MONTREAL — Younger age, faster diagnosis, and undergoing treatment in Europe were among the factors associated with greater likelihood of survival in cases of progressive multifocal leukoencephalopathy (PML) in multiple sclerosis patients treated with natalizumab (Tysabri), a researcher reported here. Analysis of the first 79 cases of PML in patients receiving natalizumab found that these were the strongest survival predictors, according to John Foley, MD, of the Rocky Mountain Multiple Sclerosis Clinic in Salt Lake City. others included distribution of MS lesions and titers of JC virus — the actual cause of PML — in cerebrospinal fluid at diagnosis, he told attendees at the annual meeting of the Consortium of Multiple Sclerosis Centers.Action Points  

• Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
• Not that younger age, faster diagnosis, and undergoing treatment in Europe were among the factors associated with greater likelihood of survival in cases of progressive multifocal leukoencephalopathy (PML) in multiple sclerosis patients treated with natalizumab (Tysabri).

PML is a rare but extremely serious side effect of natalizumab treatment. its emergence led to the drug’s removal from the U.S. market just a few months after it was launched, but development of a strict risk evaluation and mitigation strategy led the FDA to approve the drug again.

At this point, the rate of PML appears to be just over one per 1,000 patients treated.

The drug inhibits leukocyte migration and may also alter the balance of CD4- and CD8-positive T-cells, increasing vulnerability to infections within the brain.

JC virus is widespread. Studies by natalizumab’s manufacturer, Biogen Idec, indicate that roughly half of MS patients are seropositive for infection. in most people, the latent infection is harmless, but when they become immunocompromised, as in AIDS, it can become active and deadly.

A total of 124 patients have been diagnosed with PML worldwide following treatment with natalizumab. Foley said the most recent data indicated that about 80% have survived, a rate that has grown since the first cases were seen.

The study he reported here was a follow up to an analysis by the same group of researchers, published last month in Neurology, covering the first 35 PML patients.

The same general patterns were generally seen with the addition of more patients but, not surprisingly, the specific numbers differed somewhat.

Foley and colleagues obtained patient information from the treating physicians as well as from Biogen Idec’s registry, comparing characteristics of survivors with those of fatal cases.

Median duration of follow up for the survivors was 9.6 months (range 1.2 to 29.1 months). among the fatal cases, the median time from PML diagnosis to death was 2.1 months.

Most of the deaths and much of the morbidity in the PML cases were actually attributable to immune reconstitution inflammatory syndrome (IRIS) following withdrawal of natalizumab, Foley indicated.

Comparisons of survivors with fatal cases revealed the following differences:

• Median age: 43 in survivors, 53 in fatalities
• Median time from symptom onset to PML diagnosis: 27 days in survivors, 41 days in fatalities
• Median JC virus loads in cerebrospinal fluid (CSF) at diagnosis: 132,000 copies/mL in survivors, 287,000 copies/mL in fatalities

Moreover, while patients in the U.S. represented 43% of the worldwide PML total, they accounted for 81% of the fatalities.

The survival rate in the U.S. was 62% versus 93% in Europe, Foley said.

Differences in practice patterns

Foley said the reasons for the disparity were uncertain, but he speculated that several differences between the U.S. and Europe in practice patterns may help explain it.

He said that U.S. patients receiving natalizumab were older and had more widespread disease than their European counterparts. also, physicians in the U.S. may be more reluctant to treat aggressively with steroids when IRIS develops, he said.

“A lot of the U.S. cases probably are dying more during the IRIS phase when there is a lot of cell necrosis,” he said. he also indicated that U.S. physicians may have been slower to diagnose PML after symptoms develop.

It is possible that more virulent JC virus strains are endemic in the U.S., he said, although much remains to be learned about the virology of JC virus.

Foley also identified several factors that were virtually identical in the survivors and fatal cases. These included the gender balance, median duration of natalizumab treatment, and prior immunosuppressant therapy.

The latter two have been found in Biogen Idec’s analyses to be powerful predictors of PML development, along with JC virus infection status.

Another finding in the new study was that most patients surviving PML appear to need a long time to recover. among 38 patients with Karnofsky performance ratings by their physicians at least six months after PML diagnosis, only five were in the “mild” disability category.

Half were rated as moderately impaired, and 37% were severely disabled and required custodial care.

One implication of the study, Foley said, is that it may be advisable to begin natalizumab treatment earlier in the disease in patients negative for JC virus. that may improve the survival chances in those extremely rare patients who still go on to develop PML.

At this point, according to Biogen Idec’s data, no patient shown to be seronegative for JC virus exposure has developed PML.

But Robert Fox, MD, of the Cleveland Clinic, told MedPage Today that there is some risk that a seronegative patient will become infected during natalizumab treatment. Early data appear to indicate that the annual risk is on the order of 1% to 2% annually, he said.

The serological test now being studied for assessing JC virus status in MS patients also seems to have a false-negative rate of about 2.5%, he said.

Consequently, Fox said, it is likely that patients on natalizumab will need regular retesting every six months to confirm their continued negativity.

The study was supported by Biogen Idec.

Foley reported consulting fees from Biogen Idec, Genzyme, and Teva. several co-authors were Biogen Idec employees.

Fox reported consulting fees from Biogen Idec, Teva, Genentech, and Novartis.