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Case study: to complete a course of cladribine or have AHSCT abroad?
A patient with rapidly-evolving severe MS is having doubts about the decision to be treated with cladribine. Should she abort the cladribine and have AHSCT?
I am a 49-year-old female who is a non-smoker, a non-drinker and I am currently unemployed. I, unfortunately, lost my job during the pandemic and shortly afterwards went blind in my left eye due to optic neuritis. I was treated with steroids and my vision recovered.
My MS history: I had a normal brain MRI in 2000 when I presented with an episode of twitching in my fingers and toes. In 2017, I presented with paresthesia in my lower arms and some difficulty walking which resolved spontaneously. I was misdiagnosed as having anxiety.
In Sept 2020 I presented with optic neuritis and left-sided weakness, which had been present for some time prior to ON and extreme fatigue. My walking distance was reduced from more than 10,000 steps a day to 6,000 steps a day when a footdrop sets in.
An MRI with gadolinium in October 2020 showed 12 lesions in the brain with two relatively large ones in the left middle cerebellar peduncle and in the lower medulla at the cervical medullary and eight lesions on the cord at levels C2, C3, C5-C6, T1, T2, T8 and T9. No lesions enhanced.
A diagnosis of MS was made without a lumbar puncture or spinal tap.
I relapsed again in February 2021 with an episode of urinary incontinence, numbness of the left cheek and reduced walking distance which is now down to 3,000 steps before fatigue sets in. A repeat MRI in April, without gadolinium, shows a new lesion on the right middle cerebellar peduncle.
I will probably never know whether my MS onset was 21 or 4 years ago. Either way, it is bad news. My current EDSS is 3.5. I walk daily, swim 500m three times a week, practice yoga and have a very clean diet. I have no other co-morbidities and am otherwise healthy (BMI 21)
My current medications are:
4000 IU Vitamin D daily
Cladribine 10mg started August 17th, due to take the second set of tablets next week, but I am considering delaying this and instead of having HSCT abroad.
My current EDSS 3.5 with cog fog, occasional numbness in extremities, slight balance issues, mild bladder issues, reduced walking distance and fatigue. My cognition has not formally been assessed but I think this has been affected too.
What type of MS do I have?
From your case study description, I am going to assume you have MS and are well informed about MS. You are clearly asking all the right questions. It is also clear based on your description above that you have relapsing MS.
What prognostic group do I fall into?
Yes, you are correct you fall into the poor prognostic group with a high lesion load, posterior fossa and spinal cord lesions. You have had two relapses, and probably a third subclinical relapse, in the last year and have motor and sphincter (bladder) involvement. Your EDSS and walking distance have also deteriorated in the last year and you may have cognitive problems.
I would have offered you a lumbar puncture to make sure of the diagnosis and to measure your spinal fluid neurofilament levels. Please note many MSologists don’t think these are necessary.
What is the risk of not being treated with a disease-modifying therapy (DMT)?
Based on your profile above the risk of not treating you is high and you would likely progress quite quickly. You have made the right decision to be treated.
Do I have active MS?
Yes, you have active MS defined clinically with relapses and disease progression and on MRI with a new lesion between scans. Based on contemporary criteria you have rapidly evolving severe MS.
Am I eligible for treatment with a DMT?
Yes, in our centre you will have been eligible for all licensed treatments except for fingolimod, which is only used 2nd-line and siponimod because it is licensed for active SPMS. Under our local London AHSCT guidelines, you would be ineligible for AHSCT as you have to have failed a high efficacy DMT. However, in Sheffield and possibly other centres, you could be considered for AHSCT as they have treated some patients first-line.
What is the difference between a maintenance/escalation DMT and an IRT (immune reconstitution therapy)?
Based on your desire to have AHSCT you seem to understand the difference between maintenance/escalation and an IRT and have chosen the latter route by being treated with cladribine.
Do I understand the difference between short-term intermittent and long-term continuous immunosuppression?
Do I understand the concept of treat-2-target?
What are the attributes of the specific DMTs?
How can I derisk or reduce my chances of getting certain adverse events on specific DMTs?
I am not going to address these questions in regard to your case.
Your other questions:
I am keen to do everything I can to halt progression whilst I am still able to walk and relatively able which is why I am considering HSCT. I don't feel that time is on my side. My MS is highly active or rapidly evolving and the poor prognosis is terrifying me. I know you do not approve of getting HSCT overseas, but could you advise me on having the transplant done all things being equal?
Yes, in an ideal world AHSCT is the most effective treatment available and I would support your decision to be treated with AHSCT. However, it takes time to set things up and to get all the necessary processes in place for AHSCT. Because of this, I would have probably offered you natalizumab, which is our most rapidly-acting high-efficacy DMT, to get on top of your disease activity quickly. This would then have allowed us to check your JC virus status and to think about the next steps in terms of your management. Natalizumab is the pause/thinking DMT. In many patients who are JCV negative and go onto natalizumab stay on it as it can be very effective in controlling inflammation quickly. In addition, many patients have disability improvement and notice reduced fatigue and clearing of their cog-fog. The use of natalizumab like this underpins our Attack-MS study strategy to use natalizumab within 7 days of presentation in highly active MS.
Things I am worried about:
If my MS started 21 years ago, am I too far into the disease process to be a good candidate for HSCT?
No. I am not sure your disease did start 21 years ago. Your symptoms back then are quite atypical and your MRI was normal. I wouldn’t over-interpret that episode. It is a pity your symptoms were misdiagnosed 4 years ago. You are another example of what a difference 4-years can make in the course of MS; time really is brain and in your case spinal cord. There is now good data showing how much better pwMS do if started on treatment within 1 year of symptom onset compared to a delayed start of treatment.
If my MS started 4 years ago, it has been very aggressive and I have a heavy lesion load. Do I go to Mexico sooner to halt the progression of my disability without waiting to fail a DMT in which case I will be older and potentially have more lesions/disabilities?
Time is not on my side and I don't want to progress any further.
No, I would not recommend going to Mexico. It is expensive and there are undefined risks associated with being treated in a foreign country. My AHSCT colleagues refer to the Mexican protocol as AHSCT-light as the dose of cyclophosphamide used is much lower than other more accepted AHSCT protocols and it is combined with rituximab (anti-CD20). The latter is usually continued for another 2 years when you return from Mexico. Is it the AHSTC-light or the rituximab that is treating the MS? The latter is a moot point.
I can feel my MS symptoms most days so although early days into the cladribine, I am an anxious person and stress exacerbates my symptoms. My mobility has reduced by 75% in a year and my MS feels very active. Although risky, I feel it is more favourable to try and halt the progression with HSCT rather than risk further disability and have been offered a place in Mexico.
In general, it seems you have committed yourself to cladribine. I would therefore continue with completing the two courses and see how you do. I would however have a low threshold for using another agent if you have breakthrough disease activity.
In general, based on your profile I would probably have preferred you to be treated with alemtuzumab than cladribine. However, in the current situation with COVID-19 and the need for vaccinations cladribine is the more suitable of the two licensed IRTs.
Should I delay taking my second set of cladribine for an easier washout and take the place in Nov/Jan/July?
No, I would not recommend this for the reasons above. You will be surprised at how quickly cladribine works as an anti-inflammatory therapy and in patients with highly active MS is a very effective DMT. The latter is based on its impact on relapse rates, disability progression and NEDA (no evident disease activity). I suspect the decision to treat you with cladribine is quite a wise one during the current pandemic and was taken to protect you in case you got COVID-19 and to make sure you are vaccine ready.
I sincerely hope this deals with all your questions? Your case also illustrates why it is sometimes important to pause and define the objectives of an MS treatment. It is clear there is no one correct answer to how one particular patient is managed. This is why medicine is an art and not a science.
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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 Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust. The advice is intended as general advice and should not be interpreted as being personal clinical advice. If you have problems please tell your own healthcare professional who will be able to help you.