Progress for progressive multifocal leukoencephalopathy
By Warren R. Heymann, MD
May 8, 2019
Vol. 1, No.9
Progressive multifocal leukoencephalopathy (PML) is a nightmare. For any dermatologist seeing patients with autoimmune diseases, HIV, lymphoproliferative disorders, or who are on immunosuppressive medications (azathioprine, chlorambucil, cyclophosphamide, glucocorticoids methotrexate, TNF inhibitors, and rituximab), PML is a “sword of Damocles,” despite its rarity when such medications are utilized for dermatologic disorders.
PML is caused by a lytic infection with the John Cunningham (JC) virus leading to progressive damage of oligodendrocytes in the central nervous system (CNS). PML is due to reactivation of a dormant systemic JC virus infection, usually in the setting of systemic immunosuppression. PML presents with progressive cortical symptoms such as paresis, cognitive deficits, sensory deficits, gait disturbances, difficulties with coordination, hemianopia, or aphasia. The diagnosis of PML is confirmed with a combination of clinical, radiographic, and laboratory data. For a definite diagnosis, a positive CSF PCR for JC virus in addition to compatible clinical and imaging findings is mandatory. The prognosis of PML depends on the underlying cause of immunodeficiency and the ability to restore the host’s immune response. The mortality rate for PML is as high as 56.2% for autoimmune diseases, 68.4% for post-transplantation patients, and 83.3% for those with neoplasms. (1)
PML is not an abstraction to dermatologists. Efalizumab was voluntarily removed from the market a decade ago, when several psoriatic patients developed fatal PML after using the drug for at least three years. (2)
PML is distinct from reversible posterior leukoencephalopathy (RPL), a hypertensive encephalopathy characterized by headache, altered mental status, vision abnormalities, and seizures. Fortunately, RPL is reversible with blood pressure control and removal of the immunosuppressive agent. (3) Grattan et al described the first case of RPL in a 65-year-old woman treated with ustekinumab for psoriasis. Approximately 2.5 years after she began ustekinumab therapy, she experienced an acute onset of confusion, headache, nausea, vomiting, and seizures. Computed tomographic scans and magnetic resonance images of her head revealed characteristic findings, including white matter abnormalities consistent with edema in the absence of infarction. Cerebrospinal fluid tests were negative for the JC virus. The patient experienced a full neurologic recovery, with a reversal of the radiologic findings. (4)
It has been demonstrated that PD-1 expression is up-regulated on CD4+ and CD8+ cells in patients with PML and is specifically enriched on JC virus–specific CD8+ cells. Increased expression of PD-1 and programmed death ligand 1 (PD-L1) in PML lesions from autopsy specimens has been observed. It was therefore hypothesized that PD-1 blockade could be useful therapy for PML patients. Cortese et al administered pembrolizumab every 4 to 6 weeks to eight adults with PML, each with different predisposing conditions. Each patient received at least one dose but no more than three doses. Pembrolizumab induced down-regulation of PD-1 expression on lymphocytes in peripheral blood and in cerebrospinal fluid (CSF) in all eight patients. Five patients had clinical improvement or stabilization of PML accompanied by a reduction in the JC viral load in the CSF and an increase in in vitro CD4+ and CD8+ anti–JC virus activity. In the other three patients, no meaningful change was observed in the viral load or in the magnitude of antiviral cellular immune response, and there was no clinical improvement. Additionally, the authors observed that treatment with pembrolizumab had no influence on the underlying hematologic or immunologic disorders; they concluded that the promising data warrants further investigation for the potential use of checkpoint inhibitors for PML. (5)
In the same issue of the New England Journal of Medicine there were another two articles devoted to PD-1 inhibition and PML. Walter et al presented the case of a 60-year-old woman with a diagnosis of idiopathic primary immunodeficiency who developed PML; after 8 weeks of treatment with the PD-1 inhibitor nivolumab, her neurologic symptoms improved. (6) Rauer et al detailed the case of a patient with a diffuse large B-cell lymphoma treated with chemotherapy and rituximab prior to developing PML. The neurologic symptoms and MRI lesions all improved after five pembrolizumab infusions. (7)
I concur with Koralnik who, in his New England Journal of Medicine editorial “Can immune checkpoint inhibitors keep JC virus in check?” states that while these findings are encouraging, controlled trials of PD-1 inhibitors for PML will be necessary to determine their efficacy. (8) Regardless, for anyone with a potential PML death sentence, PD-1 inhibitors at least offer the hope of a dream of remission, compared to a virtually guaranteed nightmare.
Point to remember: PD-1 inhibition holds promise for patients with progressive multifocal leukoencephalopathy.
Our expert’s viewpoint
Robert A. Somer, MD
Professor of Medicine
Head, Division of Hematology-Oncology
MD Anderson-Cooper Healthcare
Cooper Medical School of Rowan University
As Dr. Heymann states, PML is a horrible “iatrogenic” complication for those cases due to immunosuppressive therapy. In 2018, colleagues at MD Anderson published a phase II trial using adoptive T-cell therapy for patients with PML; 3 patients showed improvement of their PML after an infusion with donor T cells targeting the BK virus. The BK virus is quite similar to the JC virus and provided a proof-of-principle that immunotherapy can be a potentially viable option for this potentially fatal viral infection. Targeted immunotherapy has long been known to be valuable in malignancies and autoimmune disorders. These most recent studies also show that targeted immunotherapy is becoming useful for other disorders — including infectious diseases such as PML. The therapeutic horizons of these approaches continue to expand exponentially.
1. Bartsch T, Rempe T. Leopoldt F, Riedel C, et al. The spectrum of progressive multifocal leukoencephalopathy: A practical approach. Eur J Neurol 2019; 26: 566-e41.
2. Kothary N, Diak IL, Brinker A, Bezabeh S, et al. Progressive multifocal leukoencephalopathy associated with efalizumab use in psoriasis. J Am Acad Dermatol 2011; 65: 546-551.
3. Lin EJ, Reddy S, Shah VV, Wu JJ. A review of neurologic complications of biologic therapy in plaque psoriasis. Cutis 2018; 101: 57-60.
4. Gratton D, Szapary P, Goyal K, Fakharzadeh S, et al. Reversible posterior leukoencephalopathy syndrome in a patient treated with ustekinumab: A case report and review of the literature. Arch Dermatol 2011; 147: 1197-1202.
5. Cortese I, Muranski P, Enose-Akahata Y, Ha SK, et al. Pembrolizumab treatment for progressive multifocal leukoencephalopathy. N Engj J Med 2019; 380: 1297-1605.
6. Walter O, Treiner E, Bonneville F, Mengelle C, et al. Treatment of progressive multifocal leukoencephalopathy with nivolumab. N Engl J Med 2019; 380: 1674-1676.
7. Rauer S, Marks R, Urbach H, Warnatz K, et al. Treatment of progressive multifocal leukoencephalopathy with pembrolizumab. N Engl J Med 2019; 380: 1676-1677.
8. Koralnik IJ. Can immune checkpoint inhibitors keep JC virus in check? N Engl J Med 2019; 380: 1667-1668
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