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?
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.||Country||Reported||Setting||Confounding factor(s)|
|1||Germany||May 2017||Compassionate Use programme||Prior DMT (Natalizumab)|
|2||Canada||April 2018||Post-marketing||Prior DMT (Fingolimod)|
|3||USA||May 2018||Post-marketing||Prior DMT (Natalizumab)|
|4||USA||June 2018||Post-marketing||Prior DMT (Natalizumab)|
|5||USA||July 2018||Post-marketing||Prior DMT (Natalizumab)|
|6||Luxembourg||September 2018||Post-marketing||Prior DMT (Natalizumab)|
|7||USA||February 2019||Post-marketing||Prior DMT (Natalizumab)|
|8||USA||October 2019||Post-marketing||Age (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.