Ocrevus Use Linked to PML in Man, 78, With PPMS, Case Report Says

A 78-year-old man with multiple sclerosis (MS) developed the brain infection progressive multifocal leukoencephalopathy (PML) after two years of treatment with Ocrevus (ocrelizumab), a recent case report detailed.

Treatment was discontinued and, as the patient’s symptoms worsened, he was moved to off-label treatment with pembrolizumab (a cancer treatment, brand name Keytruda) before he died.

While nine other cases of PML have been associated with Ocrevus treatment, each of these patients had switched to Ocrevus from another disease modifying therapy (DMT) with lasting effects on the immune system.

This case is the first reported in a patient with primary progressive MS (PPMS), taking Ocrevus without a previous history of DMT use. It emphasizes the importance of discussing the risks and benefits of treatments like Ocrevus, especially in elderly patients at higher risk for infections, the researchers wrote. 

The case study, “Progressive Multifocal Leukoencephalopathy in a Patient With Progressive Multiple Sclerosis Treated With Ocrelizumab Monotherapy,” was published in the journal JAMA Neurology. 

Most MS therapies aim to suppress the immune system and reduce inflammation to protect the myelin sheath, the fatty coating surrounding nerve fibers. However, immune suppression increases a person’s risk of infections. 

PML is caused by infection with the JC virus, also called polyomavirus 2. A common virus, it is harmless except in people with weakened immune systems, where it can lead to inflammation and progressive damage to white matter, the part of the brain with myelinated nerve fibers. 

Worldwide, more than 95% of PML cases are caused by HIV infection (the virus that causes AIDS) and blood cancers, which either directly or through their treatments suppress the immune system. PML has also been linked to the use of Tysabri (natalizumab), which treats MS by blocking inflammatory immune cells from entering the brain.

In rare occurrences, PML has been associated with therapies that target the CD20 protein to suppress the growth of antibody-producing B-cells, such as the MS therapies rituximab, Kesimpta (ofatumumab), and Ocrevus. 

“Notably, no cases had been previously reported with rituximab or ocrelizumab [Ocrevus] monotherapy for multiple sclerosis,” the study noted.

Researchers at the North Shore University Hospital in New York reported the case of a 78-year-old with PPMS who developed PML while receiving Ocrevus as a sole therapy.

The man had been diagnosed with MS almost three decades before, after developing gradual walking problems and leg weakness on one side. He had not been treated with an immunotherapy until starting with Ocrevus soon after its approval in 2017, when he was 76 years old. 

Before treatment, the patient tested positive for the presence of antibodies against the JC virus, indicating a previous infection, and the risk of PML was discussed before initiating therapy. He tolerated Ocrevus well, but continued to experience difficulties with walking. 

Two years after Ocrevus’ start and six months after his last infusion, problems with vision and with confusion began. Initial exams revealed his vision was restricted to one side of each eye (homonymous hemianopia), and an MRI scan found brain lesions. 

Analysis of the cerebrospinal fluid (the liquid surrounding the brain and spinal cord) found high numbers of the JC virus, which confirmed a diagnosis of PML. 

Blood work found low levels of white blood cells but was negative for HIV. Analysis of a blood sample taken before Ocrevus therapy also showed lower-than-usual white blood cell counts, but only slightly. Although white blood cells dropped after starting Ocrevus, they varied above and below normal levels until PML. 

The patient’s symptoms progressed over the next few weeks and included vision loss, speech difficulties, and facial droop. Ocrevus was discontinued, and he was prescribed Keytruda off label “based on literature suggesting its benefit” and medications for PML. 

However, his vision, language skills, and motor function “declined rapidly,” and repeated MRI scans showed extended PML. He ultimately decided on palliative care two weeks after receiving the first dose of Keytruda, and died one month after PML was diagnosed. 

An autopsy revealed a reduction in lymph tissue caused by immunotherapy, but no evidence of blood cancers. Brain examination found extensive myelin damage, and JC virus-infected oligodendrocytes, cells that produce myelin. 

“While we believe that [Ocrevus] was associated with PML in the present case, it is important to note other potential factors,” the investigators wrote. “Older age may have also played a role in the development of PML in the patient, as it has emerged as a risk factor for immunotherapy-related PML.”

While “PML will continue to be rare with anti-CD20 therapy, this case emphasizes the importance of a thorough discussion of the potential risks and benefits of [Ocrevus] in older patients with primary progressive MS and underscores the need for further research aimed at the needs of the growing elderly MS population,” they added.