cladribine / leustatin / mavenclad

[jimmylegs]

had a neuro appointment this morning. as long as my status continues fine, no pressure re pharma rx options.
an mri which had fallen off the radar is back on track.

i was researching cladribine this morning in prep. found a note on its ability to lower neurofilament light chain, but it was only a couple of case reports.

went to refresh on what if anything vit d3 can do in the neurofilament light chain department.
looks like per one study (1st below) that serum vit d3 levels above 100 nmol/l are most likely to maintain normal neurofilament light chain levels
also per another study (2nd below) that treatment with 20K IU d3 per week did not improve neurofilament light chain levels when in combination with a DMT
improvements to NFLC status seen via d3 alone, without a DMT, did not achieve statistical significance. (i note that the d3 only group got the lowest mean NFLC levels overall at week 96 but also had a lower mean starting NFLC in comparison to any placebo group, so one way or another the change was not dramatic enough to pull off significance).
only 28/35 participants in the 20K IU/wk d3 treatment group achieved levels at or above 100 nmol/l (ie in study 2 below, 20% did not achieve the d3 levels associated with best NFLC effect per study one below).

so, this only looks at one piece of a complex puzzle but since my last serum d3 test came back at 166 nmol/l, i'm not in any rush to try cladribine just on the off-chance it may help with a possibly non-existent elevated neurofilament light chain problem.

• Disease activity in progressive multiple sclerosis can be effectively reduced by cladribine (2018)
  https://www.msard-journal.com/article/S ... 0/abstract
  
  Methods
  We report on two pwPMS, who were treated with subcutaneous cladribine undergoing CSF NfL testing, alongside MRI and clinical follow-up, before and after treatment.
  Results
  Cladribine treatment was well tolerated without any side effects. CSF NfL after treatment revealed significant reduction (by 73% and 80%, respectively) corroborating the MRI detectable drop in disease activity. Disability mildly progressed in one, and remained stable in the other pwPMS.

• Vitamin D and axonal injury in multiple sclerosis (2015)
  https://journals.sagepub.com/doi/abs/10 ... 8515606986
  
  Results:
  There was an inverse association between serum 25(OH)D and CSF-NFL levels in categorical (dichotomized at 75 or 100 nmol/l) analyses. A dose-response effect for 25(OH)D levels on CSF-NFL levels (p for trend=0.034) was also present. Serum 25(OH)D levels above 100 nmol/l were associated with lower CSF-NFL levels independently of ongoing MS treatment.
  Conclusion:
  High 25(OH)D levels are associated with decreased axonal injury in MS.

• Vitamin D supplementation and neurofilament light chain in multiple sclerosis (2019)
  https://onlinelibrary.wiley.com/doi/abs ... /ane.13037
  
  Results
  Serum levels of 25‐hydroxyvitamin D more than doubled in the vitamin D group. Compared to placebo, vitamin D supplementation had no overall effect on the change in serum levels of NFL from baseline (P = 0.93 at week 48 and P = 0.56 at week 96). In the subgroup of patients not receiving disease‐modifying therapy, NFL decreased by 30.9% to week 48% and 32.6% to week 96 from baseline in the vitamin D group as compared to the placebo group (P = 0.06 for both time points).
  Conclusion
  With a possible exception for patients not treated with disease‐modifying drugs, weekly supplementation with 20 000 IU vitamin D3 did not affect NFL levels in these RRMS patients.
  
  There was a negative correlation between NFL and body mass index (r = 0.30, P = 0.01), and an unexpected positive correlation with 25‐hydroxyvitamin D (r = 0.25, P = 0.04). As previously reported, the mean serum concentration of 25‐ hydroxyvitamin D was more than doubled in the vitamin D group and was 123.2 nmol/L at week 96. There was also a minor increase from 57.3 nmol/L to 61.8  nmol/L in the placebo group. At week 96 25‐hydroxyvitamin D levels were above 100 nmol/L in 28/35 of the patients in the vitamin D group and 2/33 in the placebo group. ...

[jimmylegs]

noting in passing

Cladribine induces long lasting oligoclonal bands disappearance in relapsing multiple sclerosis patients: 10-year observational study (2018)
https://www.ncbi.nlm.nih.gov/pubmed/30368223

and

Cerebrospinal fluid oligoclonal bands in multiple sclerosis and clinically isolated syndromes: a meta-analysis of prevalence, prognosis and effect of latitude (2013)
https://www.ncbi.nlm.nih.gov/pubmed/23431079

ok who can find the study that examines the interaction if any between vit d3 status and presence/absence of o-bands? so far, not me.

[Jaded]

Difficult decision jimmylegs.

When I was diagnosed in 2005 they didn't offer me any DMDs. I think the protocol in the UK has changed now - they seem to work so they tend to offer them rather than wait for a relapse. I haven't had one since dx but now am probably SP.

Interesting about the val & D3 combo here. What were the issues reported Scott1?

I am taking D3 daily and 2 acyclovir of 400g each. I only introduced the daily D3 about 9 months ago but before then I took it intermittently.

[jimmylegs]

yeah i think she'd like it better if i were more enthused about the meds, but for now i am not, and she's okay with it. i'm hopeful that with some more physical activity i can improve stamina that i seem to have lost since getting really sick this time last year. ramping up the fitness schedule starting later this month

[Jaded]

Good luck with that jimmylegs!

[jimmylegs]

thx!

[jimmylegs]

• Benefit-risk assessment of cladribine using multi-criteria decision analysis (MCDA) for patients with relapsing-remitting multiple sclerosis (2019)
  http://eprints.lse.ac.uk/91544/
  
  Purpose: To apply Multi-Criteria Decision Analysis (MCDA) methods in a structured benefit risk assessment of cladribine and newer approved disease modifying drugs (DMDs) for patients with relapsing-remitting multiple sclerosis (RRMS).
  
  Methods: Decision conferencing with clinical neurologists as decision makers was used to create an MCDA model incorporating available evidence on DMDs for RRMS and clinical judgements about the relevance of the evidence. Benefit-risk assessments were conducted for DMDs in both patients with RRMS and those RRMS patients with high disease activity (HDA; defined as ≥ 2 relapses in the previous year). Treatment options included cladribine and recently approved DMDs available in European Union countries at the time of assessment (December 2015): alemtuzumab, dimethyl fumarate, fingolimod, natalizumab, and teriflunomide. To account for the relative importance of DMD effects, scores for the MCDA model were weighted to ensure that the most clinically important attributes carried more weight in the final benefit-risk calculation. The neurologists weighted different efficacy and safety attributes without any reference to individual DMDs to disassociate the assessment of weights with any specific DMD. The neurologists did not do direct comparisons between DMDs.
  
  Findings: The highest overall weighted preference value for the RRMS model was for dimethyl fumarate (63) followed closely by cladribine (62). For patients with RRMS and HDA, cladribine had the highest overall weighted preference value (76) followed by alemtuzumab (62) and natalizumab (61). The benefit-risk balance of cladribine in patients with RRMS and specifically those with RRMS exhibiting HDA characterised by high relapse activity (≥2 relapses in the previous year) was more favourable than the other DMDs included in the model.
  
  Implications: The balance of high efficacy and the safety profile makes cladribine an important treatment option to consider, both in patients with RRMS and those with HDA. Regular, single-country meetings could be organised to explore how differences in cultural values (scores and weights) and updated input data, might affect the usefulness of MCDA in different, real-world, dynamic clinical settings.

still far from convinced, but paying attention...

[jimmylegs]

• Effect of Cladribine Tablets on Lymphocyte Reduction and Repopulation Dynamics in Patients with Relapsing Multiple Sclerosis (2019)
  fft: https://www.sciencedirect.com/science/a ... 4819300392
  
  Highlights
  •Long-term lymphocyte counts were evaluated (CLARITY, CLARITY Extension & PREMIERE)
  •Absolute lymphocyte counts were evaluated to 312 weeks, B and T cells to 240 weeks
  •The results suggest that cladribine tablets may be an immune reconstitution therapy
  
  Abstract
  Background
  : Immune reconstitution therapies (IRT) for patients with multiple sclerosis are used for short, intermittent treatment periods to induce immune resetting and allow subsequent treatment-free periods. Cladribine tablets are postulated to be an IRT that causes selective and transient reductions in CD19+ B cells and T cells, followed by reconstitution of adaptive immune function.
  
  Objective
  : To characterize long-term lymphocyte count changes in pooled data from the 2-year CLARITY and subsequent 2-year CLARITY Extension studies, and the PREMIERE registry (Long-term CLARITY cohort).
  
  Methods
  : Data from patients randomized to placebo (n = 435) or cladribine tablets 10 mg (MAVENCLAD®; 3.5 mg/kg cumulative dose over 2 years, referred to as cladribine tablets 3.5 mg/kg; n = 685) in CLARITY or CLARITY Extension, including time spent in the PREMIERE registry were pooled to provide long-term follow-up data. The study investigated absolute lymphocyte counts (ALC) up to 312 weeks and B and T cell subsets up to 240 weeks after the first dose, in patients receiving placebo or cladribine tablets 3.5 mg/kg administered as two short (4 or 5 days) weekly treatments at the start of months 1 and 2 in each treatment year, followed by no further active treatment.
  
  Results
  : Treatment with cladribine tablets 3.5 mg/kg resulted in selective reductions in B and T lymphocytes. Lymphocyte recovery began soon after treatment in each of years 1 and 2. Median ALC recovered to the normal range and CD19+ B cells recovered to threshold values by week 84, approximately 30 weeks after the last dose of cladribine tablets in year 2. Median CD4+ T cell counts recovered to threshold values by week 96 (approximately 43 weeks after the last dose of cladribine tablets in year 2). Median CD8+ cell counts never dropped below the threshold value.
  
  Conclusion
  : These results show the dynamics of lymphocyte count changes following treatment with cladribine tablets 3.5 mg/kg. The immune cell repopulation results provide further evidence that cladribine tablets may represent a form of IRT.

[jimmylegs]

Cladribine: mechanisms and mysteries in multiple sclerosis (2018)
https://www.ncbi.nlm.nih.gov/pubmed/29991490

"Conclusions
Cladribine is a safe and effective form of induction therapy for relapsing MS. Its mechanism of benefit is not fully understood but the most striking action is selective, long-lasting, depletion of B lymphocytes with a particular predilection for memory B cells. The in vivo relevance of its other immunomodulatory actions is unknown. The hypothesis that cladribine’s action of benefit is to deplete memory B cells is important: if correct, it implies that selective targeting of this cell population and sparing of other lymphocytes could modify disease activity without predisposing to immunosuppression-related complications.
...
It is largely excreted unchanged in the urine..." (oh great...)

this is the sort of content i would like to understand better (once i have time to get into it):

"...
Cellular mechanisms
Cladribine is actively transported into cells via specific transmembrane nucleoside transporters and extruded by ATP-binding cassette C4 exclusion pump.34 35 Whereas deoxyadenosine is vulnerable to ADA-mediated conversion to deoxyinosine, cladribine is resistant (but not insensitive) to the action of ADA due to the substitution of a chlorine atom for a hydrogen at position 2 of the purine ring.36 The initial phosphorylation of cladribine to cladribine-monophosphate is catalysed predominantly by deoxycytidine kinase (DCK), although there is some contribution from mitochondrial deoxyguanosine kinase.34 35 The action of DCK is opposed by the phosphorylase activity of cytosolic 5’-nucleotidases (5-NT). The cytosolic 5-nucleotidase isozymes c-NT1A and c-NT1B are the predominant enzymes involved in cladribine metabolism given their specificity for adenosine metabolites.37 38 DCK catalyses the rate-limiting step in the nucleotide salvage pathway, which is involved in replenishing the deoxynucleoside-triphosphate (dNTP) pool for DNA synthesis. The relative levels of enzymatic activity of DCK and 5-NT appear to determine the sensitivity (or resistance) of the cell to cladribine toxicity: a high DCK:5-NT ratio renders the cell more susceptible to cladribine toxicity in cell lines and in patient-derived peripheral blood lymphocytes.38–46 Sequential phosphorylation of cladribine by DCK, AMP kinase and nucleoside diphosphate kinase generates cladribine-triphosphate (CdA-TP), the active form that mediates cellular cytotoxicity (figure 1)."

[1eye]

Hey I just got an email ad for Mavenclad (cladribine) and its apparently approved, but my doctor friend says never take a new treatment in the first 25 years. Give them time to debug.

That said, my back and leg pain appears to be receding on its own.

I like when that happens. But it's a new symptom with leg spasms. Maybe a back injury complicated by existing MS damage. Really bad when I try to stretch first thing when I wake up.

Still waiting to hear about the Las Vegas trial.

The way I see it, whatever works will not undo done damage, but when the damage stops being done over and over, you may have enough telomeres left to get some function back.

I am still on 300 mg/day biotin + 300 mg/day rice bran filler.

What I like is that I can still grow new muscle, at 65. I have been getting better at climbing stairs (two handrails) since growing season is here and I have to water my seedlings downstairs.

I'm still learning new stuff on the piano, still riding my electric recumbent tricycle. Trying to finish a book about my grandfather in Okinawa in 1945.

Who knows where it will all lead?

[NHE]

Hey I just got an email ad for Mavenclad (cladribine) and its apparently approved, but my doctor friend says never take a new treatment in the first 25 years. Give them time to debug.

Well, the prescribing information has a black box warning about an increased risk of cancer. Caution seems to be the rational approach.

https://www.emdserono.com/content/dam/w ... lad-pi.pdf