Case study: how do you define a rituximab failure?

This patient with MS is anxious that he may have early secondary progressive MS and rituximab is failing him. He is keen to explore AHSCT. Is this appropriate?

Case Study

I am a 43-year-old male with multiple sclerosis. I have had two previous clinically documented episodes. First, an episode of optic neuritis when I was 29 years old. This was confirmed by MR with a lesion in my optic nerve, but there were no other lesions or signs of nerve damage. Lumbar puncture showed no OCBs in my CSF. No medication was offered. I made a complete recovery and was asymptomatic for nearly 10 years after that. 

Time is brain and spinal cord. Photo by Nathan Dumlao on Unsplash

I experienced a minor relapse of optic neuritis about 4 years ago. Again, no new lesions on the MR or any uptake of contrast, but they could see the old lesion on the optic nerve. Again I made a complete recovery which lasted about 3 years after this. No medication was offered.

I was diagnosed with ‘relatively active’ RRMS seven months ago. Still, no OCBs in my CSF, but now the MRI showed 10-12 new lesions since the previous MRIs, five years ago. These lesions are periventricular, in my brain stem, spinal cord, and cerebellum.

Over about the last 1 year, I have been gradually worsening, especially my gait, bladder function, and pain (later diagnosed as trigeminal neuralgia). The neurologist still considers me to have RRMS, but I think I may be transitioning to SPMS. 

I’ve been on Rituximab for 6 months. During that time I have worsened quite markedly in gait and pain. No new or enhancing lesions since I stated Rituximab - latest MR two months ago, 4 months after I started Rituximab. The neurologist estimates my current EDSS to be 3.5-4, whereas it was about 2.5 before starting Rituximab.

The data have shown that aHSCT is highly effective in active RRMS, but data also indicates that aHSCT could stabilize the condition (at least EDSS and brain volume) for 5-10 years in SPMS or individuals transitioning from RRMS to SPMS (Boffa et al. Neurology. 2021 Jul 27;97(4):203; Mariottini et al. Mult Scler. 2021 Jan;27(1):61-70.)

Although stabilization is not a perfect response, I do not know of any other form of treatment that has a similarly good effect in individuals transitioning to SPMS, or who have SPMS. Rituximab seems to have some effect in slowing progression in adults < 51 years, but it is still nowhere near the effect reported of aHSCT in this population. I understand that the data is limited, and there are no RCTs of aHSCT in this particular population so we do not know if the effect of aHSCT is different from the natural course of MS. However, stabilization for up to a decade seems clearly superior to what has been reported in other trials of high-efficacy DMTs and what I am experiencing.

On the basis of having RRMS (or early SPMS), low-moderate EDSS, no comorbidities, otherwise good health, age < 45, and a deterioration of function despite being on a high-efficacy DMT, I, therefore, want to pursue getting aHSCT at the earliest possible time. I understand that it is often a criterium to have a full clinical relapse or new lesions while on a high-efficacy DMT, but I think Rituximab has failed. I am quite intimidated by the risks of aHSCT, and the risk of side effects is higher than the likelihood of a good response. However, I still think it would be worth the risk. I had a high fever as a response to the third dose of covid-vaccine and all of my symptoms were exacerbated, as well as new symptoms of dizziness, and numbness in my mouth and right arm. Do you have any input on this matter? Thank you.

Other information:

Medication: Rituximab. Trileptal (oxcarbazepine) 450mg x 2.

Employment: Full time.

Lifestyle and symptom management:

Exercise: Regular resistance and training on a stationary bike.

Mental health: Weekly sessions with a psychotherapist.

Sleep: OK, but increasingly susceptible to negative effects of short sleep.

Regularity: Attempting a regular timing of all lifestyle factors, especially sleep-wake

rhythm.

Diet: Wahls paleo protocol.

Supplements: Vit D, biotin 150mg x 3, fish oil.

Prognosis: (according to your post on number of risks):

Number of  risk markers at first attack in 2007: 1 (though some were not assessed)

Prof G’s opinion

Should I assume rituximab has failed you? The latter is in the eye of the beholder and depends on your treatment target. Is your treatment target (1) no evident-inflammatory disease activity (NEIDA or NEDA-2), i.e. no relapses or no focal MRI activity, or (2) no evident disease activity (NEDA or NEDA-3), i.e. no relapses, no focal MRI activity and no disability progression. If the latter then you would possibly be eligible for AHSCT under the  London MS-AHSCT guidelines (see below). I suspect your MS is likely to have started more than 15 years ago, despite your initial MRI showing no lesions, there may have been ongoing MS disease activity beneath the threshold of the MRI scanner. However, the AHSCT MDT (multidisciplinary team) will likely set your disease onset at 14 years ago when you had your first attack of optic neuritis when you were 29 years old. This would make you eligible for AHSCT based on disease duration.

The main issue that will arise is that you have only been on rituximab for only 6 months and this is not really sufficient time to judge its effectiveness. Most DMTs have therapeutic lag and take time to have an effect. It is clear from the ocrelizumab NEDA data that a lot of inflammatory activity still occurs in the first 6 months only to settle down after that.  This is why I would suggest exploring the logistics of AHSCT and other treatments whilst you give rituximab some more time to work. 

I note you are OCB negative on two occasions. This means you have no evidence of a CNS or intrathecal (within the meninges of the CNS) oligoclonal B-cell response. This may suggest that B-cells are not driving your MS pathology and is one of the reasons why we excluded OCB-negative subjects from the PPMS ocrelizumab trial. What I am trying to say is that you may have a type of MS that may not necessarily be responsive to anti-B-cell therapies. 

I must also warn you that I am not convinced of the data that AHSCT is necessarily effective in switching off or controlling smouldering MS, which you may have. The AHSCT data in early relapsing MS is very convincing but less so in more advanced or progressive disease. I am not saying it will not be effective, I am simply stating that we need better well-controlled studies to show AHSCT is effective in people with both secondary and primary progressive MS before recommending it for progressive MS. I have done a separate Newsletter on the proposed mechanisms underlying smouldering MS and if the hypotheses are correct AHSCT will not target several of these mechanisms.

When it comes to smouldering MS there are several drivers of the pathology and one may be microscopic inflammation that is not being targeted by rituximab. Also in general anti-CD20’s effects on end-organ damage markers, i.e. brain volume loss, is not that good. Recently Fredrik Piehl, a Swedish neurologist, told me that in a Swedish cohort of patients with MS brain volume loss was higher in rituximab-treated patients than interferon-beta patients. This is why the highly effective IRTs (alemtuzumab and AHSCT), which have a profound effect on brain volume loss, are more compelling as a treatment option in MS. I am aware of several Norwegian centres that are using alemtuzumab. Have you explored this as a potentially safer treatment option than AHSCT? 

In summary, I would support your need to seek a more effective therapy compared to rituximab. I am not convinced you have failed rituximab yet. In our centre, we only rebaseline pwMS on anti-C20 therapy at 6 months and start the treatment response clock ticking at this timepoint. However, I understand your anxiety and the implication from your description that ‘time is brain and spinal cord’  and that when a decision is potentially made to escalate treatment it may come too late in the course of your disease. I am interpreting your request for advice as being that you don’t want to have any regrets. 

If you were an NHS patient I would explore your eligibility for alemtuzumab and HSCT in more detail with a repeat MRI with gadolinium of both the brain and spinal cord. I would do a repeat lumbar puncture to recheck for OCBs and to measure neurofilament light chain levels. These investigations are to see if you have any evidence of ongoing inflammatory activity. I would also check to make sure you are B-cell depleted; if not I would screen you for anti-rituximab antidrug antibodies. The latter occurs in about 5-8% of rituximab treated patients and is one reason for treatment failure. In parallel, I would refer you to our pan-London AHSCT MDT (multidisciplinary team meeting) to see if they consider you eligible for AHSCT. If we get the green light from them and we document inflammatory activity I would meet with you to discuss your treatment options. 

The decision between alemtuzumab and AHSCT is a complex one that you would have to make yourself and it will depend on how risk-averse you are and whether or not you want to have the most effective treatment,  i.e. AHSCT, when we can’t guarantee you that it will halt smouldering MS.  I assume you are aware that the cyclophosphamide used in AHSCT can affect your fertility and if this is an issue you would need to bank sperm. AHSCT is one treatment that by its nature takes a long time to prepare for; in my experience, it takes 3 months or more before it can be done.

MS Clinical Criteria adopted by the London MS-AHSCT Collaborative Group

The eligibility criteria are broadly based on the consensus protocol agreed for a Phase 3 trial of AHSCT in MS (Saccardi et al, 2012). Justification for the criteria is further provided by evidence from AHSCT trials and observational studies (as referenced).

Referral criteria:

1. Diagnosis of MS made by a neurologist

2. Able to walk, need at most bilateral assistance to walk 20mt without resting

3. In RMS, failed at least one highly active approved therapy (currently MITOX, FTY, NTZ, ATZ) because of demonstrated lack of efficacy

4. New MRI activity within last 12 months

Inclusion criteria:

1. Age 18 to 65 years

2. Disease duration <=15 years from diagnosis of MS

3. Diagnosis of MS according to McDonald’s criteria

4. For PPMS, CSF OCB+

5. For RMS, failed at least one highly active approved therapy (currently MITOX, FTY, NTZ, ATZ) because of demonstrated lack of efficacy (relapse, MRI activity as defined at point 7 after being on DMT for at least 6 months, EDSS increase)

6. EDSS score 0-6.5

7. Inflammatory active MS as defined by ≥1 Gd+ (>3mm) lesion(off steroids for one month) or ≥2 new T2  lesions in MRI within last 12 months detected at interval comparison with previous MRI

8. Approved by the MDT

Exclusion criteria:

1. Prior treatment with total lymphoid irradiation and autologous or allogeneic hematopoietic stem cell transplantation

2. Contraindication to MRI including but not limited to metal implants or fragments, history of claustrophobia or the inability of the subject to lie still on their back

3. Presence of any active or chronic infection

4. Any significant organ dysfunction or co-morbidity that the Investigators consider would put the subject at unacceptable risk

5. Poorly controlled depression or recent suicidal attempt

6. Inability to give written informed consent

7. Unable to walk 20mt with or without support, or wheelchair dependent

8. Eligible for an ethically approved clinical trial where AHSCT is offered as one of the treatment arms

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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.