#ECTRIMS2021: Cladribine and COVID-19

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How safe is cladribine during COVID-19?

I have been saying that based on its mode of action cladribine works as a semi-selective B-cell depleting agent similar to an anti-CD20 or anti-CD19 therapy. However, cladribine has an advantage as it is used as an IRT (immune reconstitution therapy) so is not associated with continuous immunosuppression. Cladribine is also CNS penetrant and hence targets CNS resident B-cells.

Another advantage of cladribine is that as it kills B-cells in the periphery new migrant naive cells are emerging from the bone marrow. Hence peripheral B-cell counts don’t drop to zero, which explains why pwMS treated with cladribine are vaccine ready and make good antibody and T-cell responses to the COVID-19 vaccines. Importantly, the latter seems to be independent of where in the cladribine treatment cycle vaccinations occur and appears to be independent of peripheral lymphocyte counts. 

The following is the safety data I presented and ECTRIMS in relation to pwMS treated with cladribine who had COVID-19. Importantly, out of 503 cladribine-treated pwMS, there were only 3 fatalities (0.6%). This is an order of magnitude lower than that recently reported with ocrelizumab (Hughes et al. Mult Scler Relat Disord. 2021 Apr;49:102725.).

The list of other adverse events is self-explanatory. 

Overall of the high-efficacy B-cell depleting DMTs, cladribine is emerging as the one DMT that seems to be the best tolerated with a low risk of severe COVID-19 and at the same time allowing to receive COVID-19 vaccinations with confidence. The fundamental difference is that cladribine is an IRT and many HCPs and pwMS don’t feel comfortable with the fact that after an IRT you have to play a wait-and-see game, i.e. no treatment until MS disease activity returns. If you are one of these people you need to ask yourself if you are not prepared to have an IRT could you please ask yourself how are we the MS community going to ever find a cure for MS? 

20210908-ECTRIMS-2021-Safety-Update_Typeset-ePoster_v08-2

Please note that I am the principal investigator on the oral cladribine phase 3 programme and have been involved with its development since 2002. I am therefore heavily conflicted so you may want to interpret anything I say that is positive about cladribine with caution. 

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice. 

#ECTRIMS2021: how long does cladribine work?

Barts-MS rose-tinted-odometer: ★★★★★★★ 
A 7-Star Bright Yellow Saturday #FFFF00

How good is cladribine as an immune reconstitution therapy? 

The CLASSIC-MS study was our attempt to get back all the pwMS who had participated in the original phase 3 programme, from 15 years ago. The following poster is from my late-breaking poster at ECTRIMS and describes what has happened to the subjects from the CLARITY and CLARITY extension study and does not include subjects with clinically isolated syndrome from the ORACLE study. 

As you can see the subgroup of subjects from CLASSIC-MS is similar to the overall population of subjects in the original trial. Therefore we think these results are representative of the overall population.

The median time to follow-up in the CLASSIC-MS study was 10.9 years (range 9.3, 14.9). 

The remarkable observation is how few study subjects progressed (to be presented later in more detail) with less than 1 in 5 needing a walking aid to manage 100m. 

56% of cladribine treated subjects did not require a follow-on DMT compared to only 27% of subjects that were not treated with cladribine. These results indicate that the duration of action of cladribine may be much longer than we realise and is beginning to mirror what we see in clinical practice with this particular agent. 

Given this data and the other attributes of cladribine, it is going to be a serious contender for the go-to DMT at the bottom of the therapeutic pyramid on which to build an induction-maintenance strategy and combination therapies. 

Oral cladribine has several favourable attributes for managing MS, particularly during the COVID-19 pandemic:

  1. High-efficacy DMT allowing flipping of the pyramid
  2. Good COVID-19 outcomes 
  3. Oral therapy, therefore reduced hospital contacts
  4. No cell lysis syndrome or infusion-type reactions
  5. No pre-dosing with steroids
  6. Innate immunity intact
  7. Only moderate reduction in T-cell counts
  8. Less impact on CD8+ compared to CD4+ T-cells
  9. Antiviral immunity relatively intact
  10. Vaccine immunity intact
  11. Low monitoring requirements
  12. Small risk of lymphocyte count being less than 500/mm3
  13. CNS penetration targeting CNS resident B and T cells
  14. Post-dosing immune reconstitution
  15. Good seroconversion post-COVID-19 vaccination
  16. Cost-effective; providing value to the NHS

Giovannoni et al. Long-term efficacy for patients receiving cladribine tablets in CLARITY/CLARITY extension: Primary results from 9–15 years of follow-up in the CLASSIC-MS study. ECTRIMS 2021, P975.

Introduction: CLASSIC-MS (NCT03961204) was an exploratory, ambispective Phase IV study designed to evaluate the long-term efficacy of cladribine tablets (CladT) in the real-world setting, for patients with relapsing multiple sclerosis (RMS) who were previously enrolled to Phase III (parent) trials.Objectives: To report primary results for CLASSIC-MS in terms of long-term mobility and disability beyond the treatment courses that patients received in the parent trials, with the aim of informing future treatment approaches.

Methods: This analysis represents patients in CLASSIC-MS who participated in the Phase III CLARITY trial whether or not they participated in CLARITY Extension, and who had received ≥1 course of CladT or placebo. The primary objective of CLASSIC-MS was the evaluation of long-term mobility (no wheelchair use/bedridden; i.e. EDSS <7 in the 3 months prior to first visit in CLASSIC-MS). The main secondary objective was long-term disability status (no requirement for an ambulatory device; i.e. EDSS <6 any time since last parent study dose [LPSD]). Analyses are descriptive and shown in relation to exposed/never exposed to CladT in CLARITY.

Results: The CLASSIC-MS population who previously participated in CLARITY/CLARITY Extension comprised 435 patients with RMS (67.8% female; mean±SD EDSS score, 3.87±2.07 at CLASSIC-MS baseline), with a median time since LPSD of 10.9 (range 9.3–14.9) years and a median disease duration of 20.7 (range 13.9–46.5) years at CLASSIC-MS baseline. A total of 90.6% (n=394) were exposed to CladT during CLARITY/CLARITY Extension, including 160 patients who received the approved cumulative dose of 3.5 mg/kg over 2 years; the remaining 9.4% (n=41) were never exposed. The proportion of patients not using a wheelchair/bedridden in the 3 months prior to CLASSIC-MS (i.e. EDSS <7) was 90.0% of the CladT exposed cohort and 77.8% of the never exposed cohort. Regarding long-term disability status, the proportion of patients with no requirement for an ambulatory device (i.e. EDSS <6) was 81.2% of the CladT exposed and 75.6% of the never exposed cohorts, respectively.

Conclusions: Baseline patient characteristics suggest that patients enrolled in CLASSIC-MS were a representative sample of all patients included in the original parent studies. Reported findings for CLASSIC-MS, with a median of 10.9 years’ follow-up after CLARITY/CLARITY Extension, suggests sustained efficacy of CladT in terms of long-term mobility and disability status.

20210922-ECTRIMS-2021-CLASSIC-MS_Typeset-ePoster_v06

Disclaimer: Please note that I am the PI on the oral cladribine programme including the CLASSIC-MS study and have been involved with the development of oral cladribine as a DMT for MS since 2002. I was a member of the original advisory panel that Serono put in place when they decided to in-license the oral formulation for development. Therefore you need to interpret what I say about cladribine and oral cladribine very carefully. In short, I am likely to be very biased. 

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MS-Selfie Newsletter  /  MS-Selfie Microsite

Preventive Neurology

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice.

Early cladribine treatment prevents MS

Barts-MS rose-tinted-odometer: ★★★★★★ (6-star bull’s blood red #8a0303)

Yesterday’s post on using cladribine to prevent CIS from converting to MS and whether this is MS prevention or an MS cure generated a robust debate. Good, this was the purpose of the post; i.e. to get you thinking. 

As you are aware that as the diagnostic criteria for MS evolve many people diagnosed with CIS in the past actually have MS when the new diagnostic criteria are applied retrospectively. This then allows you to see how well cladribine works in preventing conversion to MS in the small subgroup of subjects who have ‘CIS’ and not MS when they were treated with cladribine. 

The subjects who were still CIS after applying the newer McDonald diagnostic criteria showed that cladribine’s treatment effect improved with a reduction in risk of conversion to clinically definite MS by 63% on low-dose cladribine and by 75% on high-dose cladribine compared to placebo. I am not sure the MS community has clocked how effective cladribine really is when used early. 

This post-hoc analysis also suggests that people with CIS treated with lower doses of cladribine actually do better than those on higher doses. The dose-effect is pretty clear when you look at the time to next attack or three-month confirmed disability worsening. Have we optimised the dose of cladribine? When you are trying to prevent/cure MS maybe not!

Any predictions? I predict that a proportion of patients with CIS treated early with cladribine may never go on to have a second attack or disability progression and hence are prevented from developing MS or cured of their MS, depending on how you define MS. Anyone taking bets? 

Freedman et al. The efficacy of cladribine tablets in CIS patients retrospectively assigned the diagnosis of MS using modern criteria: Results from the ORACLE-MS study. Mult Scler J Exp Transl Clin. 2017 Oct 9;3(4):2055217317732802.

Background: Multiple sclerosis (MS) diagnostic criteria have changed since the ORACLE-MS study was conducted; 223 of 616 patients (36.2%) would have met the diagnosis of MS vs clinically isolated syndrome (CIS) using the newer criteria.

Objective: The objective of this paper is to assess the effect of cladribine tablets in patients with a first clinical demyelinating attack fulfilling newer criteria (McDonald 2010) for MS vs CIS.

Methods: A post hoc analysis for subgroups of patients retrospectively classified as fulfilling or not fulfilling newer criteria at the first clinical demyelinating attack was conducted.

Results: Cladribine tablets 3.5 mg/kg (n = 68) reduced the risk of next attack or three-month confirmed Expanded Disability Status Scale (EDSS) worsening by 74% vs placebo (n = 72); p = 0.0009 in patients meeting newer criteria for MS at baseline. Cladribine tablets 5.25 mg/kg (n = 83) reduced the risk of next attack or three-month confirmed EDSS worsening by 37%, but nominal significance was not reached (p = 0.14). In patients who were still CIS after applying newer criteria, cladribine tablets 3.5 mg/kg (n = 138) reduced the risk of conversion to clinically definite multiple sclerosis (CDMS) by 63% vs placebo (n = 134); p = 0.0003. Cladribine tablets 5.25 mg/kg (n = 121) reduced the risk of conversion by 75% vs placebo (n = 134); p < 0.0001.

Conclusions: Regardless of the criteria used to define CIS or MS, 3.5 mg/kg cladribine tablets are effective in patients with a first clinical demyelinating attack. ClinicalTrials.gov registration: The ORACLE-MS study (NCT00725985).

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice. 

Prevention vs. cure

Barts-MS rose-tinted-odometer: ★★★★★ (a bright blue buzz – #0096FF)

I was at a mid-summer party last night when someone suggested that I should not waste my time trying to answer peripheral or trivial questions in relation to MS and focus on the really big questions. 

This got me thinking about which are the biggest MS questions in MS that I can try to tackle and answer. Apart from (1) MS prevention, i.e. does preventing primary EBV infection with a sterilizing EBV vaccine prevent MS, the next major question must relate to (2) curing MS

The BIG-C issue is one I have been exploring on this blog for several years but is hampered by defining what an MS cure looks like and then looking for it. The problem with the latter is the issue of smouldering MS, which clouds the definition of a cure. Even if you cure someone from the biological drivers of MS, if they have relatively advanced MS they may still get worse from downstream smouldering processes that become independent of the initial MS attack(s). So the only solution is to test the hypothesis of an MS cure is very early in the disease, i.e. at the RIS (radiologically-isolated syndrome) or CIS (clinically-isolated syndrome) stage. 

To cure MS what treatment strategy do you need to use?  I have made the point that we can only cure MS with an IRT (immune reconstitution therapy) and at present we only have three IRTs that are used routinely in MS., i.e. cladribine, alemtuzumab and AHSCT. It is clear that cladribine is the safest IRT and has the added advantage as being the most CNS penetrant, which I think is important. Cladribine levels in the spinal fluid of treated patients are high enough to have an effect on CNS resident T and B-cells. Cladribine is also the safest and easiest IRT to use and therefore the most likely to get widely adopted. I am convinced  that a proportion of pwMS treated early, within 12 to 24 months of MS diagnosis, with either alemtuzumab and AHSCT are cured. Despite the stunning results of this treatment approach the adoption of both alemtuzumab and AHSCT as a mainstream treatment for MS has been abysmal. I suspect cladribine as an early effective treatment would have a greater chance of being adopted. My conclusion then is that the IRT has to be cladribine and it has to be done evry early at the CIS or RIS stage. 

But this experiment has already been done. The ORACLE study below was of oral cladribine in CIS. So what has happened to these patients? We don’t know, which is why Merck is doing the CLASSIC MS study to try and find out what has happened to these patients with CIS. Wouldn’t it be brilliant if a significant proportion of the cladribine exposed patients have not developed MS compared to those in the placebo group? Would this be sufficient to convince the wider MS community that very early cladribine treatment cures a proportion of people with CIS, i.e. prevents them from developing MS?  I suspect not. This is why a new global RIS-CIS study will need to be done. 

Please note some people would argue that stopping people with CIS from getting MS is MS prevention, whereas others would argue, including me, that CIS is already MS and hence preventing CIS from becoming MS is an MS cure. This is not just semantics but challenges disease definitions and is an important philosophical debate. This is why I want to study medical philosophy to tackle some of these issues.


Kaplan–Meier estimates of time to conversion to CDMS and McDonald MS in the intention-to-treat population during the double-blind period. Cumulative percentage probability of conversion to (A) CDMS according to the Poser criteria and (B) MS according to the 2005 McDonald criteria. CDMS=clinically definite multiple sclerosis. MS=multiple sclerosis. Figure from Lancet Neurol 2014.

Leist  et al. Effect of oral cladribine on time to conversion to clinically definite multiple sclerosis in patients with a first demyelinating event (ORACLE MS): a phase 3 randomised trial. Lancet Neurol. 2014 Mar;13(3):257-67.

Background: Patients who develop relapsing-remitting multiple sclerosis (MS) present with a first clinical demyelinating event. In this double-blind, multicentre, randomised, phase 3 study we investigated the effect of oral cladribine on conversion to clinically definite MS in patients with a first clinical demyelinating event, when given at the same doses shown to be effective in relapsing-remitting MS.

Methods: Between Oct 21, 2008, and Oct 11, 2010, we recruited patients aged 18-55 years, inclusive, from 160 hospitals, private clinics, or treatment centres in 34 countries. Eligible patients had a first clinical demyelinating event within 75 days before screening, at least two clinically silent lesions of at least 3 mm on a T2-weighted brain MRI scan, and an Expanded Disability Status Scale score of 5.0 or lower. Patients with a first clinical demyelinating event ≤75 days before screening were randomly assigned (1:1:1) to receive cladribine tablets at cumulative doses of 5.25 mg/kg or 3.5 mg/kg or placebo. Randomisation was done with a central web-based randomisation system and was stratified by geographic region. Masking was maintained using a two-physician model. The primary endpoint of this 96-week study was time to conversion to clinically definite MS according to the Poser criteria. This study is registered with ClinicalTrials.gov, number NCT00725985.

Findings: Of 903 participants assessed for eligibility, 616 patients received cladribine 5.25 mg/kg (n=204), cladribine 3.5 mg/kg (n=206), or placebo (n=206). At trial termination on Oct 25, 2011, cladribine was associated with a risk reduction versus placebo for time to conversion to clinically definite MS (hazard ratio [HR] for 5.25 mg/kg=0.38, 95% CI 0.25-0.58, p<0.0001; HR for 3.5 mg/kg=0.33, 0.21-0.51, p<0.0001). Adverse events were reported in 165 (81%) patients in the cladribine 5.25 mg/kg group, 168 (82%) patients in the cladribine 3.5 mg/kg group, and 162 (79%) patients in the placebo group. We noted no increase in risk of adverse events with active treatment versus placebo apart from lymphopenia, which was a severe event in 10 (5%) patients in the 5.25 mg/kg group and four (2%) patients in the 3.5 mg/kg group.

Interpretation: Both doses of cladribine significantly delayed MS diagnosis compared with placebo. The safety profile of cladribine was similar to that noted in a trial in patients with relapsing-remitting MS. Further research could clarify the potential effects of oral cladribine treatment in the early stages of MS.

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice. 

Curing MS

Barts-MS rose-tinted-odometer: ★★★★★

I have been asked many times if we can cure someone who has MS. I have tried to explain what an MS cure may look like many times on this blog and have actually published articles defending the definition. 

I explained in a previous post that you may be cured of your MS, but still, have worsening or progressive disease. The difference between progressive disease, which is due to previous MS damage and ageing is that the former should burn out, i.e. after a period of time, your worsening disability should eventually stop or flat-line. In comparison, MS-induced premature ageing is unlikely to stop. In comparison defining a cure in people who are young, with reserve capacity, who have been treated earlier is a much easier task. 

From a biological perspective you can be cured but still have neurological deficits from previous damage, which need to be targeted with so-called ‘repair’ and ‘neuroregenerative’ therapies. These are separate processes and are independent of a so-called biological cure. 

Based on our current understanding of MS a cure can only really occur in relation to IRTs (immune reconstitution therapies; e.g. alemtuzumab, cladribine & HSCT), i.e. treatments that are given as short courses that address the underlying ‘cause’ of MS. Maintenance treatments that need to be given continuously can’t cure MS, because when you stop the treatment MS disease activity tends to return and in some cases, particularly with anti-trafficking agents (natalizumab and fingolimod), to a greater extent than before, which we call MS rebound.

For arguments sake let’s say we have treated a group of pwMS early in the course of their disease with an IRT and they have gone into long-term remission with no evident disease activity (NEDA). How long should we wait before declaring a victory over their MS; 10, 15, 20 or 25 years? In the past, we have proposed defining a cure as NEDA at 15 years post-treatment as a starting point (see our MSARD Editorial below). Why 15 years? This is the most commonly accepted time-point used for defining benign MS and therefore it is a standard end-point that could potentially be accepted by the wider MS community. However, this may be wishful thinking many in the field are saying that we can’t cure MS, therefore, we should not even be having this discussion. Do you agree? 

The average time to the onset of secondary progressive MS is ~14-15 years so one would expect to see a significant proportion of people manifesting with SPMS in this 15-year timeframe. If we have gotten the autoimmune hypothesis wrong and IRTs don’t work then I would estimate at least a third of treated subjects should have SPMS at 15 years. The problem with 15 years is that it is a long wait if you have MS. Many pwMS want to know ‘now’ if an IRT offers a cure, therefore we need data to convince the naysayers to support the ‘cure hypothesis’. Hopefully, convincing data, such as the HSCT data below, will change their minds and get them to at least offer IRTs to more of their patients.

In the past, I have proposed a deep phenotyping project to look at pwMS who are NEDA-2 post-IRT to see if we can find any evidence of ongoing inflammatory, or neurodegenerative, MS disease activity. I proposed interrogating them in detail and comparing them to a similar cohort of pwMS who are being treated with maintenance DMTs. Deep phenotyping is simply a term that refers to the interrogation of the CNS to see if the IRT has stopped ongoing damage and protected reserve capacity.

The study that has come closest to reaching this 15-year time point is the Canadian myeloablative HSCT cohort (see below). Mark Freedman, the principal investigator, has told me that all of these patients remain NEDA-2 (no relapses or MRI activity) although some have worsened in relation to their disability, which may be a result of previous damage and not ongoing MS disease activity. However, the most impressive observation is that this cohort of patients, who all had very active MS prior to HSCT, has ‘normalised’ their rate of brain volume loss or atrophy after an initial precipitous drop in brain volume due to pseudoatrophy and/or chemotherapy-induced neurotoxicity. Mark Freedman has also said that about a third of these patients, who have had lumbar punctures, have lost their OCBs (personal communication). However, the spinal fluid analyses have all been done quite early after HSCT hence we don’t know how many subjects who have reached 10 years of follow-up or more have persistent OCBs. Wouldn’t this be an interesting fact to know?

When the 10-year lumbar puncture and spinal fluid analysis was done in a group of Polish subjects treated with intravenous cladribine, 50% had lost their spinal fluid oligoclonal IgG bands (OCBs) at 10 years and this group of OCB-negative patients tended to have stable disease compared to those who hadn’t lost their OCBs. This is why we are doing the SIZOMUS (Ixazomib) and the DODO (high-dose ocrelizumab) studies to try and scrub the CNS clean of pathogenic B-cells and plasma cells that may be driving low-grade smouldering MS. Exciting? You bet! These two studies are one of the reasons I get up in the morning, look at myself in the mirror and say nobody can say Barts-MS isn’t doing innovative MS research. 

The question I am now asking myself is switching a definition of a cure to a biological one a better strategy? This is a new line of thinking that has been brewing in my head for the last 12 months or so. If EBV is the cause of MS can we simply put pwMS into remission and clear them of EBV? This is why I want to do the iTeri and similar studies, i.e. to give an IRT and follow it with a drug that prevents EBV reactivation (antiviral) or scrubs B-cells of EBV (EBNA-1 antagonists). 

I am sure many cynics will be saying no not Prof G thinking aloud. Yes, I am thinking aloud. If only a minority of pwMS treated with IRTs go into long-term remission why can we increase the proportion by using the induction-maintenance approach that targets the cause of MS? What do you think?

If you agree with this strategy I am going to need help to get the iTeri concept study funded.  

DEFINING A CURE:

Banwell et al. Editors’ welcome and a working definition for a multiple sclerosis cure. Multiple Sclerosis and Related Disorders. 2013; 2(2):65-67.

…. Defining a cure in MS is a difficult task. How long should we wait before declaring a victory; 15, 20 or 25 years? Oncologists have back-tracked on this issue and instead of a cure they now prefer to use the term NEDD, or no evidence of detectable disease, at a specific time-point knowing full well that a limited number of subjects will relapse and present with recurrent disease after this point. We propose using the term NEDA, or no evident disease-activity, at 15 years as a starting point for defining a cure. Why 15 years? This is the most commonly accepted time-point used for defining benign MS and therefore it is a usual endpoint. In addition, the median time to the onset of secondary progressive MS is ~10-11 years (Kremenchutzky, Rice et al. 2006) and is well within the 15-year time window of our proposed definition of a cure. At present NEDA is defined using a composite of a) no relapses, or b) no EDSS progression, or c) no MRI activity (new or enlarging T2 lesions or no Gd-enhancing lesions) (Havrdova, Galetta et al. 2009; Giovannoni, Cook et al. 2011). This description is currently based on data that is routinely collected in contemporary clinical trials (Havrdova, Galetta et al. 2009; Giovannoni, Cook et al. 2011). The definition of NEDA will evolve with technological innovations and clinical practice, and in the future, it will almost certainly include MSer-related outcomes, grey matter disease activity, an index of brain atrophy and hopefully a CSF biomarker profile…..

References:

Giovannoni, G., S. Cook, et al. (2011). “Sustained disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: a post-hoc and subgroup analysis.” Lancet Neurol 10(4): 329-337.

Havrdova, E., S. Galetta, et al. (2009). “Effect of natalizumab on clinical and radiological disease activity in multiple sclerosis: a retrospective analysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study.” Lancet Neurol 8(3): 254-260

Kremenchutzky, M., G. P. Rice, et al. (2006). “The natural history of multiple sclerosis: a geographically based study 9: observations on the progressive phase of the disease.” Brain 129(Pt 3): 584-594.

THE CURE #1?

Atkins et al. Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial. Lancet. 2016 Aug 6;388(10044):576-85. 

BACKGROUND: Strong immunosuppression, including chemotherapy and immune-depleting antibodies followed by autologous haemopoietic stem-cell transplantation (aHSCT), has been used to treat patients with multiple sclerosis, improving control of relapsing disease. We addressed whether near-complete immunoablation followed by immune cell depleted aHSCT would result in long-term control of multiple sclerosis.

METHODS: We did this phase 2 single-arm trial at three hospitals in Canada. We enrolled patients with multiple sclerosis, aged 18-50 years with poor prognosis, ongoing disease activity, and an Expanded Disability Status Scale of 3.0-6.0. Autologous CD34 selected haemopoietic stem-cell grafts were collected after mobilisation with cyclophosphamide and filgrastim. Immunoablation with busulfan, cyclophosphamide, and rabbit anti-thymocyte globulin was followed by aHSCT. The primary outcome was multiple sclerosis activity-free survival (events were clinical relapse, appearance of a new or Gd-enhancing lesion on MRI, and sustained progression of Expanded Disability Status Scale score). This study was registered at ClinicalTrials.gov, NCT01099930.

FINDINGS: Between diagnosis and aHSCT, 24 patients had 167 clinical relapses over 140 patient-years with 188 Gd-enhancing lesions on 48 pre-aHSCT MRI scans. Median follow-up was 6.7 years (range 3.9-12.7). The primary outcome, multiple sclerosis activity-free survival at 3 years after transplantation was 69.6% (95% CI 46.6-84.2). With up to 13 years of follow-up after aHSCT, no relapses occurred and no GdGd-enhancing lesions or new T2 lesions were seen on 314 MRI sequential scans. The rate of brain atrophy decreased to that expected for healthy controls. One of 24 patients died of transplantation-related complications. 35% of patients had a sustained improvement in their Expanded Disability Status Scale score.

INTERPRETATION: We describe the first treatment to fully halt all detectable CNS inflammatory activity in patients with multiple sclerosis for a prolonged period in the absence of any ongoing disease-modifying drugs. Furthermore, many of the patients had substantial recovery of neurological function despite their disease’s aggressive nature.

THE CURE #2?

Rejdak et al. Cladribine induces long lasting oligoclonal bands disappearance in relapsing multiple sclerosis patients: 10-year observational study. Mult Scler Relat Disord. 2019 Jan;27:117-120. 

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.

Results: 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.

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust. 

#MSCOVID19: Cladribine 3 vs. Ocrelizumab 1 vs. Fingolimod 0

Barts-MS rose-tinted-odometer: ★★★★★

Finally, the early Israeli COVID-19 vaccine seroconversion rates are out as a peer-reviewed publication. This data is not new but comes with being vetted by the scientific community and hence can be quoted and discussed at scientific meetings.

Protective humoral immunity was 97.9% in healthy subjects, 100% untreated pwMS, 100% in cladribine-treated pwMS, 22.7% in ocrelizumab-treated pwMS and 3.8% in fingolimod-treated pwMS. As I have said before this is only half the story and we need to know what happens on the T-cell side. 

IgG antibodies to the virus implies a good T-cell response as well; this is because to class switching to IgG happens in the germinal centres with T-cell help. The corollary does not necessarily hold, i.e. if you don’t make IgG antibodies you can’t assume that vaccine-induced T-cell responses are absent. This is why I predict, based on the fact that both ocrelizumab and fingolimod treated pwMS recover from COVID-19 implying their T-cells are working and helping to clear the virus, that both ocrelizumab- and fingolimod-treated patients are likely to have some T-cell immunity to SARS-CoV-2 spike protein post-vaccination. 

Please note this is a prediction and we will need to wait for more detailed immunological studies. Even if patients on these agents have some T-cell responses the question will remain whether this blunted vaccine-induced immunity against SARS-CoV-2 will be sufficient to protect these patients against getting COVID-19 or repeated episodes of COVID-19? This question will take much longer to answer, but I suspect this limited immunity won’t be sufficient because vaccine immunity is likely to wane with time and new immune escape variants of SARS-CoV2 will emerge. Already public health officials are planning for rounds of booster vaccines to cover new variants. What this means is that vaccine-readiness will become uppermost in the minds of pwMS and HCPs when deciding on which DMTs to choose for particular patients.

The good news is that if you have MS and have been treated with cladribine there is no blunting of vaccine-induced responses. This is not surprising and was predicted based on the immunology of cladribine and justifies my previous blog post taking the NMSS to task on their ill thought out initial COVID-19 vaccine guidelines. Fortunately, these have been updated and pwMS on cladribine can be confident to go ahead with getting vaccinated ASAP. 

Figures from Ther Adv Neurol Disord 2021, Vol. 14: 1–8.

I would extrapolate the ocrelizumab vaccine data to the other anti-CD20 therapies, i.e. rituximab, ofatumumab and ublituximab, but not necessarily the fingolimod data to the other S1P modulators. There is evidence that fingolimod not only traps lymphocytes in lymph nodes but also depletes lymphocytes. In comparison to fingolimod, ozanimod and ponesimod deplete lymphocytes less intensely and at least for ponesimod, the recovery of lymphocytes is very rapid implying lymphocytes are not depleted on this drug.  So I would not be surprised if ponesimod, and possibly ozanimod, have less of an effect on vaccine responses than fingolimod. As for siponimod, I predict it will be closer to fingolimod in terms of its effect on neoantigen (new antigen) vaccine responses such as the COVID-19 vaccines. 

Does this data change anything about my current practice? No, not really, it is entirely in keeping with what I predicted. My advice is still #GetVaccinatedASAP. This data however may impact what treatment patients with MS decide to start off on; if vaccine responses are important to you, say for travel and/or work reasons, you may want to avoid S1P modulators and anti-CD20 therapies.

Please note I have put on my rose-tinted glasses; the sun is shining outside and spring is wonderful 😉

Achiron et al. Humoral immune response to COVID-19 mRNA vaccine in patients with multiple sclerosis treated with high-efficacy disease-modifying therapies. Ther Adv Neurol Disord 2021, Vol. 14: 1–8.

Background and Aims: The National Multiple Sclerosis Society and other expert organizations recommended that all patients with multiple sclerosis (MS) should be vaccinated against COVID-19. However, the effect of disease-modifying therapies (DMTs) on the efficacy to mount an appropriate immune response is unknown. We aimed to characterize humoral immunity in mRNA-COVID-19 MS vaccinees treated with high-efficacy DMTs.

Methods: We measured SARS-CoV-2 IgG response using anti-spike protein-based serology (EUROIMMUN) in 125 MS patients vaccinated with BNT162b2-COVID-19 vaccine 1 month after the second dose. Patients were either untreated or under treatment with fingolimod, cladribine, or ocrelizumab. A group of healthy subjects similarly vaccinated served as control. The percent of subjects that developed protective antibodies, the titer, and the time from the last dosing were evaluated.

Results: Protective humoral immunity of 97.9%, 100%, 100%, 22.7%, and 3.8%, was observed in COVID-19 vaccinated healthy subjects (N = 47), untreated MS patients (N = 32), and MS patients treated with cladribine (N = 23), ocrelizumab (N = 44), and fingolimod (N = 26), respectively. SARS-CoV-2 IgG antibody titer was high in healthy subjects, untreated MS patients, and MS patients under cladribine treatment, within 29.5–55 days after the second vaccine dose. Only 22.7% of patients treated with ocrelizumab developed humoral IgG response irrespective to normal absolute lymphocyte count. Most fingolimod-treated MS patients had very low lymphocyte count and failed to develop SARS-COV-2 antibodies. Age, disease duration, and time from the last dosing did not affect humoral response to COVID-19 vaccination.

Conclusions: Cladribine treatment does not impair humoral response to COVID-19 vaccination. We recommend postponing ocrelizumab treatment in MS patients willing to be vaccinated as a protective humoral response can be expected only in some. We do not recommend vaccinating MS patients treated with fingolimod as a protective humoral response is not expected.

Conflicts of Interest

Preventive Neurology

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.

Prof G guilty as accused!

Barts-MS rose-tinted-odometer: ★★

Guilty as accused! 

I did a very one-sided post this weekend on the pros of oral cladribine as a treatment for MS during the COVID-19 pandemic. One commentator asked ‘what about the cons?’. As with all immunosuppressive therapies, there is a risk of secondary malignancies. In fact, both the EMA and FDA labels mention secondary malignancies as a complication of cladribine therapy. We think the short-term cancer risk, i.e. within the first 2 years, was driven by the very low numbers of cases in the placebo arms of phase 3 trials. The cancer rate in the cladribine-exposed subjects was in keeping with the expected background rates compared to subjects on other DMTs and people from the general population from data in an international population-based cancer registry (GLOBOCAN). So I am not convinced that cladribine is associated with a short term cancer risk. However, the jury is out in relation to the intermediate to longterm risk. However, the safety data from the extension and post-marketing surveillance studies look very promising and based on the biology and mode-of-action of cladribine I think this risk is likely to be low.  

Although cladribine works via DNA mechanisms it is not a mutagen; i.e. it does not cause mutations in DNA.  When cladribine is incorporated into DNA it inhibits DNA polymerases, the enzymes that extend the DNA chain. The cell then senses this as a problem and this triggers apoptosis the biological process that causes the cell to trigger a suicide programme called ‘programmed cell death’. The reason why cladribine is so selective for lymphocytes is that the enzyme that activates cladribine is only found in high concentrations in lymphocytes and the other cells that don’t express this enzyme are resistant to cladribine’s effects.  

Saying this secondary malignancy is a complication with all immunosuppressive therapies regardless of their mode of action. The reason is that we rely on peripheral tumour immune surveillance, i.e. our immune system find early cancers and attacks and destroys them. Suppress the immune system intensely enough and for long enough and certain cancers will develop. For example, fingolimod, and I suspect the whole S1P modulator class, is associated with skin cancer (basal and squamous), lymphoma and potentially other cancers, e..g. Kaposi’s sarcoma. Anti-CD20 therapies may be linked to breast cancer. Natalizumab, CNS lymphoma. Alemtuzumab, cervical cancer and possibly thyroid cancer, although one could argue the thyroid cancer risks with alemtuzumab may be due to ascertain bias from the high rate of thyroid screening due to thyroid secondary autoimmunity. The only DMTs not associated with secondary malignancies are the immunomodulators, i.e. interferon-beta, glatiramer acetate and teriflunomide. 

Is there anything you can do about the immunosuppressive cancer risk? Yes, there is. You need to enrol and stick to your country’s cancer screening programmes. In the UK there are three national programmes; cervical, breast and colon. Breast cancer screening starts at the age of 50 and stops at the age of 70. Colon cancer screening starts at the age of 50 or 60, which depends on where you live in the UK. Cervical cancer screening is for women between 25 and 64 years of age. However, there is a push to extend cervical cancer screening beyond 64 now that cervical smear screening is being replaced with vaginal swabs, which are self-administered, and use PCR testing to detect HPV, the virus that causes cervical cancer. HPV testing is so much more pleasant for women and more reliable and reproducible than looking for abnormal cells under a microscope. 

In the UK the prostate cancer screening programme is available on request, i.e. you can request a PSA (prostate-specific antigen) test. National PSA prostate cancer screening was dropped as the PSA assay was too unreliable. It generated too many false positives or detected very small cancers that were unlikely to cause any problems. In comparison, some of the treatments for prostate cancer cause more harm. In fact, most men who die in old age have asymptomatic prostate cancer at post-mortem; if something else rather than the cancer was going to kill these men why bother about detecting cancer?  Please note the dropping of the national prostate cancer screening programme has been controversial and some people think it was a mistake. In many countries, PSA screening is still being done at a national level. 

In some parts of the UK, there are pilot lung cancer screening programmes with high-resolution spiral chest CT scans being offered. The early results are very impressive in targeted groups at high-risk of lung cancer such as heavy smokers or ex-smokers. I am convinced that lung cancer screening is likely to become routine in the UK in smokers in the not too distant future. 

Other groups for cancer screening include high-risk subjects for example patients with dysplastic naevus syndrome of the skin, who are at risk of melanoma, those with well-defined genetic conditions associated with specific cancers, patients with a very strong family history of specific cancers, patients with inflammatory bowel disease, anal cancer screening in HPV and HIV postive men-who-have-sex-with-men, oesophageal cancer screening in patients with Barrett’s oesophagus, etc. 

A few years ago I asked our renal transplant team for advice about their cancer screening programme for their transplant patients. In short, they don’t do anything that is outside of the national cancer screening programme. The reason they gave is that when you start screening a younger population than that defined by the national screening programmes you are likely to detect more false positives cancers, which leads to unnecessary intervention that cause more harm. You also create cancer anxiety syndrome; i.e. patients start to worry excessively about developing cancer. I have a few patients on DMTs who suffer from this condition; so it is real. 

However, there are some self-screening programmes that you can engage in, for example, self-examination of your breasts and testes for woman and men, respectively, and the regular examination of worrisome skin lesions. The following are just three YouTube videos on how to do breast, testes and skin lesion self-examinations.

As MS HCPs we are meant to prompt you to make sure you are registered with your GP and are enrolled in the screening programmes. Outside of HPV screening in women about to start an immunosuppressive therapy, I tend to forget to do this. This is another example to have proformas of standardised checklists to make sure we don’t forget this important task. 

I would be interested to know what your experience has been with regard to your awareness about cancer risk on immunosuppressive therapies, cancer screening and self-examination. In this study below despite the vast majority of the woman being aware of breast self-examination, a large minority didn’t examine their breasts every month. Does this apply to you? 

Watanabe et al. Awareness of Self-Examination, Screening, and Risk Factors for Breast Cancer Among Women Awaiting Care at the Outpatient Clinic of a Mastology Unit. J Cancer Educ. 2020 Oct 9. doi: 10.1007/s13187-020-01892-1.

This study aimed to evaluate the awareness and practice of breast self-examination (BSE) and the awareness of screening and risk factors for breast cancer among patients from a mastology clinic and to associate such findings with sociodemographic factors of that population. A total of 202 randomly selected patients from the outpatient clinic of the Mastology Unit of São Paulo School of Medicine were interviewed. A structured questionnaire was used and included questions regarding sociodemographic variables, questions to assess the knowledge and practice of BSE, and knowledge of mammographic screening and risk factors for breast cancer. The vast majority of patients were aware of the existence of BSE (93.1%). BSE was performed by most patients (64.9%), although only 20.3% performed it adequately. Only 21.8% of respondents showed awareness of the best screening method for breast cancer. Furthermore, 17.3% of patients showed adequate awareness of risk factors for breast cancer. The analysis of sociodemographic variables showed that older, postmenopausal, and less-educated women showed better practice of BSE. Overall, the patients had no adequate awareness of BSE, mammographic screening, and risk factors for breast cancer, and the majority failed to practice BSE adequately, particularly the group of patients with the higher level of education. These data show that educational measures regarding the practice of BSE and, especially, mammograms should be emphasized, regardless of education level or family income of the patient.

PS (4-Mar-2021): In response to a request from one of the comments in the survey: “…you could you please comment on cancer risk for anti CD20+ treatments, as well as cancer-related topics for younger pwMS”. I have therefore added the presentation from Professor Hauser from the MSVirtual2020, the 8th Joint ACTRIMS-ECTRIMS Meeting, from September 2020. As you can see the rate of malignancies and female breast cancer in ocrelizumab-treated patients remained broadly within the range reported in the general population from epidemiological data. Please note these patients have been followed for over 7 years. I hope this helps.

CoI: multiple

Twitter: @gavinGiovannoni                                              Medium: @gavin_24211

#MSCOVID19: specifically for NHS England

Barts-MS rose-tinted-odometer: ★★★★★

Early on in the pandemic, I did a blog post on why I thought oral cladribine was the ideal DMT for managing MS (26-April-2020) remotely. I summarised cladribine’s attributes in a simple 12-point list. This list can now be updated to include (1) data on good COVID-19 outcomes in pwMS who have been treated with cladribine, (2) about vaccine readiness, i.e. pwMS vaccinated with COVID-19 vaccine make a good antibody response and (3) on its cost-effectiveness and value.

The Mouse Doctor prodded me by email yesterday to ask NHS England to allow us to use cladribine more liberally because of the pandemic and the unique challenges it is placing on MS services. MD suggests using or at least offering it 1st-line to patients with just active MS and not only those with highly-active disease. I can’t really do what MD wants because NHS England has a process for changing its advice. I also need to remind MD that as the principal investigator on the phase 3 CLARITY study I am so conflicted that nobody would take anything I say seriously. Hence an updated blog post.

Cladribine’s pros:

Cladribine is a high-efficacy DMT therefore it potentially allows you to flip the pyramid and offer it first-line.

Cladribine is an oral therapy; hence no visits to COVID-19 hot hospitals or institutions.

Cladribine kills cells gradually by a process called apoptosis. Cells dying from apoptosis are phagocytosed or swallowed by macrophages and as a result, there is no cell lysis or bursting open of the cells and the release of their contents that causes a cytokine release syndrome. This means there is no need to pre-treat patients with steroids, which we try to avoid because they increase your chances of getting severe COVID-19. 

Cladribine does not deplete monocytes and neutrophils and has a moderate impact on so-called NK cells. As the innate immune system is left intact there is a low risk of bacterial and other infections during the depletion phase and the innate cells can help fight viral infections, such as SARS-CoV-2.

T lymphocytes are in general depleted by about 40%-50% and most patients don’t drop their counts below 500/mm3. In the phase 3 programme about a quarter of patients had a grade 3 or 4 lymphopaenia, but this tended to occur after the second course in year 2 in subjects who were redosed when their lymphocyte counts had not recovered to above 800/mm3. We have used the trial data to model grade 3 and 4 lymphopaenia. I.e. less than 500/mm3, and estimate that less 5% of cladribine treated subjects will develop lymphocyte counts less than 500/mm3 if we stick to the redosing guidelines. This is very important as lymphopaenia is probably the most important risk factor for viral and severe viral infections. 

In the T-cell compartment, the CD8+ T-cells were less effected than CD4+ T-cells. This is important because CD8+ T-cells are the cells responsible for fighting viral infections. This probably explains, apart from a small risk of herpes zoster reactivation, why we didn’t see an increase in viral infections compared to placebo in cladribine treated subjects in the phase 3 trial programme. The viral infections that did occur tended to be non-specific upper respiratory tract infections and were mild to moderate. In fact, the infection profile on cladribine, including the zoster signal, was much more similar to that which we see with ocrelizumab compared to alemtuzumab. 

Cladribine-treated pwMS who get COVID-19 are not at increased risk of getting severe COVID-19.

Cladribine is a remarkably good depleter of B-cells. B-cells number drop quicker than T-cells numbers; i.e. within days to weeks. In addition, B-cells are depleted by about 85-90% and importantly memory B-cells are severely depleted and to a similar level that we see with alemtuzumab. Importantly, when the B-cell numbers return these are so-called naive B-cells, which come from the bone marrow and are not memory B-cells. These are the cells you need to make vaccine responses.

Please note that because ocrelizumab and rituximab are given as maintenance or continuous therapy there is a small increase in the incidence of serious infections over with time and the development of hypogammaglobulinaemia. This is not seen with cladribine. Once the immune system reconstitutes post-cladribine it can fight infections, immune survey the body for cancers and mount immune responses to new viral infections, such as SARS-CoV-2, and vaccines.

In relation to vaccines both live and inactivated component vaccines can be given after cladribine. New data indicates that cladribine-treated with MS make good antibody response to COVID-19 vaccines (see vaccine post from yesterday).

The other important thing about cladribine is the monitoring requirements are low. Once you have had a course you only need a full blood count to be done at month 4 and 7 in each treatment year. The rationale for this is that the 4-month time-point is where the nadir occurs and the 7-month time point is to check for recovery of lymphocyte counts.

When you look at how cladribine works, i.e. it needs to be activated by an enzyme call DCK (deoxycytidine kinase) and broken down by an enzyme called ADA (adenosine deaminase), the profile of cells expressing the correct ratio of these enzymes matches the B-cell population that expresses CD19 and CD20 and explains why B-cells are more susceptible to the effects of cladribine than T-cells. 

Another advantage of cladribine is that as a small molecule it penetrates the CNS. Cerebrospinal fluid (CSF) levels are about 25% of what is found in the peripheral blood and at a level that would target B- and T-cells within the brain and spinal cord. I think this property of cladribine is very important and is one of the reasons why we are exploring cladribine as a treatment for progressive MS in the CHARIOT-MS trial. 

Please note that I am not saying cladribine is entirely safe. It has a well-defined risk-benefit profile that is less risky than what has been suggested by many people. These risk-benefit profiles simply allow you to counsel patients with active MS about their treatment options during the COVID-19 pandemic.

Oral cladribine is cost-effective. NHS England has negotiated a value-based pricing deal with the manufacturer for a rebate if anyone treated with cladribine switches to another agent within 4-years of starting treatment. This makes cladribine a very good option; you are only paying for the drug if it is effective. Isn’t this the future of pharmaceutical drug pricing?

We think cladribine is a highly effective therapy that has many positive attributes for managing MS during the COVID-19 pandemic.  

P.S. MD adds Point 17. Risk of PML in JC+ individuals is low (Thanks Jason)

Do you agree? 

CoI: multiple

Twitter: @gavinGiovannoni                                         Medium: @gavin_24211

#MSCOVID19: cladribine is being unfairly tarnished with alemtuzumab’s brush

Barts-MS rose-tinted-odometer: ★★★★★

I think the North American MS community have made some mistakes with their COVID-19 vaccine recommendations, in particular, the NMSS COVID-19 vaccine guidelines for cladribine. In view of the immunology of cladribine’s mode of action and new data that is emerging, I would suggest the NMSS considers updating its guidelines. 

Lemtrada and Mavenclad

If you are about to start Lemtrada or Mavenclad, consider getting the Pfizer BioNTech or Moderna COVID-19 vaccine so that the second vaccine injection is done 4 weeks or more prior to starting Lemtrada or Mavenclad. If you are already taking Lemtrada or Mavenclad, consider administering the vaccine injections starting 12 weeks or more after the last Lemtrada or Mavenclad dose, with the optimal timing of the vaccine 24 weeks or more after the last DMT dose2. When possible, resume Lemtrada or Mavenclad 4 weeks or more following the second vaccine injection. This suggested scheduling is not always possible and getting the vaccine when it becomes available to you may be more important than timing the vaccine with your DMT. Work with your MS healthcare provider to determine the best schedule for you.

Lumping cladribine and alemtuzumab together as being immune-depleters of the same ilk is simply wrong. Alemtuzumab is more of a sledgehammer and is relatively non-selective in depleting both T-cells and B-cells and it also hits innate immunity, in particular monocytes. This is why there is a major infection signal (e.g. listeriosis) with alemtuzumab in the 4-6 weeks after each course of treatment. The latter does not occur with the doses of cladribine we use to treat people with MS.

In comparison, the mode of action of cladribine is very subtle and more in keeping with a selective B-cell depleting agent. Cladribine depletes B-cells by about 85-90% and hits mainly memory B-cells, in other words, large numbers of naive B-cell persist in the peripheral blood. We think as memory B-cells are being killed fresh naive B-cells are being released from the bone marrow. This is important because it is the naive B-cell population that is required to make new antibody responses to vaccines. 

Cladribine only depletes T-cells by about 50% a level that in general is not sufficient to put patients at risk of opportunistic infections or even viral infections. When we recently reanalysed all of the cladribine safety data there was no novel or new exogenous (from outside the body) viral infection signal. The only viral infection signal we saw was zoster or shingles, i.e. a reactivation of a latent virus, which is common and occurs with all immunosuppressive therapies. 

Another very big difference between cladribine and alemtuzumab is the fact that cladribine leaves the innate immune system intact, which is important for fighting infections and for processing vaccine antigens and presenting them to the immune system. 

Another factor that is different is the temporal profile of immunodepletion that occurs with alemtuzumab and cladribine. Alemtuzumab causes rapid cell lysis with its effect noticeable in hours to days; in other words, peripheral blood lymphocyte and monocyte counts are depleted to very low levels (nadir) very quickly. In comparison, cladribine works by triggering apoptosis of cells and lymphocytes die slowly over weeks to months reaching a nadir at about 3 to 4 months after each course. Therefore for the NMSS guidance to say “consider administering the vaccine injections starting 12 weeks or more after the last Mavenclad dose, with the optimal timing of the vaccine 24 weeks or more after the last DMT dose” is actually recommending giving the vaccine from the start of the nadir. 

Unlike alemtuzumab, I think the timing of vaccination in patients treated with cladribine is unlikely to make much of a difference because both the afferent (antigen processing and presentation) and efferent (B-cells/antibodies and T-cells) limbs of the immune system is intact, i.e. there is enough hardware or cells at all times post cladribine to make an immune response. Saying this the summary of product characteristics of cladribine clearly states that live vaccines should be avoided until the immune system has reconstituted and the cells counts have returned to normal. Please note this refers to live vaccines and doesn’t apply to the currently licensed COVID-19 vaccines, which are not live attenuated vaccines or LAVs.

The good news is that the above predictions are being borne out by some real-life flu and VZV vaccine data in cladribine-treated patients that have been presented at ACTRIMS this week. My interpretation of this data is that regardless of when a vaccine is administered in patients on cladribine the appear to mount a good antibody response. I agree the number of subjects studied is small and no subject has had grade 4 lymphopaenia (<200/mm3), but these data at least confirm what you would expect to happen based on immunological principles. 

My advice, therefore, remains the same for pwMS on DMTs; during the height of the pandemic having some immunity to SARS-CoV-2 is better than having no immunity. This is why you should get vaccinated ASAP. If you live in an environment where the background risk of COVID-19 is low then you may want to optimise the timing of your vaccine, when you are next dosed with an immunodepleting therapy or when you start or switch therapies.


Roy & Boschert. Analysis of Influenza and Varicella-Zoster Virus Vaccine Antibody Titers in Patients with Relapsing Multiple Sclerosis Treated with Cladribine Tablets. P059 – ACTRIMS 2021

Background: There is a lack of data available to determine the effect of cladribine tablets (CladT) on the antibody response to vaccination in patients with relapsing multiple sclerosis (MS).

Objectives: To investigate the immunoprotective response to seasonal influenza and varicella-zoster virus (VZV) vaccination in patients treated with CladT (3.5mg/kg over 2 years) for relapsing MS.

Methods: Blood samples collected during the MAGNIFY-MS study (NCT03364036) from 9 patients with relapsing MS treated with CladT who received seasonal influenza (n=8) or VZV vaccinations (n=1; Shingrix) as a standard of care were retrospectively analyzed. Two control blood samples (baseline sample before starting CladT and closest sample available just before vaccination) and two post-vaccination blood samples (closest sample available after vaccination) were examined. Quantitative antibody titers in response to the seasonal influenza and VZV vaccine were measured by hemagglutination inhibition (HAI) assay and Enzyme-Linked Immunosorbent Assay (ELISA), respectively. The seroprotection titer level for the seasonal influenza vaccine is considered ≥40, and was ≥100 IU/L for the VZV vaccine.

Results: Influenza: All patients vaccinated against influenza A and B during year 1 or 2 of CladT treatment retained seroprotection titers of ≥40 in post-vaccination samples across all strains present in the vaccine administered. The number of seropositive patients (HAI ≥40) with a ≥4-fold and ≥2-fold increase against at least 1 strain in post-vaccination titers were 3/8 and 7/8, respectively. VZV: Post-vaccination antibody titers were 40-fold increased over the protective titer at all time points (titers >4748 IU/L).

Conclusions: In this small retrospective investigation, post-vaccination antibody titers in patients treated with CladT for relapsing MS remained at levels that offer protective immunity against seasonal influenza and VZV.

Wu et al.  Evaluating the Impact of Cladribine Tablets on the Development of Antibody Titers: Interim Results from The CLOCK-MS Influenza Vaccine Substudy. P071 ACTRIMS 2021

Background: Cladribine tablets have been approved in more than 80 countries for the treatment of relapsing forms of multiple sclerosis (RMS), and are hypothesized to function as an immune reconstitution therapy with potential to cross the blood-brain barrier. The CLOCK-MS study (cladribine tablets: collaborative study to evaluate impact on central nervous system biomarkers in multiple sclerosis), is a 24-month, open-label, randomized, multicenter, collaborative Phase IV biomarker research study. The COVID-19 pandemic, and pending vaccine availability, have raised important questions around the impact of MS disease modifying therapies on vaccine efficacy.

Objectives: To evaluate the potential impact of prior treatment with cladribine tablets on the development of antibody titres post-influenza vaccination via a sub-study of CLOCK-MS.

Methods: The CLOCK-MS main study will enroll approximately 50 subjects age 18-65, diagnosed with relapsing-remitting MS or active secondary progressive MS, who had inadequate response to, or were unable to tolerate, an alternate drug indicated for the treatment of RMS. Study participants who have taken at least one dose of cladribine tablets and are planning to obtain one standard-of-care influenza vaccine are eligible to take part in the sub-study if they consent to blood draws. Blood sampling will occur 1) 3 Weeks Pre-Vaccine (within 21 days prior to obtaining a standard of care vaccine), 2) 4 Weeks Post-Vaccine (+/- 7 days), and 3) 6 Months Post-Vaccine (+/- 7 days). Measurements of antibody responses will be performed.

Results: So far 5 patients have been enrolled in this sub-study and had initial titers drawn. All patients fulfilled the per-label requirements for vaccination after cladribine tablets treatment. Initial results at Week 4 post-vaccination will be presented.

Conclusions: The impact of cladribine tablets, a lymphocyte-lowering agent, on the immune system’s ability to develop antibodies in response to a vaccine has not yet been studied. These results are expected to provide preliminary observations around the impact of cladribine tablets on influenza vaccine efficacy in patients with RMS.

CoI: multiple

Twitter: @gavinGiovannoni                                      Medium: @gavin_24211

#MSCOVID19: ABN Guidance Update

Barts-MS rose-tinted-odometer: ★★★

The ABN have updated their COVID-19 guidelines, which are beginning to move towards the evidence. However, the guidance on cladribine is not supported by the evidence nor the science, i.e. how cladribine actually works and its impacts the immune system.

The latest guidance states “the risk of severe COVID-10 disease is increased for many months after ocrelizumab and cladribine”. I am not sure there is evidence to support the statement about cladribine. Ocrelizumab and other anti-CD20 therapies are given continuously and hence the risk does not go away. However, cladribine is an immune reconstitution therapy and is reversible. Even in the depletion phase of treatment, the level of immunodepletion is modest, particularly for CD8+ T cells (see slide show below) and innate immunity is left intact. In our opinion, this pattern of immunodepletion is not sufficient to pose a risk to people with MS treated with cladribine and is supported by the emerging pharmacovigilance data.

The good news is that the guidelines state that for both ocrelizumab and cladribine “self-isolation for all that time is not appropriate except for individuals with multiple other risk factors”, which is compatible with our practice.

I am also reassured that their guidance has also softened for alemtuzumab; i.e. “we would anticipate pwMS being advised to strictly self-isolate for at least four weeks after an alemtuzumab administration”. This has been our practice since we started dosing alemtuzumab again. The rationale for the 4 week time period I assume is based on the impact of alemtuzumab on innate immunity and is supported by trial data; i.e. the viral infection risk falls rapidly after four weeks, presumably because monocyte counts recover.

The ABN is also recommending two weeks of self-isolation after high-dose steroids, which is pragmatic advice based on the risk of severe COVID-19 identified in the Italian registry studies.

The new guidance has also made a comment about vaccine readiness; “patients contemplating ocrelizumab should be advised that they may not be able to receive a future SARS CoV2 vaccine if it is a live vaccine, and they may not respond immunologically to a dead or inactivated vaccine. Consideration should be given to delaying ocrelizumab re-treatment”. It is interesting that none of the other DMTs is specifically mentioned when it comes to vaccine readiness. I am sure live viral vaccines will also be contraindicated in patients on S1P modulators (fingolimod and siponimod) and on some of the other immunosuppressive DMTs such as natalizumab and possibly even teriflunomide based on their current SmPCs.

The interesting thing about vaccine readiness is we don’t know about how important T-cell responses are in relation to these emerging vaccines and whether or not people on anti-CD20 therapies will mount an adequate protective T-cell response to the SARS-CoV-2 spike protein and other antigens. Everyone focuses on antibody responses when they may not be that important in protective anti-SARS-CoV-2 immunity.

I am sure we haven’t heard the last on MS DMTs and vaccine readiness. This is why I would urge all the DMT manufacturers to do the necessary studies to provide us with the necessary evidence-base to make clinical decisions.

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