LAUSR

Dear Dr. Federico, T h e d e v e l o pme n t o f p r o g r e s s i v e mu l t i f o c a l leukoencephalopathy (PML) under immunosuppressive therapy using CD20 inhibitors such as rituximab is still a rarely observed event in everyday clinical practice and requires increased attention. Furthermore, there is still no causal and evidence-based therapy for the disease. In the recent past, several cases of successful therapy attempts using the programmed cell death 1 protein-inhibitor (PD1) pembrolizumab have been described [1]. In this report, we present the case of a 54-year-old woman who developed an infratentorial PML as a result of combined rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisolone (R-CHOP) therapy and in whom three doses of pembrolizumab showed no clinical improvement. The patient was originally diagnosed with diffuse large cell B cell lymphoma of the non-germinal center B cell (nonGCB)–like type of the small intestine in December 2018. A combined therapy of surgical resection and intravenous chemotherapy was performed using 6 cycles of R-CHOP resulting in complete clinical remission. In November 2019, she was introduced to our clinic with a newly occurring weakness of the right hand, a speech disorder, and dizziness. A neurological examination revealed hemiataxia of the right side of the body. Laboratory tests (including inflammatory indices) were unremarkable. A cerebral magnetic resonance imaging (cMRI) showed a lesion in the area of the right cerebellar hemisphere resembling an edema, without contrast enhancement (Fig. 1, at admission). The secondary involvement of the CNS by DLBCL was excluded because no evidence of clonal B cell population in flow cytometry of the sample of the lumbar puncture was found. Furthermore, cMRI showed neither diffusion restriction nor contrast enhancement which would contribute to the diagnosis of CNS Lymphoma. The microbiological findings were unremarkable. The virological analysis revealed John Cunningham virus (JCV) in the aspirate finally leading to the diagnosis of PML. Afterwards, we initiated an individual healing attempt with an off-label therapy using mirtazapine with daily target dose of 45 mg (three times/day) and cidofovir infusions. A cMRI revaluation (Fig. 1, 15 days) showed a clear extension of the PML lesion. A second lumbar puncture showed an inflammatory process with a lymphocytic pleocytosis and a high content of cytotoxic T-cells. Consistent with these findings, a florid infection with an increase in the JC viral load by more than two log levels to 3,500,000 copies/ml was determined by quantitative PCR (Fig. 2). In order to restore the immune function, we further escalated the therapy adding the PD1 inhibitor pembrolizumab with the aim of activating JC virusspecific T cells using the same scheme Cortese et al. described (2 mg/kg of body weight, every 4 weeks; altogether three infusions) [1]. Unfortunately, the symptoms of the patient worsened with increasing neurogenic dysphagia, a progressive dysmetria and paresis of the right side in spite of a second infusion of pembrolizumab. A follow-up MRI revealed a further progression of the defect areas including bilateral parts of the brain stem (Fig. 1, 40 days). Despite our efforts, the patient’s condition continued to deteriorate even after the third administration of pembrolizumab. The patient underwent meanwhile a tracheostoma and a percutaneous endoscopic gastrostomy. The last cMRI showed again a progression of * Jakob Stögbauer [email protected]