Progressive Multifocal Leukoencephalopathy (PML) is a serious infection of the central nervous system caused by reactivation of JC (John Cunningham) Polyoma virus. Initial childhood viral infection is asymptomatic or manifests as nonspecific viral syndrome, after which the virus remains dormant in lymphoid structures.  Later in immunocompromised individuals, this virus can reactivate, spreading to central nervous system, causing PML. Ibrutinib, a Bruton's Tyrosine Kinase inhibitor, commonly used to treat Chronic Lymphoid Leukemia (CLL), could trigger PML.

We present a 67 yr old female with CLL, initially diagnosed in 2014 treated with 6 weeks of Rituximab, leading to disease remission. She had recurrence in 2017 requiring initiation of Ibrutinib, with intermittent treatment for the next 3 years, complicated by bone marrow suppression leading to prolonged hold in medication for the next 2 years with subsequent relapse in Jan 2022 requiring reinitiating of Ibrutinib. Patient subsequently hospitalized for acute encephalopathy with MRI demonstrating vasogenic edema suggestive of PML. CSF showed elevated WBCs (8 cells/mm³) and JC virus PCR positive in CSF and serum. Patient eventually declined clinically and was transitioned to hospice care. 

Development of PML from Ibrutinib use has been previously reported but the incidence seems extremely low, and the causal relationship between Ibrutinib use and development of PML is not clearly established.  To date, there are about 2-3 case reports suggesting a causal link between Ibrutinib and PML. We are reporting a case where a patient who initially tolerated Ibrutinib with good clinical response and disease remission for 3 years later developed PML when the medication was reinitiated 2 years later for the relapse of CLL. This case further supports the evidence that the prolonged use of Tyrosine kinase inhibitors could potentially cause PML with poor neurological outcome.