Treatment of Progressive Multifocal Leukoencephalopathy

By Hai H. Hoang, MD

Assistant Professor of Clinical Neurology, Weill Cornell Medical College

SYNOPSIS: Progressive multifocal leukoencephalopathy, a rare opportunistic viral infection that occurs in patients who have chronic immunosuppression, has defied all attempts at treatment. This observational study, which pooled patient data from multiple centers around the world, showed that there is some benefit using checkpoint inhibitors to help reconstitute the immune system of these patients. However, survival, at best, is 50% of those treated.

SOURCE: Boumaza X, Bonneau B, Roos-Weil D, et al. Progressive multifocal leukoencephalopathy treated by immune checkpoint inhibitors. Ann Neurol 2022; Sep 24. doi: 10.1002/ana.26512. [Online ahead of print].

Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection of the central nervous system caused by reactivation of JC polyomavirus (JCV) in immunocompromised patients. Although the JCV is ubiquitous in humans, it is only associated with pathogenicity when the body is immunosuppressed. Thus, the main treatment for PML is immune reconstitution to activate the immune system so it can attack and suppress the JCV. Steroids are immunosuppressants and inhibit the immune system. Steroids are not used to treat PML unless the strategy of immune reconstitution leads to an overactive immune system, also known as immune reconstitution inflammatory syndrome (IRIS).

Among the treatments studied, mirtazapine’s mechanism of action includes 5-HT blockade, which is thought to be one of the receptors that JCV uses to enter neurons. Pembrolizumab is an immune checkpoint inhibitor and, in case reports and limited case series, has been shown to reactivate the immune system and suppress the JCV. Withdrawal of immunosuppressants and initiation of chimeric antigen receptor (CAR)-T cell therapy are two treatment strategies that either will remove the offending medication or start a cell therapy to suppress JCV, respectively.

Inhibitory immune checkpoint molecules (such as programmed cell death-1 [PD-1]) are receptors expressed by activated T cells and are important in the maintenance of peripheral tolerance. In cancer, chronic infection, and other situations of chronic antigen stimulation, tumor or viral evasion results from persistent upregulated expression of PD-1 and other immune checkpoint molecules triggering inhibitory signaling pathways that mediate a complex state of T cell dysfunction referred to as exhaustion. T cell exhaustion is reversed by immune checkpoint inhibitors (ICI). This has been suggested as a strategy to reinvigorate antiviral activity in chronic infections, such as PML.

The authors conducted a retrospective, multicenter survey of published and unpublished cases of patients who received ICI as add-on treatment to standard of care for PML. The primary outcome was survival one year after ICI. Secondary outcomes evaluated the proportion of patients who experienced control of JCV replication and who developed contrast-enhancing lesions on brain magnetic resonance imaging (MRI) and/or PML-IRIS. Study data were obtained from a total of 91 patients with proven PML who received ICI, with 79 patients from nine countries meeting study criteria. Patient comorbidities included hematologic malignancies (38/79), primary immunodeficiencies (14/79), human immunodeficiency virus/acquired immunodeficiency syndrome (12/79), chronic inflammatory diseases (8/79), solid neoplasm (5/79), and transplant recipients (2/79).

One-year survival following ICI initiation was 51.9% and similar across all groups. Of the 38 patients who died, the cause of death for 26 patients was attributed to PML; seven patient deaths were attributed PML-IRIS; and three patient deaths were attributed to progression of both PML and the underlying disease, or of the underlying disease only.

Detection of contrast-enhancing lesions on baseline brain MRI was associated with a trend toward a better survival. The following variables were not associated with survival: demographics (sex, age), PML-predisposing condition, time from symptom onset to PML diagnosis and ICI initiation, treatment history, measures of disease severity (extent of MRI lesion burden or clinical disability accrued), or immune status (blood lymphocyte and T cell counts). Thirty-two adverse events were identified in 24 patients. Nine patients had dermatological manifestations, five patients had gastrointestinal manifestations, and nine patients had infusion-related adverse events. Discontinuation of treatment because of adverse events only occurred in seven patients.

COMMENTARY

This study provides “real-world” reports of the effects of ICI in patients with PML. The low incidence of PML makes randomized clinical trials very challenging. The only sources of data that physician scientists can study regarding ICI are case reports and small case series. This study aimed to pool these data and evaluate the one-year survival rate after ICI administration.

The 50% survival rate, one-year after ICI initiation, provides a statistical number that clinicians can use to counsel patients and family members. However, survivability using ICI treatment can be predicted with “a flip of the coin.” Unfortunately, many clinical variables were not associated with survivability, and we cannot counsel patients based on their unique clinical features.

Although detection of contrast-enhancement was associated with improved survival, this feature is rare at the time of diagnosis and only occurs when the patient’s immune system has begun to mount an immune response.

The observational, retrospective, and non-comparative design limit this study. Additionally, the multicentered patient evaluations were not standardized among the centers, leading to interpretation of data and variables at the discretion of the institution. Overall, this study offers important information regarding the effects of ICI for PML. Given the rarity of this condition, I applaud the authors of this study and their efforts at providing more data so that physicians can counsel patients and family members on how to navigate this devastating disease.