Progressive multifocal leukoencephalopathy associated with obinutuzumab–bendamustine: combination therapy with mirtazapine and immunoglobulin

Progressive multifocal leukoencephalopathy (PML) is a severe opportunistic infection of the central nervous system resulting from JC virus (JCV) reactivation, often leading to substantial neurological morbidity and mortality. While associated with various immunotherapies, the incidence of PML specifically following obinutuzumab-bendamustine as first-line therapy remains under-reported. We aim to highlight this potent regimen as a trigger for JCV reactivation and evaluate therapeutic strategies. We describe a patient who presented with cognitive decline two years after completing obinutuzumab-bendamustine therapy for follicular lymphoma, accompanied with profound lymphopenia and hypogammaglobulinemia. A diagnosis of PML was established based on deep white matter lesions on brain MRI and a positive cerebrospinal fluid (CSF) polymerase chain reaction for JCV. Treatment consisted of daily mirtazapine together with intravenous immunoglobulin (IVIG) supplementation. At the 2-year follow-up, the patient demonstrated sustained radiological stabilization, cognitive improvement, and undetectable JCV viral load in CSF. Obinutuzumab-bendamustine therapy represents a distinct clinical trigger for PML due to its dual-arm immunosuppressive effects on humoral and cellular immunity. While endogenous cellular immune restoration likely played a primary role in viral clearance, adjunctive mirtazapine and IVIG may represent a feasible supportive strategy, particularly following B-cell-depleting therapy. The therapeutic contribution of this combined regimen requires further investigation.