PD-1-inhibitor pembrolizumab for treatment of progressive multifocal leukoencephalopathy

Abstract

The reactivation of human JC polyoma virus (JCPyV) results in lytic infection of oligodendrocytes and neuronal cells. The corresponding clinical picture is called progressive multifocal leukoencephalopathy (PML) and results mostly from a disease-related or drug-induced immunosuppression. The opportunistic brain infection leads to a progressive demyelination of multiple areas of the central nervous system. Patients can present with various neurological deficits ranging from slight motoric symptoms to marked aphasia or reduced vigilance. Currently, there is no effective causal therapy for PML. Survival depends on the ability to achieve timely immune reconstitution. If the immune system cannot be restored, PML progresses rapidly and often ends fatally within months. Recently, some evidence for positive response has been reported in patients treated with immune checkpoint inhibitor therapy. Here, we provide a case series of three PML patients with underlying hematological malignancies who were treated with anti-PD-1-antibody pembrolizumab at Hannover Medical School. All patients received an extensive diagnostic follow-up including cerebrospinal fluid analysis, brain imaging, and lymphocyte-phenotyping via flow cytometry. Our patients had very different outcomes, with the only patient showing a specific anti-JCPyV immune response in the sense of an increased JCPyV antibody index clearly benefiting most from the treatment. Our results partly support the hypothesis that anti-PD-1 therapy may represent a promising treatment option for patients with PML. However, there is a current lack of pre-therapeutic stratification regarding the therapeutic response rates. Before larger studies can be initiated to further evaluate the efficacy of anti-PD-1 antibodies in PML, it is imperative to develop a reliable strategy for selecting suitable patients.

Pembrolizumab for the treatment of Progressive Multifocal Leukoencephalopathy (PML) in a patient with AIDS: A case report and literature review

“…PML manifests as various neurological deficits and is a progressive condition unless immune reconstitution is achieved [4] . Initiation of antiretroviral therapy in HIV patients and withdrawal of immunosuppressive medications in MS patients can help achieve immune reconstitution but in patients with hematological malignancy and primary immunodeficiency, it is difficult to achieve immune reconstitution [5] .…”

“…Currently, there are no known effective therapeutic drugs available for PML. Recently, the anti-PD-1 immune checkpoint inhibitor, pembrolizumab has been the drug of interest for the treatment of PML [4] . It is seen that in PML patients, an immune checkpoint protein called programmed cell death protein 1 (PD-1) expression is increased in CSF CD4 + and CD8 + lymphocytes and on macrophages of PML lesions [1] , [7] .…”

“…There are only 3 reported cases of pembrolizumab used in PML patients with HIV [ Table 1 ] [1] , [12] . All other PML cases with causes of immune compromise other than HIV, treated with pembrolizumab are listed in Table 2 [1] , [3] , [4] , [5] , [7] , [10] , [11] , [13] , [14] , [15] , [16] , [17] . Overall, 17 out of 28 cases had reported improvement or stabilization of neurological symptoms.…”

Innovative therapeutic concepts of progressive multifocal leukoencephalopathy

“…One patient with long-standing Waldenstrom's disease showed marked improvement in his PML-associated symptoms during therapy with pembrolizumab and ultimately became symptomfree, whereas the other two patients suffered a fatal course of PML despite anti-PD-1 therapy. Both had been previously treated with rituximab and had no detectable CD20-and CD19-positive cells in their blood at the time of diagnosis [66].…”

Immune checkpoint inhibitors for progressive multifocal leukoencephalopathy: Identifying relevant outcome factors

“…We found 20 articles (14 case reports and six case series) reporting a total of 37 patients who received an ICI in order to treat PML [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. One patient was excluded from the present report because PML had already stabilized before ICI administration [3] and another patient because reported data were insufficient to determine the eventual clinical course [13].…”