Tag: case study

An ethical quandary

Barts-MS rose-tinted-odometer: ★★

The two case studies below are creating an ethical quandary in my MS practice. Can you help me please?

Case 1

The first is the 40-year old woman with MS who is NEDA-2 (no evident disease activity) on DMF (Tecfidera) with no documented relapses in the last 4 years and a series of annual MRI scans with no new or enlarging T2 MS lesions. However, there has been a worsening of her disability; increasing bladder problems and a progressive spastic paraparesis (weak legs). Her EDSS has moved from 4.0 to 5.5 in the last three years. She has self-diagnosed herself as having secondary progressive MS and wants to switch to siponimod. Unfortunately, according to the current NICE approval and NHSE guidelines, this patient is ineligible for siponimod because she has inactive MS (NEDA-2). 

Do I recommend she stops her DMF so that her MS can reactivate, which will then make her eligible for siponimod? Most MSologists would say yes, mainly because the development of SPMS is one of NHS England’s stopping criteria. The problem I have is we, the patient and I,  have no idea how active her MS will become if and when her MS reactivates. For example, she could have a catastrophic spinal relapse that leaves her doubly incontinent and quadriplegic or it may be on the other side of the spectrum, i.e. one or two new asymptomatic MRI lesions on her annual MRI follow-up. If you were in her position would you stop your treatment to develop active MS? 

Case 2

The second is the 40-year old woman who started natalizumab as a first-line therapy 11 years ago after presenting with two disabling relapses in a four-month period. She has done exceptionally well on natalizumab, i.e. she is NEDA-3 (no relapses, no MRI activity and no change in her EDSS). In fact, her original disabilities from the two relapses recovered. At present she is fully functional, working full-time and very active physically. For example, she plays competitive tennis in her local sports club and ran the London marathon 2 years ago. Her current EDSS is 1.0.

The problem is that her serial annual MRI studies demonstrate that she has progressive macroscopic (visible by the naked eye) brain volume loss. Being an intelligent woman and a self-taught MS expert she knows this is a poor prognostic sign and she wants to stop natalizumab and have HSCT or alemtuzumab. She is aware from reading The MS-Blog (formerly the Barts-MS blog) that alemtuzumab and HSCT have a greater impact than natalizumab on end-organ damage or brain volume loss. After HSCT and alemtuzumab treatment brain volume loss is on average in the normal range (please see BEYOND NEDA).

Would you allow this patient to switch treatments? Under the current London MS HSCT guidelines she would not be eligible for HSCT as she has not failed natalizumab; please note, progressive brain volume loss is not considered a treatment failure. What about alemtuzumab? Applying the strict NHSE guidelines she would not be eligible for alemtuzumab as her MS is inactive at present. However,  one could argue that we need to go back to 2010 when she started natalizumab and ask ourselves now would she have been eligible back then if alemtuzumab had been available? The answer is yes as she had what we call rapidly evolving severe MS; in 2021 someone with rapidly evolving severe MS could be treated with alemtuzumab first-line.  Should we apply treatment criteria retrospectively? 

This patient is JCV negative. If, however, she seroconverted to being JCV positive it would be easier to justify to NHS England for the switch to alemtuzumab, i.e. NHSE guidelines support the principle of derisking PML. The one thing I can’t tell this patient is whether or not alemtuzumab or HSCT will have an impact on her brain volume loss as we simply don’t have the data from a cohort of patients making the switch from natalizumab to alemtuzumab 10+ years into their disease. In other words will the smouldering or real MS that causes the accelerated brain volume loss respond to a potent IRT treatment strategy 11 years after diagnosis? This patient understands there is no data on natalizumab-switchers to support her request, but she is willing to take the risk of either alemtuzumab or HSCT. What do I advise her?

HELP! It is not easy being an MSologist. Please note these two scenarios are based on real patients of mine and are not hypothetical and represent the MS world I live and practice in. 

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.

#COVIDMS COVID-19 case study 2

I hope you enjoyed the first COVID-19 case study. The following is another case study that has just arisen in our unit.

Case study: The patient has highly-active DMT having failed a trial of dimethyl fumarate (DMF). She had a brain-stem relapse and her MRI had shown several new lesions. She was switched to oral cladribine and had her first-cycle of 5 days of treatment two weeks ago. She is due for her second cycle of oral cladribine in 2 weeks time. She is very concerned about COVID-19 infection. She works in London and communtes daily to work on the overground.

The COVID-19 ABN guidelines advise us not to do give her her second cycle of oral cladribine.

How are you going to manage this patient?

Postscript – 18 March 2020

Please note I am going to curate these case studies on a dedicated COVID-19 microsite to allow readers to access them in one place.

There is no right or wrong answer her only an opinion and an informed choice. 

This patient has highly-active MS and needs it treated. As she has committed herself to treatment with oral cladribine she will likely be mildly lymphopaenic already from the first cycle of cladribine. 

If we stick to the SIN or ABN guidelines we would have to suspend dosing. However, we may not have given her sufficient cladribine to have an effect on her MS. We do know that one course of cladribine does work and there is published data from Australia that shows this quite convincingly (see MS-Base data below). 

If we don’t complete her course of cladribine could we use an alternate DMT? I would not recommend platform therapies as she has failed on DMF, although teriflunomide may be a holding strategy. Why teriflunomide? It works better second or third-line and has broad antiviral properties that may make it an ideal DMT in this situation. 

Natalizumab would also be an option, but as she does not fulfil the current guidance for being treated with natalizumab under the NHSE DMT treatment algorithm this is not an option at present. Fingolimod will leave her immunosuppressed and starting her on fingolimod when she has a cladribine-induced lymphopaenia is unknown territory and likely to increase her level of immunosuppression. 

My recommendation would be for her to complete her first course of cladribine and to be extra-vigilant about hygiene and social distancing and avoiding high-risk travel. I also want to remind you that the level of immunosuppression after one course of cladribine is relatively moderate. Cladribine only drops T-cell counts by about 40-50% and the levels usually don’t fall into the range that is associated with opportunistic infections. When you analyse the safety profile of those subjects in the CLARITY and CLARITY EXTENSION studies, even those that develop grade 3 or 4 lymphopaenia (lymphocyte counts less than 500/mm3), there really is no obvious viral or severe viral, infection signal apart from herpes zoster. Therefore, I suspect the risk to this patient from severe COVID-19 infection is low. 

Based on the lymphocyte pharmacodynamics and the integrated safety analysis I would classify cladribine as an intermediate risk DMT in relation to severe COVID-19 infection in the same class as ocrelizumab. I really don’t know why it is being put in the same risk category as HSCT and alemtuzumab. 

MS-BASE single course of oral cladribine data

Kalincik et al. Cladribine Versus Fingolimod, Natalizumab and Interferon β for Multiple Sclerosis. Mult Scler, 24 (12), 1617-1626 Oct 2018. 

Objective: This propensity score-matched analysis from MSBase compared the effectiveness of cladribine with interferon β, fingolimod or natalizumab.

Methods: We identified all patients with relapse-onset multiple sclerosis, exposure to the study therapies and ⩾1-year on-treatment follow-up from MSBase. Three pairwise propensity score-matched analyses compared treatment outcomes over 1 year. The outcomes were hazards of first relapse, disability accumulation and disability improvement events. Sensitivity analyses were completed.

Results: The cohorts consisted of 37 (cladribine), 1940 (interferon), 1892 (fingolimod) and 1410 patients (natalizumab). The probability of experiencing a relapse on cladribine was lower than on interferon ( p = 0.05), similar to fingolimod ( p = 0.31) and higher than on natalizumab ( p = 0.042). The probability of disability accumulation on cladribine was similar to interferon ( p = 0.37) and fingolimod ( p = 0.089) but greater than natalizumab ( p = 0.021). The probability of disability improvement was higher on cladribine than interferon ( p = 0.00017), fingolimod ( p = 0.0025) or natalizumab ( p = 0.00099). Sensitivity analyses largely confirmed the above results.

Conclusion: Cladribine is an effective therapy for relapse-onset multiple sclerosis. Its effect on relapses is comparable to fingolimod and its effect on disability accrual is comparable to interferon β and fingolimod. Cladribine may potentially associate with superior recovery from disability relative to interferon, fingolimod and natalizumab.

Lymphocyte depletion kinetics and impact on subsets post cladribine

Stuve et al. Effects of Cladribine Tablets on Lymphocyte Subsets in Patients With Multiple Sclerosis: An Extended Analysis of Surface Markers. Ther Adv Neurol Disord, 12, 1756286419854986 2019 Jun 18 eCollection 2019

Background: Cladribine tablets 3.5 mg/kg cumulative over 2 years (CT3.5) had significant clinical/imaging effects in patients with clinically isolated syndrome (CIS; ORACLE-MS) or relapsing-remitting MS (RRMS; CLARITY and CLARITY Extension). 

Objective: This analysis compared the effect of cladribine tablets on the dynamics of immune cell reduction and reconstitution in ORACLE-MS, CLARITY, and CLARITY Extension during the first year of treatment (i.e. the first course of CT1.75) in patients randomized to CT3.5.

Methods: Lymphocyte subtypes were analyzed using multiparameter flow cytometry. Changes in cell counts and relative proportions of lymphocytes were evaluated at weeks 5, 13, 24, and 48.

Results: Across studies, consistent and comparable selective kinetics of immune cell populations occurred following the first treatment year with CT. A rapid reduction in CD16+/CD56+ cells (week 5 nadir), a more marked reduction in CD19+ B cells (week 13 nadir), and a less-pronounced effect on CD4+ (week 13 nadir) and CD8+ T cells (week 24 nadir) was shown. There was little effect on neutrophils or monocytes. Lymphocyte recovery began after treatment with CT3.5. Regarding relative proportions of naïve and memory T-cell subtypes in ORACLE-MS, the proportion of naïve-like naturally occurring T-regulatory cells (nTregs) decreased, and the proportion of memory-like nTregs increased, relative to total CD4+ T cells.

Conclusions: CT3.5 has comparable effects on the immune systems of patients with CIS or RRMS. The pronounced reduction and recovery dynamics of CD19+ B cells and relative changes in the proportion of some immune cell subtypes may underlie the clinical effects of CT3.5.

The safety profile of cladribine showing that severe viral infections are not a clinical problem

Cook et al.  Safety of Cladribine Tablets in the Treatment of Patients With Multiple Sclerosis: An Integrated Analysis. Mult Scler Relat Disord, 29, 157-167 Apr 2019.

Background: Treating patients with relapsing multiple sclerosis (MS) with cladribine tablets (two times 4 or 5 days of treatment each year for 2 years) results in long-lasting efficacy, with continued stability in many patients for 4 or more years. Safety and tolerability outcomes from individual clinical studies with cladribine tablets have been reported previously.

Objective: Report safety data from an integrated analysis of clinical trials and follow-up in patients with MS to further characterize the safety profile of cladribine tablets.

Methods: Data for patients treated with cladribine tablets 10 mg (MAVENCLAD®; 3.5 mg/kg cumulative dose over 2 years, referred to as cladribine tablets 3.5 mg/kg) as monotherapy (n = 923) or placebo (n = 641) in Phase III clinical trials (CLARITY, CLARITY Extension and ORACLE-MS) and followed up in the PREMIERE registry were aggregated (Monotherapy Oral cohort). To better characterize rare events, additional data from earlier studies which involved the use of parenteral cladribine in patients with MS, and the ONWARD study, in which patients were given cladribine tablets in addition to interferon (IFN)-β or placebo plus IFN-β were included in an All Exposed cohort (cladribine, n = 1926; placebo, n = 802). Adjusted adverse events incidences per 100 patient-years (Adj-AE per 100 PY) were calculated for the integrated analyses.

Results: The incidence rate of treatment-emergent adverse events (TEAEs) in the Monotherapy Oral cohort was 103.29 vs. 94.26 Adj-AEs per 100 PY for placebo. TEAEs that occurred more frequently with cladribine tablets were mainly driven by the TEAEs of lymphopenia (Adj-AE per 100 PY 7.94 vs. 1.06 for placebo) and lymphocyte count decreased (Adj-AE per 100 PY 0.78 vs. 0.10 for placebo) as anticipated due to the mode of action of cladribine. An increase in TEAE incidence rate was also observed in the cladribine tablets 3.5 mg/kg group vs. placebo for herpes zoster (Adj-AE per 100 PY 0.83 vs. 0.20, respectively). There were no cases of systemic, serious disseminated herpes zoster attributed to treatment with cladribine tablets. In general there was no increase in the risk of infections including opportunistic infections with cladribine tablets versus placebo, except for herpes zoster. Periods of severe lymphopenia (< 0.5 × 109 cells/L) were associated with an increased frequency of infections, but the nature of these was not different to that observed in the overall patient group treated with cladribine tablets 3.5 mg/kg. Within the constraints of a limited sample size, malignancy rates in the overall clinical program for cladribine in MS did not show evidence of an increase compared to placebo-treated patients and there was no increase in the incidence of malignancies over time in cladribine-treated patients.

Conclusion: The AE profile for cladribine tablets 3.5 mg/kg as a monotherapy has been well-characterized in a pooled population of patients from early to more advanced relapsing MS. There was no increased risk for infections in general except for a higher incidence of herpes zoster. Lymphopenia was amongst the most frequently observed TEAEs that occurred at a higher incidence with cladribine relative to placebo. There was also no increase in malignancy rates for cladribine relative to placebo.

Disclaimer: Please note this post, as with all of my blog posts, represents my personal opinions and not the views of my colleagues at Barts-MS.

CoI: multiple

#COVIDMS COVID-19 relevant case study

The following is a modified and anonymised email I received from a very concerned patient with MS. His treatment plan has been changed because of the COVID-19 epidemic. How would you advise him?

Dear Prof Giovannoni

I am a 51-year-old lady with active RRMS. I have only had MS for 3 years. 

I am due to have my first ocrelizumab infusion in 2 weeks time. 
My MS is active; I had a new lesion on my last MRI and my disability is progressing rapidly. My EDSS has moved from 2.5 to 3.5 in the last year. I was on glatiramer acetate, which I stopped a week ago. 

My MS team have advised me to delay ocrelizumab treatment indefinitely and to start dimethyl fumarate next week.
My job involves dealing with many members of the public in a very busy retail environment.

Could you advise me if it is okay to start ocrelizumab if my MS team are willing to provide treatment and whether I should self-isolate after treatment because of the amount of contact I have with the public? 

I realise that the Coronavirus situation is a very fast-moving situation, but as I am now only a few weeks away from my treatment date, I want to think through and carefully consider what to do. I don’t want to end up not having the most effective treatment for potentially another  6 to 12 months and missing the therapeutic window to slow down the progression of my MS. 
 
Any advice you can give me is greatly appreciated. 

Thank you 

With best wishes

******

This case illustrates the clinical issues the COVID-19 epidemic is raising and is only one example of what we are having to face in the clinic. There are no easy straightforward answers.

Post-script 14-March 2020

The core issue is that this patient appears to want to get on top of their MS disease activity as soon as possible and doesn’t want to take a chance on a lower efficacy option. If this is the case it excludes interferon-beta and teriflunomide as option, which would be the logical choices based on their putative anti-viral effects. 

I would not recommend DMF. Firstly, DMF is less effective as a second-line DMT and it is immunosuppressive with about 15% of treated patients developing a treatment-related lymphopaenia of <800/mm3. As this usually comes on within the first 6-12 months in may not be the best DMT to start with. 

In a normal treatment environment, fingolimod would be an option, but as it is immunosuppressive I would probably steer away from it as a treatment option. In addition, if a COVID-19 vaccine does emerge quite soon and high-risk patients get early access to the vaccine you don’t want to be on fingolimod. Fingolimod has been shown to blunt vaccine responses. 

Based on its impact on T-cells and innate immunity alemtuzumab is a no-no. You could make the same argument about cladribine, which is now enshrined in print in the Italian and ABN COVID-19 DMT guidelines. However, the data does not necessarily support these positions. The level of T -cell depletion post-cladribine is ~50% for CD4+ T-cells and ~40% for the CD8+ T-cells making a much safer IRT than alemtuzumab. The data on infections in patients who received cladribine in the phase 3 CLARITY  trial, including the subgroup who developed grade 3 & 4 lymphopaenia, is very reassuring with no severe viral infection signal. The advantage of cladribine is that with immune reconstitution occurs this patient will be able to receive a COVID-19 vaccine if and when it becomes available. 

For similar reasons to cladribine, ocrelizumab will be relatively safe.  However, once you start ocrelizumab you need to commit to at least 3 or 4 courses to prevent neutralizing anti-ocrelizumab antibodies. As ocrelizumab blunts vaccine responses it is not the ideal DMT thinking ahead to a vaccine. Ocrelizumab blunts vaccines responses.

This leaves natalizumab. Natalizumab is a high efficacy DMT, with a rapid onset of action and can be reversed by plasma exchange if necessary. It also will not exclude vaccination from a component (non-live) COVID-19 vaccine. From a theoretical perspective, natalizumab cannot be assumed to be safe if this patient became infected with COVID19. Natalizumab has been shown to slightly increase your chances of getting an upper respiratory tract infection and may hence increase the chances of a more severe COVID-19 infection. Then there is the theoretical risk that natalizumab may select for neurotropic strains of COVID-19, but I think this is only a theoretical risk at present. I would also predict that natalizumab has a chance of creating potential COVID-19 superspreaders as it blocks trafficking of T-cells into the gut. Even if this patient was JCV+ve I would still potentially go ahead with natalizumab treatment. To reduce the PML risk this patient could be converted to extended interval dosing of natalizumab after 6 months or switched to another DMT in sy 6-12 months. The elephant in the room is NHS England (NHSE); this patient doesn’t appear to fulfil the current criteria for treatment under the NHSE treatment algorithm. This case, however, highlights, why it is important that NHSE relaxes is criteria for using natalizumab to address the unmet need during the COVID-19 epidemic. 

The other aspect is this patient is in contact with the general public that may increase his chances of being exposed to COVID-19, which may be more important than the other factors predicted above. So if this patient can’t reduce their risk of potential exposure to the virus in the hope of hanging on until a vaccine or anti-COVID-19 anti-viral become available then one of the immunomodulatory DMTs will make the most sense. This is why I would favour teriflunomide as the DMT of choice. It is also worth mentioning that when teriflunomide is used 2nd- or 3rd-line it is more effective. Teriflunomide also does not exclude vaccines later on; vaccine responses to component vaccines is maintained on teriflunomide. 

If this patient is unhappy with the logic of going onto teriflunomide, my second choice would be natalizumab,  followed by cladribine or ocrelizumab. 

This case demonstrates the complexities of treating active MS during the COVID-19 epidemic. There are no right or wrong answers. Whatever decision you make there will be compromises. You may have to compromise on efficacy to increase the safety of the patient concerned and to potentially leverage the other attributes of DMTs to justify your treatment decision, for example in the case of teriflunomide that it is broadly antiviral and does not affect vaccine responses.

CoI: multiple

What is end-organ damage?

Help! How do I manage progressive brain atrophy in a patient who is NEDA-3?

End-organ damage is a catch-all phrase for the degeneration of the brain; it occurs as part of the ageing process that some consider pathological and others as a normal fact of life. I have hinted that I consider it both because end-organ damage is potentially modifiable via lifestyle modifications and pharmacological interventions. If it was a normal process it should not be modifiable. How can you be more normal than normal? Making ageing a disease also has political ramifications, for example, it will almost certainly incentivise Pharma to develop treatments for ageing.

In MS end-organ damage is massively accelerated by the MS disease process itself, i.e. inflammation and demyelination, and from delayed downstream processes triggered by inflammation, for example, energy failure, microglial activation, ongoing inflammation driven by antibodies, possible slow viral infection and its consequences and comorbidities. It is clear that all people with MS will have end-organ damage, but what can we do about it? To be honest, apart from early treatment to prevent damage, we haven’t got an evidence base about how to manage this problem in MS.

As an example, I saw a patient earlier this week. He has relapsing-remitting MS diagnosed in the mid-2000s and started on interferon-beta (Avonex). He also has type 1 diabetes which he developed when he was 14 years of age, 8 years before he was diagnosed with MS. His diabetes was poorly controlled initially but is now well controlled on an insulin pump. He has renal (proteinuria), eye (retinopathy) and hypertension as complications of his diabetes. His hypertension is controlled on medication. He has been relapse-free and his MRI has not shown any obvious new lesions over the last 6 years; i.e. he is NEDA-3. He does not smoke, but he drinks between 3 and 4 units of alcohol per day. He was referred to me because he is sick and tired of injecting himself with interferon and he has heard of a new drug called ocrelizumab. He wants to be switched to it because is more efficacious and only give every 6 months. His treating neurologist said no, hence his referral to me for a second opinion.

When I went through his history it is clear he has had no relapses in the last 6 years and is fully functional and working full-time. I reviewed his MRIs and I agree he has no new lesions over the last 6 years, but he has developed quite profound and progressive brain atrophy over this timeframe; he is definitely not NEDA-4. What do I do?

Do I switch him from interferon-beta to ocrelizumab? Or do I leave him on Avonex, which is doing its job and rendering him NEDA-3?

If I do switch him to ocrelizumab, will it normalise his brain volume loss? Will he become NEDA-4?

What is causing his brain volume loss? MS, hypertension, diabetes, alcohol or something else?

Do I tell him about his gross brain atrophy, which he is blissfully unaware of?

Do I offer him a formal cognitive assessment to see if he has cognitive impairments? If he has a cognitive assessment and they come back abnormal, which they are likely to, how do I tell him? Will knowing he cognitively impaired affect his management?

Do I offer him a lumbar puncture to measure his spinal fluid neurofilament levels?

Do I recommend any add-on off-label treatments that may help?

Or do I just take the easy option and send him back to his neurologist with a recommendation to leave things as is?

Can I suggest we debate these issues over the next few days and I can then potentially do a live webinar on the issue of end-organ damage and how to handle the problem of progressive brain volume loss on DMTs when you are NEDA-3.