麻豆传媒

Progressive multifocal leukoencephalopathy (PML) occurring with ocrelizumab (Ocrevus) monotherapy developed in a 78-year-old man with progressive multiple sclerosis (MS), the first such case known, researchers reported.

"This report details the first and only case, to our knowledge, of pathologically proven PML occurring with ocrelizumab monotherapy in a patient without prior immunomodulation," wrote Asaff Harel, MD, MSc, of Lenox Hill Hospital in New York City and Zucker School of Medicine at Hofstra/Northwell, and co-authors, in .

The case emphasizes the importance of "a thorough discussion of the risks and benefits of ocrelizumab, especially in patients at higher risk for infections such as elderly patients," they added.

PML is caused by reactivation of latent John Cunningham (JC) virus infection and often leads to death or severe disability. Drug manufacturer Genentech has reported ; all were carry-over cases involving prior treatment with either natalizumab (Tysabri) or fingolimod (Gilenya), two MS drugs also linked to PML. Another anti-CD20 drug, rituximab (Rituxan), often used off-label in MS, has been when used to treat rheumatic diseases.

This case, first but with many details lacking, is the only one associated with ocrelizumab alone. The 78-year-old progressive MS patient had been treated with ocrelizumab monotherapy for 2 years when he presented with 2 weeks of progressive visual disturbance and confusion. He had right homonymous hemianopia on exam and MRI showed an enlarging non-enhancing left parietal lesion without mass effect.

Cerebrospinal fluid analysis revealed 1,000 copies/mL of JC virus, confirming PML diagnosis. Blood work at diagnosis showed the following:

• Grade 2 lymphopenia with absolute lymphocyte count of 710/μL
• CD4 of 294/μL (reference range 325-1251/μL)
• CD8 of 85/μL (reference range 90-775/μL)
• CD19 of 1/μL
• Preserved CD4/CD8 ratio (3.45)
• Negative HIV serology

Also, retrospective absolute lymphocyte count revealed intermittent grade 1 lymphopenia that preceded ocrelizumab (absolute lymphocyte count range 800-1,200/μL).

The patient's symptoms progressed over weeks to involve bilateral visual loss, right-sided facial droop, and dysphasia. Ocrelizumab was discontinued and off-label pembrolizumab (Keytruda) treatment was started. The patient continued to decline with rapid deterioration in visual, motor, and language function. He died 1 month after his initial PML diagnosis, and PML was confirmed at autopsy.

"While one could theoretically postulate that ocrelizumab use was coincidental and not contributory, I consider that possibility highly unlikely," observed Harel. "This is simply because it is extremely rare for PML to occur in the setting of only mild lymphopenia like the patient had and there were no other predisposing factors outside of the patient's age." Onset of PML 2 years after starting ocrelizumab is consistent with the notion of a possible medication effect, he added.

A more likely explanation is that PML occurred because of several factors, including the immunomodulatory function of ocrelizumab combined with age-related immunosenescence and mild lymphopenia, Harel told 麻豆传媒. "Ultimately, while PML will continue to be very rare with B-cell therapies, I think one of the big take-aways from this case is that we as a field need to learn more about the safety and efficacy of immunotherapies for our aging MS population."

The important factors in this case were old age and the fact that this patient had lymphopenia, said Gavin Giovannoni, MBBCh, PhD, of Queen Mary University of London in England, who wasn't involved with the case.

"I really think MSologists need to rethink how we manage older patients with MS," Giovannoni told 麻豆传媒. "Can we really justify chronic immunosuppression in older patients when we have safer alternatives?"

Ocrelizumab clinical trials and restricted recruitment to patients 18 to 55 years old, but the FDA approved ocrelizumab for primary progressive MS without restriction on age, Harel and colleagues noted.

"Given the lack of other treatment options, this led many older patients to opt to start the medication shortly after its approval, despite there not being specific safety data for this population," they wrote. "This issue is of paramount importance as it is estimated that a quarter of people with MS are older than 65 years, a number that will increase with time."

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