Ibrutinib treatment of mantle cell lymphoma complicated by progressive multifocal leukoencephalopathy

Objective: Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease of the central nervous system, caused by reactivation of John Cunningham polyomavirus, affecting mainly patients in an immunocompromised state. Recently, drug-associated PML is gaining attention as more cases of PML in connection with the use of various immunomodulatory drugs emerge. Over the last couple of years, sporadic reports have occurred about a possible association between PML and the use of a new immunomodulatory drug, ibrutinib (Imbruvica), primarily indicated for the treatment of various B-cell malignancies. Case report: Herein, we report a case of a 62-yearold female patient with bilateral mantle cell lymphoma of conjunctiva diagnosed at IVA clinical stage (according to the Ann Arbor staging of lymphomas) of the disease. As a first line of treatment, the patient was given 6 cycles of rituximab-based chemotherapy followed by a complete remission. Seven years later, the patient relapsed, at which point the treatment with ibrutinib was initiated. Three weeks after the initial dosage, the patient started to show signs of progressive neurological symptomatology and died 4 months thereafter due to bilateral bronchopneumonia. Due to unspecific MRI signs and negative PCR results, the diagnosis of PML was confirmed only postmortem. Conclusion: This case report demonstrates a possible severe adverse effect of the immunomodulatory drug ibrutinib and the importance of a multidisciplinary approach in its diagnosis. Since PML is a rare but highly fatal disease, it is of utmost importance to be aware of the possible connection with the use of this drug to prevent missed or delayed diagnosis, considering that timely therapeutic intervention is crucial for improved prognosis.