Clearance of JC polyomavirus from cerebrospinal fluid following treatment with interleukin‐2 and pembrolizumab in an individual with progressive multifocal leukoencephalopathy and no underlying immune deficiency syndrome

Goereci, Yasemin; Schweitzer, Finja; Wellstein, Anton; Silling, Steffi; Borchmann, Sven; Tresckow, Bastian von; Adams, Ortwin; Martin, Roland; Schlamann, M; Schroeter, Michael; Fink, Gereon R.; Wattjes, Mike P.; Warnke, Clemens

doi:10.1111/ene.14435

Cited by 15 publications

(19 citation statements)

References 7 publications

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“…This is demonstrated by a median survival of 2 months in a case series of patients with in hematologic malignancies and stem-cell transplantation [27]. Checkpoint inhibition has been applied so far in 11 cases with nivolumab therapy and 20 cases with pembrolizumab therapy (including our previous report) with varying results [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25]. Here were report on a series of 4 novel patients with PML in the context of PID or hematologic malignancy treated with pembrolizumab and follow-up data on one previously reported patient [21].…”

Section: Discussionmentioning

confidence: 99%

“…To our knowledge, 31 published patients with PML have so far been treated with either pembrolizumab or nivolumab. Treatment outcomes range from moderate improvement of symptoms with stabilization to death from disease progression [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25]. To date, there are no clear prognostic factors to identify patients in whom checkpoint inhibition will be able to ameliorate PML [26].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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“…Six patients experienced an adverse event potentially related to the treatment but none of these were fatal. Of note, one additional patient experienced an eventually fatal respiratory distress attributed to an aspiration pneumonia, but in the absence of autopsy an immune‐mediated pneumopathy could not be ruled out [7]. The occurrence of irAEs, which result from the immune restoration induced by ICIs, was not significantly associated with a better outcome but this should be further investigated in future case reports ( p = 0.1581).…”

Section: Resultsmentioning

confidence: 99%

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

Lambert

Moussaoui²,

Maquet

2021

Euro J of Neurology

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Introduction Progressive multifocal leukoencephalopathy (PML) is an infectious brain disease caused by JC virus in immunocompromised individuals. Immune checkpoint inhibitors (ICIs) recently emerged as a therapeutic hope for these patients but identification of those likely to respond to the treatment is still an unmet need. Method We performed a systematic PubMed search for reports of patients treated for PML using an ICI. Clinical, biological and radiological characteristics were contrasted between patients who responded to the treatment (RP) and those who did not (NRP). Results Thirty‐five patients were included in the present study. Twenty‐one of them reportedly benefited from the treatment. Age, blood CD4+ cells count, pretreatment viral load in the cerebrospinal fluid (CSF), PML lesions localization, treatment delay since first PML symptoms, type of ICI used and immune‐related adverse events (irAEs) occurrence did not significantly differ between RP and NRP. By contrast, a history of therapeutic immune suppression and the use of an immunosuppressive therapy at treatment initiation were significantly associated with a poor response. Besides, reaching an undetectable viral load in the CSF and reduction of the lesion load on magnetic resonance imaging after ICI administration was associated with a good clinical response. Conclusion Current data suggest that patients with PML under immunosuppressive therapy are less likely to respond to ICIs and raises the issue of the optimal management of irAEs during ICI treatment in this setting.

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“…7 More recently, some evidence for positive response has been reported in patients treated with immune checkpoint inhibitor therapy. [10][11][12][13][14][15] The blockade of checkpoint molecules such as PD-1, PD-L1, and CTLA-4, with monoclonal antibodies, has enabled the development of breakthrough therapies in oncology. Several observations suggest that the PD-1 pathway may be of relevance in PML as the percentage of PD-1 positive T-cells is elevated in blood and CSF of PML patients compared with healthy individuals.…”

Section: Pd-1-inhibitor Pembrolizumab For Treatment Of Progressive Mumentioning

confidence: 99%

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

Möhn

Wattjes

Adams

et al. 2021

Ther Adv Neurol Disord

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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.

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Clearance of JC polyomavirus from cerebrospinal fluid following treatment with interleukin‐2 and pembrolizumab in an individual with progressive multifocal leukoencephalopathy and no underlying immune deficiency syndrome

Cited by 15 publications

References 7 publications

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

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

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

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

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