*Confounding of adverse event reporting occurs when the assessment of association between exposure to a drug and an adverse event is distorted by the effect of one or several other variables that are also risk factors for the outcome of interest;3,4 in the cases detailed above, confounders included such factors as serum anti-JCV antibodies, prior treatment with another DMT (carry-over PML), age-related immunosenescence and lymphopenia;
†Carry-over PML: PML that develops a few months after stopping one DMT known to increase the risk of PML and starting a different DMT. In these cases, PML could have developed without causing symptoms while the patient was still on the previous DMT, or shortly after stopping the previous DMT.5
ALC, absolute lymphocyte count; CSF, cerebrospinal fluid; CTCAE, Common Terminology Criteria for Adverse Events; DMT, disease-modifying therapy; DNA, deoxyribonucleic acid; JCV, John Cunningham virus; PCR, polymerase chain reaction; PML, progressive multifocal leukoencephalopathy; PML-IRIS, PML immune reconstitution inflammatory syndrome; RMS, relapsing MS.
Progressive Multifocal Leukoencephalopathy (PML) is an opportunistic viral infection of the brain caused by the John Cunningham (JC) virus that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability.
Although no cases of PML were identified in ocrelizumab clinical trials, a risk of PML cannot be ruled out since JC virus infection resulting in PML has been observed in patients treated with anti-CD20 antibodies and other MS therapies and associated with risk factors (e.g., patient population, polytherapy with immunosuppressants). Physicians should be vigilant for the 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 MS disease.
If PML is suspected, dosing with ocrelizumab must be withheld. Evaluation including MRI scan, preferably with contrast (compared with pre-treatment MRI), confirmatory CSF testing for JC viral DNA and repeat neurological assessments should be considered. If PML is confirmed, treatment must be discontinued permanently.
When switching from drugs with prolonged immune effects, such as fingolimod, natalizumab, teriflunomide, cladribine or mitoxantrone, consider the duration and mode of action of these drugs because of additive immunosuppressive effects when initiating ocrelizumab.1,2
*Indications vary in different countries. The local prescribing information for your country is the primary source of information on the known and potential risks associated with ocrelizumab.