribine) in relative oligoclonal immunoglobulin
concentrations at 6 months relative to baseline is 4-3 (2-0)
(95% CI 0-1-8-5); at 12 months it was 7-3 (3-3) (95% CI
0-5-14-1).
Lisbon…I was
Nice
Did you eat "pasteis de belem"?
🙂
Yes on plane on the way over, but we regularly get them fromm the bakeries in London and I used to have a Portugese shop at the end of my road.
DrM&M (From Portugal) sometimes brings us a treat..Yum
In the paper they did reporte effect on EDSS it is in the figure but not the text
I see it
Thanks
So far the drugs that could clean the oligoclonal bands would be Natalizumab and Cladribine.
What about the Alemtuzumab and the Ocrelizumab, there would be the same possibility of eliminating the OCB's?!
The avsilable data is that OCB persist after alemtuzumab and i dont know about ocrelizumab but rituximab doesnt do it either. There is postitive data with natalizumab but that has been questioned. Antobodies based on lingo are 99.99 percent excluded
Rather confusing to hear that OCBs persist after Alemtuzumab considering that it appears to be the most effective DMT.
Blocking relapses has little to do with oligoclonal bands. Blocking relapses are associated with stopping the immune system arriving in the CNS, oligoclonal bands are there in the CNS
MD if it were possible to clean the OCBs of the liquor, would this lead to a clinical improvement of pwMS? Because OCBs appear to be increased at much higher rates in those who have a progressive course of MS from the outset.
The presence of OCB means that there is the synthesis of immunoglobulin (IgG) in the CNS, and if we clear the OCBs from the liquor we could talk about "real interruption of the disease" or even "cure"?
Did you know this
Interim Analysis of the OBOE (Ocrelizumab Biomarker Outcome Evaluation) Study in Multiple Sclerosis (MS) (S24.002)
Results: CSF samples from Weeks 12 and 24 post-ocrelizumab treatment exhibited reductions in median concentration of NfL (−24%, −47%); median number of CD19+ B cells (−86%, −82%) and median number of CD3+ T cells (−60%, −67%). Ocrelizumab was generally well tolerated, consistent with safety in the Phase 3 studies. Infusion-related reactions (44%) and 1 serious adverse event (seizure) were reported. No serious infections, malignancies or deaths were reported.
Does this mean that Ocrelizumab enters the cns ,or the results
are consequence of total deplection of peripheral blood Bcells?
http://n.neurology.org/content/90/15_Supplement/S24.002
Obrigado
Alemtuzumab not only blocking relapses, but also reduces progression, and ms related bvl.
Generally it has a remarkable and consistent effect, and some small studies have suggested it can be modify the SPMS too.
http://n.neurology.org/content/88/16_Supplement/P5.356
Ocrelizumab has a positive PPMS trial, and also a remarkable effect on RRMS.
I hope clad will be the same ballpark as Alem., OCr, and of course Nat. 4 big gun (2induction ones and 1half induction one, and ine maintained)! Sounds good!
I agree that alemtuzumab and Clad should have the same potential to inhibit progressionas ocrelizumab, possibly better, but I am not sure we with ever know (unless academics do the studies), because they have left it so late to do the trials. The patents will expire by the time they finish. They made the mistake of not doing the study.
I know some of the histroy there and is not all the companies fault.
If the trial is funded, Dr K may get supportive evidence from MSchariot but it will not be enough for registration. This has been agreed by Merck and the NIHR who hopefully withh fund the trial as they don't want to do company trials, but Merck are to supply free drug for the trial.
In the Roche camp they dont like the use of the term induction because it adds confusion. When ocrelizumab is given it is done as a split dose (2 x 300mg) and this is called induction
"CSF samples from Weeks 12 and 24 post-ocrelizumab treatment exhibited reductions in median concentration of NfL (−24%, −47%); median number of CD19+ B cells (−86%, −82%) and median number of CD3+ T cells (−60%, −67%)".
This shows that the drug is blocking active disease and so cell numbers will drop because inflammation drops. There is a study with Anne Cross as an author and rituximab showing that B and T cells go within 6 months of treatment. I would have expected the T cell number to drop . There is no mention of olligoclonal bands and so I suspect they were unchanged
If we can remove OCB from the spinal fluid (liquor). I think this will be a good thing as it means one more aspect of the immune response under control. The sooner the better. We need to see effect of early and effective treatment.
Is cladribine beneficial on OCB necause it gets in CNS and targets plasma cells or because it targets cells that produce thw survival factors. The latter is the hypothesis that I would suggest is more relevant.
Sorry I couldn't link it, but an early study in 2000 by Rice and others of 159 patients in the journal Neurology found: "No significant treatment effects were found for cladribine in terms of changes in EDSS or SNRS scores". This trial had the primary outcome of mean change in EDSS and the study participants presented with a median EDSS score of 6.0. It would be interesting to compare that study to this more recent study as doses may have been different or other variables not taken into account. It appears that disability in chronic MS is irreversible by immune suppressant drugs in contrast to RRMS.
Like alemtuzumab!
http://n.neurology.org/content/88/16_Supplement/P5.356
Clad and alem are inductions so they have long term effect. As we now the inflmation has a role in later stage (SPMS) so when we use it the later stages (EDSS4-5) we can switch off the inflamation when pwMS reach the definite SPMS state. As we know currently we dont have any SPMS treatment, so could be important to use this inductions before pwMS reach the devastating SPMS diag.
The trial by Rice was only 12 months so too short, DrK may comment on this when he has time
hello,
Is the article by De Trane et al. published or is it a meeting abstract. Woul dvery much like to read the full thing (paper or poster) if its availbale. Sounds wonderful news for pwPPMS.
Work in progress… Hopefully also update on #ChariotMS soon.
Dr Moa has a paper on our early experience with first fifty people which will surface soon, but the work of Dr de Trane clearly ahows that tailored dosing reduces the risk of severe lymphopenia. In CLARITY it was about 6-7percent on dirst dose and about 25-26 percent on second dose. In our cohort it was about less than 2 percent I think. Contrast this with more than 80 grade 3-4 lymphopenia with alemtuzumab. I hope this reduction does not equate to less effective disease control.
Dr Zhifeng Mao
Re:
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%).
Is this justification enough to for a patient or a doctor to choose SC Cladribine?
Re:
171 (107 women, 64 men) underwent at least one treatment course
What were their outcomes among this larger group? (Percentages improved/stable/declined)
You have to appreciate that most of the people treated here would be ineligible for any treatment, so the choice is sc cladribine or nothing.
This is ongoing real life treatment and not a trial and spans different disease durations and lables eg. PPMS, SPMS etc. DrK will report this in due course
EDSS is too broad and not much help
I wish we knew more details. For example, how many patients feel less/more fatigued, are there changes in other symptoms that are not reflected in the EDSS, were they worsening before cladribine, …and lots more
So i dont know