Treatment for PML Shows Promise in Early Study

April 10, 2019

A possible approach to the treatment of progressive multifocal leukoencephalopathy (PML) — a rare and often fatal viral disease of the brain that occurs in immunosuppressed patients and has no current therapy — has shown promising preliminary results.

Three different reports describe improvement in symptoms and radiological evidence of PML, an increased antiviral cellular immune response, and a reduction in viral load after administration of the immunotherapies pembrolizumab or nivolumab in a small number of patients.

"There is no treatment for PML at present, other than removing any treatment that might be causing the immune-suppressed state, and the condition is often fatal," lead author of one of the reports, Irene Cortese, MD, National Institutes of Health (NIH), Bethesda, Maryland, told Medscape Medical News.

"Our results give us some hope that we may be able to do something more for these patients — even if it is just a bridge until they can mount their own immune response. So while we have to be cautious as these findings are very preliminary, I think these drugs could have lifesaving effects," she added. 

The two monoclonal antibody drugs are known as checkpoint inhibitors. They target programmed cell death protein-1 (PD-1) — an inhibitory T-cell surface receptor that researchers have now discovered is increased on CD4+ and CD8+ lymphocytes in patients with PML.

Cortese explained that PD-1 inhibitors such as pembrolizumab are used in cancer to help leverage the intrinsic immune response when immune exhaustion has set in, which can occur when the immune system has been activated for a prolonged period. Immune exhaustion is believed to be mediated by expression of PD-1 receptors on T-cells, which leads to a loss of T-cell function. 

"Patients with PML have immune suppression by definition, so they already have a limited capacity to generate an immune response," she said. "If we can stop the PD-1 receptors on T-cells becoming activated then we may give the immune system a chance to recover and mount a response to the JC virus infection." 

The three reports of use of these drugs in PML patients were published online on April 10 in the New England Journal of Medicine.

In the first report, published as a full article, Cortese and colleagues treated eight PML patients with pembrolizumab at a dose of 2 mg/kg every 4 to 6 weeks. Each patient received at least one dose but no more than three doses.

All eight patients showed downregulation of PD-1 expression on lymphocytes in peripheral blood and cerebrospinal fluid (CSF). Five patients had clinical improvement or stabilization of PML accompanied by a reduction in JC virus (which causes PML) in the CSF and an increase in CD4+ and CD8+ anti-JC virus activity.

In the other three patients, no meaningful changes were observed in the viral load or magnitude of antiviral cellular immune response, and there was no clinical improvement.

The other two reports, both published as letters to the journal, each describe use of pembrolizumab and nivolumab in a patient with PML.

In one case, reported by a group from Germany and the United States with first author Sebastian Rauer, MD, University of Freiburg, Germany, a patient with PML associated with B-cell lymphoma who had become mute was treated with five infusions of pembrolizumab (2 mg/kg) every other week over a 10-week period. Following the start of treatment, the patient began speaking again, the size and number of PML lesions reduced, and JC virus was no longer detectable in the CSF. The patient remained stable during the course of treatment.

In the other case, reported by a French group by Guillaume Martin-Blondel, MD, PhD, Toulouse University Hospital, France, and colleagues, a patient with severe neurologic symptoms of PML and prominent PD-1 expression on T-cells was treated with nivolumab (240 mg every 2 weeks) that resulted in a reduction in JC viral load both in the CSF and blood. MRI lesions showed enhancement with gadolinium suggesting immune reconstitution. After 8 weeks of starting treatment, symptoms stabilized or improved.

Cortese noted that the prognosis for patients with PML varies enormously depending on their underlying condition. In patients with lymphoproliferative cancers the bone marrow is often so damaged that PML has a very high fatality rate of up to 90%, and PML associated with HIV can be similar, she said.

"So our results are very encouraging, with five of the eight patients we treated showing improvement, as seven of the eight patients treated had PML that had been progressing badly for several months with no reason to think that this trajectory would change. It does appear that the drug has had a life-saving effect on some of these patients."

But, she cautioned, "These are very small numbers and we didn't have a control group. But the fact that two other groups have reported similar findings gives our findings extra weight. The next step will be to do a controlled trial to try to confirm these very promising early results."

In an accompanying editorial, Igor Koralnik, MD, Rush University Medical School, Chicago, Illinois, says the current reports are encouraging for these two drugs as a treatment for PML but suggest the presence of JC virus-specific T-cells in the blood is a prerequisite for use.   

He cautions that the cost and side effect profile of these medications need to be considered as immune-related adverse events can affect multiple organ systems. He also notes that "enthusiasm is tempered" by a few cases in the literature in which nivolumab was actually reported to be associated with PML.

Koralnik agrees with the authors of the individual reports in his conclusion that "a controlled trial may be needed to determine whether immune checkpoint inhibitors are indeed able to keep JC virus in check in patients with PML."

The study was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke of the NIH. Cortese has reported holding stock in Keires AG, Nouscom AG, and PDC line Pharma. Rauer has reported receiving grants and personal fees from Bayer Vital GmbH, Biogen, Novartis, and Roche, personal fees from Sanofi Aventis, Genzyme, and Teva, and other support from ravo Diagnostika outside the submitted work. Martin-Blondel has reported receiving personal fees from Lilly, AbbVie, personal fees and nonfinancial support from Pfizer, and personal fees from Genzyme, Gilead, and ViiV Healthcare outside the submitted work. Koralnik has reported receiving personal fees from MedImmune, personal fees from UpToDate, and grants from the NIH outside the submitted work. Disclosures for coauthors are available on the journal website.

N Engl J Med. Published online April 10, 2019. Article, Letter 1,  Letter 2, Editorial

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