How does cladribine work? Clad-COVID…More Good News for ChariotMS, but it’s not all good.

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So more good news for ChariotMS. News has started to surface that you get COVID-19 responses in vaccinated individuals and if you do catch COVID-19, you do not seem to be worse than the general population. This is the message from the latest update from Merck. This is good news for ProfK, who is hoping to start recruitment for ChariotMS in June (yes, this year 2021!). However, I must say the risks for more severe COVID-19 are issues relating to disability. As people volunteering for ChariotMS are going to be more disabled, they will have to have at least their first jabs before being enrolled. Indeed this was also ProfK’s and Joela’s cunning plan, which helped getting BartsMS Vaccine delivery off the ground as early as January.

It is good that companies are keeping us informed.

Jack D, Damian D, Nolting A, Galazka A. COVID-19 in patients with multiple sclerosis treated with cladribine tablets: An update. Mult Scler Relat Disord. 2021 Mar 27;51:102929. doi: 10.1016/j.msard.2021.102929. Epub ahead of print. PMID: 33813097.

Background: We previously summarized outcomes for 46 cladribine tablets (CladT)-treated patients with multiple sclerosis (MS) and confirmed or suspected COVID-19, as reported to the Merck KGaA Global Patient Safety Database. This report updates on these findings, to 15 January 2021, for a total of 272 reported cases of COVID-19 among CladT recipients.

Methods: Case definitions: confirmed (COVID-19 diagnostic test was positive); suspected (no confirmatory test performed/reported). Cases fulfilling the criteria of hospitalized, medically significant, or fatal were designated as serious and outcomes were classified per usual pharmacovigilance practice.

Results: The evaluable cohort comprised 261 patients (confirmed COVID-19, n=160; suspected, n=101); an additional 11 patients had symptoms compatible with COVID-19 but were not evaluated further given their negative diagnostic tests. Median time to onset of COVID-19 from the most recent preceding CladT treatment course was 162 days (>5months) (n=139). Outcomes were: recovered/recovering, n=133 (51%); not recovered/not resolved, n=19 (7%); died, n=1 (0.4%); and not reported/missing/pending, n=108 (41%). Of the total cohort, 40 (15%) experienced serious COVID-19.

Conclusion: Our results suggest that CladT-treated patients with MS are generally not at greater risk of serious disease and/or a severe outcome with COVID-19 compared with the general population and other patients with MS who acquired COVID-19.

However it is not all good news

Which of the Three Monkeys are we?

There appears to be some skin issues (See below). I ask if the skin issues are so common, how were they missed in the CLARITY and ORACLE trials? In this study from Germany there are skin reactions in nearly half of the subjects (77/239), but in CLARITY they did not make the top 5% adverse events. OK some of them were associated to infections. I would have thought it was hard to miss a big red blotch and would be seen by the nurse, neuro or you. So was ProfG two of the three monkeys (see no evil, speak no evil).

The Three Monkeys of Deceiving Yourself | Disability in Business
Is this the CLARITY team?

However, in the subcutaneous cladribine skin issues have been seen before and were present in 18/35 (51%) of people during cancer treatment [Ganzel C, Gatt ME, Maly A, Ben-Yehuda D, Goldschmidt N. High incidence of skin rash in patients with hairy cell leukemia treated with cladribine. Leuk Lymphoma. 2012;53:1169 and remember we have reported skin reactions (click here), so maybe ProfK had his paw only over one eye.

As ProfG says, skin reactions are in the label but they were not that frequent. What is your experience?

Skin Reactions in Patients With Multiple Sclerosis Receiving Cladribine Treatment.Rolfes L, Pfeuffer S, Hackert J, Pawlitzki M, Ruck T, Sondermann W, Korsen M, Wiendl H, Meuth SG, Kleinschnitz C, Pul R.Neurol Neuroimmunol Neuroinflamm. 2021 Apr 9;8(3):e990.Objective: To report 77 patients with multiple sclerosis (MS) who developed skin-related adverse events (AEs) following treatment with cladribine.Methods: We evaluated our prospective bicentric cladribine cohort. Cladribine-treated patients with a skin AE were identified.Results: Two hundred thirty-nine cladribine-treated patients with MS were evaluated. Seventy-seven patients (32%) showed at least 1 skin AE at median 1 month after cladribine initiation (range: 1-12). Within first 3 months following last cladribine exposition, hair thinning (n = 28, 12%), skin rash (n = 20; 8%), mucositis (n = 13, 5%), and pruritus (n = 6, 3%) were observed. Furthermore, 35 patients (15%) developed herpes virus infections (time since last cladribine exposition: median 83 [range: 10-305]). In 15 patients, herpes zoster infection was severe (CTCAE grade ≥ 3) and required hospitalization. Delayed skin AEs (≥3 months after a cladribine treatment cycle) involved 1 case of leukocytoclastic vasculitis and 2 cases of alopecia areata. Finally, 2 patients presented with in total 3 isolated precancerous lesions (1 leukoplakia simplex and 2 actinic keratosis) and 1 patient developed a squamous cell carcinoma.Conclusion: Skin AEs are common in patients with MS treated with cladribine. Until risk management plans have been adjusted to include these phenomena, clinicians should perform a thorough clinical follow-up and in suspicious cases seek early interdisciplinary support. In light of the observed delayed skin reactions, we further emphasize the necessity of careful clinical surveillance of cladribine-treated patients for yet undescribed secondary autoimmune events.

How does Cladribne work?

Carlini F, Ivaldi F, Gualandi F, Boschert U, Centonze D, Matarese G, Salvetti M, Kerlero de Rosbo N, Uccelli A. Different Susceptibility of T and B Cells to Cladribine Depends On Their Levels of Deoxycytidine Kinase Activity Linked to Activation Status. J Neuroimmune Pharmacol. 2021. doi: 10.1007/s11481-021-09994-3. 

Deoxycytidine kinase (dCK) and 5’ deoxynucleotidase (NT5C2) are involved in metabolism of cladribine (2CdA), the
immunomodulatory drug for multiple sclerosis; by mediating phosphorylation (activation) or phosphorolysis (deactivation) of 2CdA, respectively, these enzymes promote or prevent its accumulation in the cell, which leads to cell death. In particular, lymphocytes which present with a high intracellular dCK/NT5C2 ratio are more sensitive to 2CdA than other immune cells. We aim at determining if the expression of these enzymes and/or their activity difer in specifc progenitor and mature immune cells and are infuenced by cellular activation and/or exposure to 2CdA. Flow cytometry analysis showed no diference in dCK/NT5C2 ratio in progenitor and mature immune cells. 2CdA induced apoptosis in stimulated T and B cells and unstimulated B cells. dCK expression was enhanced by 2CdA at mRNA and protein levels in activated T cells and mRNA level in activated B cells. dCK activity, measured through an in-house luminescence release enzyme assay was higher inactivated T and B cells, and such an increase was abrogated in activated B cells, but not T cells, upon exposure to 2CdAThese results reveal an important relationship between dCK activity and the effect of 2CdA on B and T cells, according to their activation status. Further study is warranted to evaluate whether dCK activity could, in the future, be a suitable predictive biomarker of lymphocyte response to 2CdA.

The authours examine the expression of the cladribine killing protein called deoxycytidine kinase and a 5 prime nucleotidase NT5C2 (figure 3) that may block this mechanisms, They didn’t find any difference in the ratio of DCK/NTC5C2 between cell types. This would suggest they should all be equally killed by cladribine. However, they are not (see below and Ceronie et al. 2018). Therefore there is probably something not quite right and there is more to know. It seems T cells are less sensitive to cladribine than B cells (see below). I guess one question is about NTC2 and how good is it at protecting against cladribine killing.

Figure 3

There is a review that says cladribine is affected by NT5C2, but there is no data presented. Jordheim et al. Biochem Pharmacol. 2013;85:497 reports that the killing by cladribine was not really affected by NT5C2 inhibitors, but in another experimental set up, cell suicide was affected. The influence may be limited relative to the level of expression. Therefore, whilst there is no question that NT5C2 may have an effect, how important is NT5C2 for dephosphorylating (removing a phosphate group and deactivating cladribine) deoxyadenosines-related compounds (cladribine). Its more designed to dephosphorylate inosines and thioinosines. It is much, much less active on adenosines (Evidence for a Cross-Talk Between Cytosolic 5′-Nucleotidases and AMP-Activated Protein Kinase. Camici M, Garcia-Gil M, Allegrini S, Pesi R, Tozzi MG.Front Pharmacol. 2020;11:609849. Therefore a simple ratio may not give the exact answer.

Stimulated T cells seem to die abit quicker and interestingly stimulation increased DCK (Carlini et al. 2021). That does not surprise me as dividing cells are more sensitive to many drugs. I feel this is one of the reasons, why anti-cancer drugs are good at killing B cells, because they have a naturally faster turnover rate than T cells.

Now…in the discussion it says we (Team ProfK) reported “B cells exhibit high levels of DCK mRNA, whereas immature B cells have lower levels (Ceronie et al. 2018). Accordingly, the authors suggested that the marked depletion of memory B cells eight months after 2CdA treatment could be explained by their high levels of the enzyme, whereas their lower levels of DCK would render immature B cells less sensitive to the drug (Ceronie et al. 2018). However, associating 2CdA sensitivity to a higher DCK mRNA expression in mature B cells compared to other B-cell subsets or other lymphoid cell subsets might only be part of a more complex picture”

However Ceronie et al. 2018 actually showed no difference in expression of DCK (Figure 3B & D). We actually said” The relatively high B cell expression levels of DCK, coupled with low levels of NT5C1 and ADA, compared to T cells, and neutrophils, and the higher turnover of B cells may create the B cell-selective depleting effect of cladribine seen in vivo. This effect coupled with the slow kinetics of memory B cell repopulation, may explain why memory B populations are vulnerable to cladribine”……..In contrast to immature and mature cells, peripheral blood memory B cells repopulate very slowly from the lymphoid organ pool mostly via germinal centre activity. The germinal centres may be particularly vulnerable to inhibition by cladribine due to the high level of proliferation and DCK expression, leading to selective long-term loss of peripheral blood memory B cells” However, this is not big shakes because we agree with the summary of this paper.

The authors make the point that the functional activity of the enzyme may be important and this is probably relevant and is something we will need to bring into our picture.

Likewise, and interestingly in this context, “it has been suggested on the basis of DCK mRNA expression data from microarray databases (Ceronie et al. 2018) that B cells are more susceptible to 2CdA than the other lymphoid cells. However, no difference in DCK expression was observed in our study between B cells and the other immune cell subsets analysed”. In support of this claim the differences in mRNA between T and B cells in the http://www.proteinatlas.org were not big, but what is highly consistent it that memory B cells are low and remain low after cladribine administration. This is clear based on data from the AAN.

There are low levels of memory B cells after cladribine.

At last the makers of cladribine are repeating our data from 3 years ago with subcutaneous cladribine using Cladribine tablets and it fits with the story in: Potential mechanisms of action related to the efficacy and safety of cladribine. Baker D, Pryce G, Herrod SS, Schmierer K. Mult Scler Relat Disord. 2019;30:176-186.

It actually makes it all re-assuringly simple and easy to understand…however, I have to say when seeing the take home message at the AAN, I still feel there remains a significant lack of clarity. This is ironic given the name of the pivotal phase III trial… Maybe it should have been called CLOUDY:-). I have been told that some neuros struggle to understand how cladribine works… This is not surprising when they are being told Th17 cells are all important, but with a measley depletion of 35%. How is this going to explain the effects of cladribine? Focus on >90% depletion of memory B cells (as found after alemtuzumab and ocrelizumab), ignore the Th17 and it is easy. Cells in the disease causing population are depleted long-term and when they return they come back into a regulated immune environment. Start with this view and then see what’s wrong and it’s probably easy to understand.

I guess pharma just has to give you every thing but the kitchen sink in case you say they are biased. Maybe they could not ‘not’ talk about T cells…….but then you think the kitchen sink causes MS:-).

Kitchen Cartoon
Can you see the problem of MS….If you are given everything without any context you just see the Kitchen Sink

004 – Characterization of Peripheral Immune Cell Dynamics and Repopulation Patterns in the First 12 Months of Cladribine Tablets (CT) Treatment: MAGNIFY-MS Study Heinz Wiendl, 

Background: The action of CT on immune cells may be key for both onset and durability of its effect in people with multiple sclerosis (MS).

Objective:To report on peripheral immune cell subset dynamics and immunoglobulin levels in the first 12 months of cladribine tablets (CT) therapy.

Design Methods: Longitudinal evaluation of peripheral blood immune cells in patients receiving CT in a sub-study of MAGNIFY-MS (NCT03364036). Absolute cell counts and %change from baseline were assessed for adaptive immune cell subtypes and immunoglobulins. Immunophenotyping was completed at baseline and months 1,2,3,6,12.

Results: Full analysis set: 57 patients (median age 37 years; 61% female; ≥2 relapses in previous year, 70%). Effector and regulatory B cells were reduced from month 1 and showed a subtype-specific repopulation pattern. Change from baseline for CD19+ B cells: month 1,-77%; month 2,-90%; month 12,-35%. Memory B cells: month 1,-74%; month 3,-93%; month 12,-87%. Plasmablasts: month 1,-28%; month 3,-78%; month 12,-51%. Regulatory B cells (CD19+, CD24bright, and CD38bright): month 1,-45%; month 3,+176%; month 6,+171%; month 12,+50%. Naïve/transitional B cells: month 1,-79%/-61%; month 3,-69%/+35%; month 12,+35%/+23%. Decrease in T cell subsets was moderate and slower, nadir occurring between 3 and 6 months. T-helper 17 CD4+ and terminally differentiated effector memory CD8+ T cell counts reached nadir at month 3 (-35% and -25%, respectively). No clinically meaningful change in serum IgG or IgM was observed over 12 months.

Conclusions: Assessment of lymphocyte dynamics following CT over 1 year demonstrates that effects occur from month 1, and are sustained in several immune cell subpopulations. CT exerts a pronounced effect on memory B cells, while immunoglobulin levels are unaffected over 12 months. Results suggest early onset of CT action, underpinned by MAGNIFY-MS MRI results, may be mediated through this specific pattern of sustained decrease and reconstitution of B and T cell subtypes in a highly active MS population.

What’s the specific pattern? Why do you have to worry about T cells? If you think about B cells, cladribine it is just as good as ocrelizumab and seemingly less problematic than alemtuzumab. So ask is ocrelizumab an immune reconstitution therapy like cladribine? Without a trial we will never know. A company is not going to do this study….any time soon I suspect.

CoI Multiple. ProfK is the Chief Investigator of ChariotMS and a member of the MAGNIFY Trial Steering Committee. PRofG was lead on the CLARITY trial.

Disclaimer: Please note that the opinions expressed here are those of the author and do not reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust or Queen Mary Univeristy of London.

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MouseDoctor

6 comments

  • Thank you, MD! You are the best!

    Give me about a month to process and understand the majority of the information in the studies referenced above 🧐

    Start course 1 on May 1…..A little hopeful and a bit scared about AE, given my history with other DMTs. I am still not right since becoming allergic to Ocr, and my bone density and body hair just started to grow back after recently eliminating Teri.

    I tried to get a detailed baseline of my memory B and T cells; however, I was told those types of tests are only performed in a research/study setting. At least I asked.

    Best I can get is…..T Helper (CD3+CD4+), T Cytotoxic (CD3+CD8+), B Lymphocytes (CD19+CD3-), NK Cells (CD3-/CD16+CD56+), and Total T Cells (CD3+). Pretty sure none of those are memory cells?

    Would be nice if I could find out why Ocr failed and then Teri failed? And why both gave me bad AE. Guess I will never know!?! My neuro and I are hopeful the next DMT will slow this s@$t down.

    • Yes they are not memory B cells the classic is CD19+, CD27+ (with ot without IgD). CD27 is a T and B marker.

  • Given the different Covid vaccine responses with Ocrelizumab and Cladribine, both of which have similar activity as MS treatments. Is it possible to use the Covid vaccination antibody results, MS results, coupled with flow cytometry results to more specifically identify what B cells are likely to be implicated in MS? Not really sure, but there seems to be 2 drugs that target B-cells, one of which pretty much eliminates vaccine response and the other that doesn’t, seems to me that this should allow the B cell subset to be narrowed down, to focus on the B involved in MS.

    • I suspect that we will see some cladribine vaccine poor responders if there are no immature/mature B cells. However the important elements are with the IRTs the drug is gone but with continuous drug that can target any responding cells

  • I have now completed the two years of Mavenclad and I have noticed that my skin is now very sensitive to sun exposure. I get burnt after a short time outside in weak sunshine, noticeably worse than I was before taking Mavenclad. I was belittled by my neurologist when I mentioned this, but I did point out that this is mentioned in cladribine patient information for the treatment of leukaemia. I am having to wear high factor sun screen even when the weather is not noticeably sunny! Do these types of skin reactions improve? I am six months after taking the final dose. I also suffered severe fatigue when taking this and it barely gets a mention on the Mavenclad patient information sheet. I am wondering why there are so many differences in the side-effect profiles of cladribine to treat leukaemia and cladribine in tablet form used for MS treatment?

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