Improvement in progressive multifocal leukoencephalopathy after pembrolizumab‐induced immune reconstruction inflammatory syndrome in a patient with follicular lymphoma

Abstract Progressive multifocal leukoencephalopathy (PML) may develop in follicular lymphoma patients treated with bendamustine‐rituximab. In this report, treatment with pembrolizumab successfully inhibited the clinical progression of PML by promoting radiologically demonstrated immune restoration inflammatory syndrome (IRIS), allowing complete clearance of the virus. These findings may further support the use of pembrolizumab in PML with special consideration for the potential occurrence of IRIS.


INTRODUCTION
In their recent publication, D'Alo et al [1], (2020 issue) thoroughly describe three cases of progressive multifocal leukoencephalopathy (PML) occurring in patients with follicular lymphoma treated with the combination of bendamustine and rituximab (BR). Deep and prolonged immunosuppression is a contributing factor for the onset of PML, a rare opportunistic brain infection caused by polyoma JC virus (JCV).
So far, only scarce and divergent information is available on PML management. The disease is usually fatal unless immune function can be restored. We would like to share our single experience involving an This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

DISCUSSION
The prognosis of patients with PML associated with an underlying hematologic cancer is poor. Reported mortality rates lie around 74-100%, with a median survival of 2 months [3]. The pathogenesis of PML is characterized by an elective cytolysis of the oligodendrocyte glial cells by JCV resulting in rapidly extending demyelinating lesions in the absence of an immune response [4]. Although the mechanisms of controlling JCV infection are not yet completely understood, both humoral and cellular immune responses probably play a role [5]. Accordingly, the presence of JCV-specific CD8 + and CD4 + T cells has been linked to the recovery from PML, while these cells were absent in cases of fatal outcome [6].
This case supports the concept that blocking the pathway of programmed death 1 (PD-1) by CPI can potentially control JCV infection by triggering effective immune reconstitution. PD-1 is present on the surface of T cells and acts as a negative regulator of immune responses. Interestingly, Tan et al showed that PD-1 expression was elevated on total CD4 + and CD8 + T-cells in PML patients when compared to healthy control subjects [7]. In the frame of chronic infection, PD-1 expression may lead to impaired viral clearance, such as HIV and hepatitis B viruses [8]. PD-1 induces T-cell quiescence and inhibits Tcell activation against virus, resulting in a viral latency [9]. Others have proposed that PD-1 inhibitors may be an adjunctive therapy for chronic infections including HIV [9]. Pembrolizumab, a humanized antibody against PD-1, induces downregulation of PD-1 expression on lymphocytes, thereby increasing CD4 + and CD8 + activity against the JCV. This restored JCV-specific cellular immune response, allowing a complete viral control [10]. Our patient presented an IRIS after the first infusion of CPI, of which "immune storm" resulted in an initial neurological worsening. Presumptively the overwhelming inflammatory response against JCV may have initially exacerbated symptoms, as it has been suggested in a patient with PML following lung transplantation and immunosuppressant dose reduction [11]. Others have showed that

CONFLICT OF INTEREST
The authors declare no conflict of interest.

AUTHOR CONTRIBUTIONS
Inès Dufour, Eric Van Den Neste, Thierry Duprez, Marie Wertz, Pascale Saussoy, Nathalie Ackermans, Souraya El Sankari, and Vincent van Pesch contributed to patient management, data collection, and revised the paper. Inès Dufour and Eric Van Den Neste wrote the paper.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.