A case of progressive multifocal leukoencephalopathy (PML) has been reported in a previously untreated MS patient who received ocrelizumab. The case was first reported on a blog posted by Dr. Gavin Giovannoni, Barts and The London School of Medicine and Dentistry. Details of the case were confirmed in an email from Roche to NeuroSens.
The case occurred in a U.S. patient with a long history of MS who had previously received no prior disease-modifying therapy. The patient was aged 78 years when PML was diagnosed. There was Grade 1 lymphopenia at treatment initiation. The patient received ocrelizumab from July 2017 to February 2019 (four infusions). A low absolute lymphocyte count (maximum Grade 2), a low CD4+ count (maximum Grade 2) and a low CD8+ count were recorded during treatment. The PML diagnosis was established according to AAN criteria (Berger et al. Neurology 2013;80:1430-1438). As of October 2019, >130,000 MS patients have been treated with ocrelizumab.
Other confirmed PML cases with ocrelizumab are generally considered to be carry-overs from prior DMT exposure. A total of seven cases were reported at ECTRIMS 2019 (Clifford et al. ECTRIMS 2019; abstract P970): six cases in anti-JCV Ab-positive patients who had previously received natalizumab (JCV index range 1.06-4.11), and one case in an anti-JCV Ab-negative patient previously treated with fingolimod. The time from ocrelizumab initiation to PML diagnosis was 18-92 days in prior natalizumab patients, and 16 days for the prior fingolimod patient. Four cases occurred in the U.S., and 1 case each was reported in Canada, Germany and Luxembourg.
The FDA’s Adverse Events Reporting System (FAERS) includes 1,669 PML cases in patients with MS (with and without comorbidities) for the period 2000-2019. A total of five cases of PML are listed for ocrelizumab, of which three mention no other DMT exposure. The database also lists seven PML cases treated with rituximab with no other DMT mentioned. However, it should be noted that on FAERS, PML may not have been confirmed and treatments may not be fully or accurately reported. FAERS also reports cases in patients treated with DMTs not generally associated with PML, including glatiramer acetate (8 cases), interferon-β (11 cases), teriflunomide (3 cases) and alemtuzumab (2 cases), with no other DMTs mentioned.
The de novo PML case with ocrelizumab is likely to raise questions about the safety of initiating cell-depleting DMTs in elderly patients. It has been suggested that age is a PML risk factor, and that alterations in the immune system may accelerate immunosenescence (Schweitzer et al. Curr Opin Neurol 2019;32:305-312). Age-related changes in immune function include decreased priming and activation by antigen-presenting cells, a more limited T cell repertoire, and decreased expression of costimulatory molecules (reviewed in Mills et al. Mult Scler 2018;24: 1014-1102; free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC6013383/pdf/nihms961288.pdf).