De novo PML on ocrelizumab

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In my career as a neurologist, I have seen three patients who developed PML (progressive multifocal leukoencephalopathy) without any apparent risk factors apart from being old. They were all over 70. Prior to the HIV epidemic, about 1 in 10 patients with PML did not have an obvious underlying risk factor except for age or immunosenescence of the elderly.  Immunosenescence is the term immunologists use to describe malfunctioning of the immune system with ageing.

Based on the fact that even ‘normal’ elderly people have a very small risk of getting PML, it comes as no surprise that age is an emerging PML risk factor in MS, and explains why relatively safe DMTs have been associated with rare cases of PML. The last case of DMF-associated PML, who had a total lymphocyte count above 500, was in her sixties and old-age partially explains the first de novo case of PML on ocrelizumab (see below). 

We received the notification from Roche today describing a case of PML in a patient treated with ocrelizumab as first-line therapy, who also had a mild lymphopaenia. The question you will be asking is why is a 76-year-old MSer being exposed to such a potent immunosuppressive agent?  I don’t know. Maybe he had very active MS and his neurologist wanted to offer him a highly effective DMT first-line (flipping the pyramid). 

As what has happened with alemtuzumab usage in the US we are likely to see a more severe and unexpected adverse event profile in MSers who are older on ocrelizumab. Being older means they are more likely to have comorbidities, immunosenescence and less biological reserve to deal with serious and life-threatening infections. 

Am I concerned about this case? Yes and no. Yes, in the sense that I would think twice about using such a potent immunosuppressive agent in an elderly person with MS. No, in that de novo PML is rare with anti-CD20 treatment and is highly unlikely to be a problem in younger people with MS. 

On reflection, cladribine would have been a better high-efficacy DMT for this patient. The fact that cladribine is a selective IRT (immune reconstitution therapy) and does not cause longterm immunosuppression makes it a safer agent in this population group. Unfortunately, when this patient was started on ocrelizumab oral cladribine was not licensed in the US and the current FDA label discourages first-line use of oral cladribine. So even if cladribine was available at the time it is unlikely that it would have been prescribed. An interesting topic that is emerging in the field is the management of MS in the elderly, including the management of highly-active MS in this population group. Maybe we should put this topic forward for one of our future triMS.online conferences?

ROCHE STATEMENT

In the interest of patient safety, and as part of our ongoing commitment to transparency, I am forwarding this information.

  • We are aware of a report of a confounded case of progressive multifocal leukoencephalopathy (PML) in a multiple sclerosis (MS) patient in the United States of America who was treated with Ocrevus®▼(ocrelizumab). The potential contribution of Ocrevus treatment to this PML case is difficult to quantify but cannot be ruled out.
  • The patient has a long-standing history of MS. They were previously untreated and hence Ocrevus was their first disease-modifying therapy (DMT). The patient was treated with Ocrevus for two years, with the initiation of treatment in July 2017 and the last dose was administered in February 2019.
  • The treating physician has reported this as a confounded case of PML. Contributing factors (confounders) reported by the physician are the patient’s age (78) with potential immunosenescence, low absolute lymphocyte count (ALC) prior to treatment with Ocrevus (max CTCAE grade 1, no subtypes available), as well as low ALC (max grade 2), low CD4+ (max grade 2) and low CD8+ counts during treatment, with Ocrevus as a probable contributor.
  • Roche follow the American Academy of Neurology (AAN) criteria to establish the diagnosis of PML, in addition to consultation with an external advisory panel of experts.
  • Patient safety is Roche’s highest priority, and, consistent with our safety reporting processes, we report to health authorities in accordance with standard pharmacovigilance processes.
  • Roche is in contact with the treating physician to help evaluate the case, providing support and expertise where appropriate. 
  • The overall benefit/risk for Ocrevus remains unchanged at this time. As of 30th September 2019, more than 130,000 people with MS have been treated with Ocrevus globally (1). To date, there have been no unconfounded cases of PML reported in patients treated with Ocrevus. All seven previous confirmed PML cases of patients treated with Ocrevus were confounded by and attributed to the previous DMT (carry-over cases). This is the first PML case in a patient treated with Ocrevus where the cause of the PML, although confounded, has not been attributed to a previous DMT.

The recommendations relating to PML in the approved product labelling for Ocrevus remain unchanged. Physicians should be vigilant for early signs and symptoms of PML, which can include any new-onset, or worsening of neurological signs or symptoms, as these can be similar to an MS relapse. If PML is suspected, withhold dosing with Ocrevus.

Please refer to the summary of product characteristics for full prescribing information here.

For ease of reference, we have collated an overview of all confirmed PML cases to date (October 2019):

Confirmed case no.CountryReportedSettingConfounding factor(s)
1GermanyMay 2017Compassionate Use programmePrior DMT (Natalizumab)
2CanadaApril 2018Post-marketingPrior DMT (Fingolimod)
3USAMay 2018Post-marketingPrior DMT (Natalizumab)
4USAJune 2018Post-marketingPrior DMT (Natalizumab)
5USAJuly 2018Post-marketingPrior DMT (Natalizumab)
6LuxembourgSeptember 2018Post-marketingPrior DMT (Natalizumab)
7USAFebruary 2019Post-marketingPrior DMT (Natalizumab)
8USAOctober 2019Post-marketingAge (78) & low lymphocyte counts prior to, and during Tx

Mills and  Mao-Draayer. Aging and lymphocyte changes by immunomodulatory therapies impact PML risk in multiple sclerosis patients. Mult Scler. 2018 Jul;24(8):1014-1022. doi: 10.1177/1352458518775550. 

New potent immunomodulatory therapies for multiple sclerosis (MS) are associated with increased risk for progressive multifocal leukoencephalopathy (PML). It is unclear why a subset of treated patients develops PML, but patient age has emerged as an important risk factor. PML is caused by the JC virus and aging is associated with immune senescence, which increases susceptibility to infection. With the goal of improving PML risk stratification, we here describe the lymphocyte changes that occur with disease-modifying therapies (DMTs) associated with high or moderate risk toward PML in MS patients, how these changes compare to immune aging, and which measures best correlate with risk. We reviewed studies examining how these therapies alter patient immune profiles, which revealed the induction of changes to lymphocyte number and/or function that resemble immunosenescence. Therefore, the immunosuppressive activity of these MS DMTs may be enhanced in the context of an immune system that is already exhibiting features of senescence.

CoI: multiple

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

21 comments

  • Prof G – if someone is in their fifties and they have been treated with Ocrelizumab for a while with no other comorbidities, at what age exactly would you advise them to stop treatment? Would there be a real risk of rebound after stopping? If so, what steps would you take as their neurologist to prevent this from happening? Thankyou for this informative blog.

    • Based on the phase 2 ocrelizumab extension trial in which study subjects were treated for 18 months and then no treatment for the next 18 months with very little or no activity for the next 18 months, suggests rebound is unlikely post-ocrellizumab. However, as with all IRTs recurrence of disease activity is likely with time, This is why we need an exit plan with anti-CD20 therapy and is one of the reasons why I want to to the iTeri study, i..e de-escalating anti-CD20 therapy to a safer maintenance compound.

  • Afternoon Prof G

    I’m 53 years old and I have been offered ocrelizumab and MS diagnosis in 2016. I’m due to start it hopefully in the next 2 wks. My MS is active daily. I was on Tecfidera but had to come off urgently, as my lymphocytes went very low. They have now reached 0.9 (yay) & following 1 more blood test to check again, possibly I can go ahead with the above.

    Having read your post on the drug & not having the JC virus, do you think this would be the best way forward for someone of 53 years? If I choose not to go ahead with ocrelizumab, there are 3 different treatments listed below. Please could you assist me and put these drugs in order of effectiveness for someone with RRMS and of my age:

    alemtuzumab (Lemtrada) • natalizumab (Tysabri) • ocrelizumab (Ocrevus) •
    • cladribine (Mavenclad) • fingolimod (Gilenya).

    I know you are unable to offer your advice via an email – but if you could rank the top 3 in order of success and effective? Thank you for keeping us all informed and guidance.
    Jane

    • I’m definitely no Dr G, but for what I’ve read from him this would be my guess:

      1) alemtuzumab, ocrelizumab and natalizumab (alemtuzumab probably the most efficacious, ocrelizumab probably the safest, assuming JCV+)
      2) oral cladribine
      3 fingolimod

    • I am beginning to form an opinion that oral cladribine or off-label parenteral cladribine is likely to be the safest long-term DMT in people who are high-risk of PML or long-term immunosuppression. This does not mean they can’t be treated with other DMTs, but the risks need to be carefully considered.

  • On a tangent — how common is highly active MS among the elderly?
    Does it usually keep progressing? With or without clear relapses?
    How often does it stabilise (stop smouldering)?

    • Re: “how common is highly active MS among the elderly?”

      I don’t know the answer to this, but it is less common. Focal inflammatory activity is less common in the elderly, but it can still occur, particularly as part of a rebound phenomenon when anti-trafficking DMTs are stopped, i.e. natalizumab and fingolimod.

  • Gavin, Thank you for this interesting blog. We have seen de novo emergence of PML in relation to treatment with other anti-CD20, rituximab treatment in the patients with rheumatoid diseases, hence, the news is not shocking to me.
    just wondering why Roche/Genentech has made no public announcement to the public, specifically the MS community.
    Best regards,
    Kallal

    • Re: “de novo emergence of PML in relation to treatment with other anti-CD20, rituximab treatment in the patients with rheumatoid diseases”

      In fact, de novo PML on anti-CD20 monotherapy is very rare. I am aware of only one case that had not been previously exposed to other immunosuppressive therapy in the past. Therefore, the risk of PML on anti-CD20 therapy alone will be low and will remain low. In the MS space, this will be complicated by previous exposures as well and immune senescence.

  • Thank you very much, Prof. G, for this post! I am 56, on Fingolimod for 8 years so far. My neuro has mentioned that maybe after 60, medication could be stopped but agreed that the rebound risk when coming off Fingolimod could be a real issue, and that the brain protective effect Fingolimod seems to have to an extent could be a benefit even if there were supposedly less inflammation in older age. I find it lamentable that, on the whole, there seems to be far less research on older people, ms and medication benefits and risks and therefore appreciate your sharing of experience from working with patients very much. If I go to MS Societies’ websites, they do not have information abou this, either. I would be very grateful if you, Prof G, or another contributor to the blog were to start a series of posts regarding older age ms and medications!

    • In the fingolimod PPMS trial, which by definition included older subjects because PPMS presents approximately 10 years later than RRMS, had several patients presenting with rebound when fingolimod was stopped. Therefore age won’t necessarily protect older MSers from rebound.

      I agree we need more information about DMTs in the older patient with MS. This is not going to come from clinical trials unless specific trials are done in the elderly.

  • What do you consider “old”? I am 60 and started Ocrevus a year ago. This term is bothersome to me and varies about doctors. I’d appreciate if you could provide your opinion. Thank you. Cathy Chester

    • Yep, 60 would be considered old as far as MS goes. Most MS trials, particularly RRMS trials, cap the age at 55 years and occasionally at 60. So we don’t have data in the 60+ year age group.

  • Perhaps doctors should consider reducing dosages for the elderly whose immune systems may not be able to withstand the full dose?

    There needs to be some sort of trials with the recent family of MAB-based immunosuppressive DMTs as they do seem to be a “one size fits all” treatment for an extremely variable and multi-faceted condition.

    Vis the number of people developing acute lymphopenia on tecfidera who might have easily tolerated a lower dose (which might well still have been effective)

    • I am not sure that I am saying older MSers should be treated differently, All I am saying is that the risk:benefit ratio changes with age. The older you are the more comorbidities you have the more likely you are to develop certain adverse events on treatment. We have seen this with fingolimod and alemtuzumab.

  • Leaving aside the specifics or generalities of any cases of rebound relapses after cessation of any existing MS drugs, any cases of PML from whatever MS drug or combination/sequence of MS drugs, etc, it is way beyond the time when Pharmaceutical companies and neurologists should have woken up to the simple inescapable fact that almost all younger people with MS will actually become older people with MS. Given the increasing incidence of MS there will also be many more older PwMS than there are currently. Funny how it seems to be getting missed that we all get older and this is not being factored into clinical trials etc. Is an older PwMS any less deserving of being included in trials or having access to treatments or do we just not bother because they are “old”? Do I dare to call it a manifestation of ageism? Sigh………………..

    • Re: “Pharmaceutical companies and neurologists should have woken up to the simple inescapable fact that almost all younger people with MS will actually become older people with MS.”

      I think they know this, but they don’t want to complicate their data with comorbidities of the elderly hence strict age cut-offs in clinical trials. I would recommend we get the regulatory authorities to address this and demand safety registers that will collect this information as part of the post-marketing commitments of the drug.

  • We know that there’s an increase in late onset MS as well as many more with MS living into a ripe old age, so collation of all data pertinent to medication and care seems to be an urgent priority.

    Your replies ProfG make a lot of reference to comorbidities in the ‘elderly’ and yet in reply to this post from last year you emphasised the comparable difference between chronological and biological age for those of us, like me, panicking at the prospect of DMTs becoming redundant to any of us post 53.

    Anna – you maybe interested in the vid by Aaron Boster in which he argues against the rationale of stopping DMTs in older patients.

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