Supplementary Material for: Progressive Multifocal Leukoencephalopathy after administration of Front-line Obinutuzumab and Venetoclax in a Patient With CLL: Case Report

Introduction: Progressive multifocal leukoencephalopathy (PML) is a rare and often fatal demyelinating disease of the central nervous system (CNS) caused by the reactivation of the John Cunningham virus (JCV) in immunocompromised patients. Obinutuzumab is type II anti-CD 20 antibody, used in combination with venetoclax for chronic lymphocytic leukemia (CLL). Case Presentation: 75-year-old female patient was diagnosed with PML after a short course of obinutuzumab and venetoclax started for a newly diagnosed CLL. There was no history of hepatitis B, C or HIV. Quantitative immunoglobulin levels were normal. She completed four infusions of obinutuzumab and subsequently started venetoclax, ramping up dose. Four days after the last dose of obinutuzumab, she developed forgetfulness and irrational behavior. Simultaneously, she had a new onset of cough and dyspnea and was subsequently diagnosed with a COVID-19 infection. One week later, her neurological condition began to deteriorate. Neurological examination did not reveal any focal neurological deficits. Magnetic resonance imaging head showed a non-specific white matter signal change extensively involving the left frontal lobe, crossing the corpus callosum into the deep white matter of the right frontal lobe. Analysis of the cerebrospinal fluid was positive for the JCV, leading to a diagnosis of PML. Following a single dose of intravenous immunoglobulin (IVIG) 0.4g/kg, the patient had a transient improvement of symptoms but subsequently deteriorated and died one month later. Conclusion: PML is a rare complication of anti-CD 20 monoclonal antibodies, including obinutuzumab. Early recognition of PML is essential to discontinue an affecting drug and initiate therapy.