Pembrolizumab for treatment of progressive multifocal leukoencephalopathy in primary immunodeficiency and/or hematologic malignancy: a case series of five patients

Abstract

Progressive multifocal leukoencephalopathy is a rare opportunistic infection of the brain by John Cunningham polyomavirus in immune-compromised patients. In cases where no overt option for immune reconstitution is available [e.g., in patients with primary immunodeficiency (PID)], the disease is lethal in the majority of patients. Immune checkpoint inhibition has been applied in recent years with mixed outcomes. We present four novel patients and the follow-up of a previously published patient suffering from progressive multifocal leukoencephalopathy (PML) due to PID and/or hematologic malignancy who were treated with the immune checkpoint inhibitor pembrolizumab. In two patients with PID, symptoms improved and stabilized. One patient died because of worsening PML another of intracranial hemorrhage which was unrelated to PML or its treatment with pembrolizumab. The fifth patient suffered from PID and died of a pre-existing immune dysregulation, possibly exacerbated by pembrolizumab. The long-term follow-up of the first patient provides support for therapeutic decisions during this therapy and is the longest published clinical course of a patient with checkpoint inhibition for PML. We conclude that pembrolizumab can control PML symptoms long term in a subgroup of patients with PID, in our cases for 21 and 36 months. However, therapy must be started early because symptoms are only partially reversible. In light of severe adverse events, application of pembrolizumab is only justified if the prognosis for the individual patient is very poor.

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] . With the increasing use of the monoclonal antibody in lymphoproliferative disorder and autoimmune disorders, the incidence of PML seems to have risen in this population.…”

“…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] . PD-1 protein interacts with its ligands on antigen-presenting cells leading to negative regulation of T cell activation [5] . Pembrolizumab is an immune checkpoint inhibitor, targeting PD-1 proteins [3] , [8] .…”

“…Pembrolizumab is an immune checkpoint inhibitor, targeting PD-1 proteins [3] , [8] . By blocking the PD-1 ligand interaction, pembrolizumab leads to increased activation of T cells [5] . It has been established that in HIV patients there is high PD-1 expression on T cells leading to reduced activation of the T cells [9] .…”

“…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.…”

Pembrolizumab for the treatment of progressive multifocal leukoencephalopathy following anti‐CD19 CAR‐T therapy: a case report

“…Adoptive BK virus‐specific cytotoxic T‐lymphocytes (CTL) have been used successfully in three cases [ 4 ]. Expression of the inhibitory Programmed death‐1 (PD‐1) co‐receptor is high on T‐cells isolated from patients with PML [ 5 ], and the use of PD‐1 checkpoint inhibitors to reinvigorate JCV‐specific T‐cell responses has shown promise [ 6 , 7 , 8 , 9 ].…”