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

Abstract

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.

Killing Two Birds With One Stone: Effective Control of Both Non-Small Cell Lung Cancer and Progressive Multifocal Leukoencephalopathy With Atezolizumab, A Case Report

“…However, these initial enthusiastic results have been tempered by later reports depicting sustained neurological degradation and death despite anti-PD1 therapy, thereby highlighting the need to determine patients most susceptible to benefit from this treatment ( 8 ). Based on the few observations reported thus far, several risk factors for treatment failure have been suggested, such as high CSF JCV copy number, concomitant use of immunosuppressive drugs, absence of pre-treatment anti-JCV activity detected in vitro , and more terminally exhausted phenotypes of immune cells ( 6 , 8 , 9 ). However, a robust and reproductible strategy to determine treatment-responsive patients is yet to be determined and should be investigated by further studies.…”

Infectious Complications of Targeted Therapies for Solid Cancers or Leukemias/Lymphomas

“…In addition, there are several case reports that have also highlighted opportunistic infections with a variety of pathogens, including Aspergillus fumigatus [ 40 , 41 , 42 , 43 , 44 , 45 ], Pneumocystis jirovecii [ 41 , 46 , 47 , 48 ], John Cunningham (JC) virus [ 49 , 50 , 51 ], CMV [ 41 , 52 , 53 ] and Campylobacter [ 54 ]. These reports highlight the need to have a threshold for investigation of opportunistic infections after treatment of immune-related adverse events and consideration of Pneumocystis jirovecii prophylaxis.…”

Promise and Challenges of Checkpoint Inhibitor Therapy for Progressive Multifocal Leukoencephalopathy in HIV

“…ICIs have been explored in limited cases of patients with PML for whom immune reconstitution was not readily achieved and thus had low expectation for survival. As of April 15, 2022, only 5 of the 53 published cases of treated PML [5,54 . Of these, one was newly stable on ART and two had a long history of ART, both with plasma HIV viral load less than the limit of detection at the time of pembrolizumab treatment; the fourth had a history of ART non-adherence and restarted ART contemporaneously to ICI treatment due to rapid worsening of PML.…”

“…ICIs have been explored in limited cases of patients with PML for whom immune reconstitution was not readily achieved and thus had low expectation for survival. As of April 15, 2022, only 5 of the 53 published cases of treated PML [ 5 , 54 ••, 56 – 67 , 68 ••, 69 – 74 , 75 ••, 76 – 80 , 81 ••, 82 ], although the number of unpublished cases of treated PML, both related to HIV and otherwise, exceeds this (personal communication). Nevertheless, evaluating the overall available experience and outcome of checkpoint inhibition in PML will likely provide helpful insights when translating this therapy’s potential to the HIV-PML population (Supplemental Table ).…”

“…The major underlying conditions contributing to PML cases include human immunodeficiency virus (HIV) infection, hematological malignancy, and exposure to immunomodulatory therapies [ 5 ]. In contrast with most opportunistic infections, no antiviral treatment currently exists for PML.…”