High Survival Rate With Natalizumab-Associated PML

Megan Brooks

May 31, 2011 — The prognosis of natalizumab (Tysabri; Biogen Idec)–associated progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis (MS) appears to be better than for PML associated with other diseases, results of a new study indicate.

"The most important point of our study is that natalizumab-associated PML has a high survival rate (71%), which we believe is likely due to earlier diagnosis of PML due to enhanced clinical vigilance and also aggressive management of PML and its complications," notes study investigator Sandra Richman, MD, MPH, of Biogen Idec Inc, Weston, Massachusetts.

The study is published in the May 17 issue of Neurology. It is also featured in a podcast on the journal's Web site.

In a linked commentary, David B. Clifford, MD, of Washington University in St. Louis, Missouri, says natalizumab-associated PML "must be understood as a major risk, but it is also somewhat manageable through early diagnosis and aggressive treatment. PML is not a death sentence."

PML Not a 'Death Sentence'

Natalizumab was approved by the US Food and Drug Administration (FDA) in 2004 to treat relapsing forms of MS. It was temporarily withdrawn from the market in 2005 after being linked with PML, a rare opportunistic infection of the central nervous system associated with the JC virus. The drug was reintroduced in 2006 with stricter safety warnings and monitoring programs.

As of February 28, 2011, 102 cases of PML had been reported among 82,732 patients treated with natalizumab worldwide.

Early on, the risk for PML in natalizumab-treated patients was estimated at about 1 case per 1000 patients. In April 2011, the FDA announced updated labeling of natalizumab to further quantify the risk in patients taking the drug. The updated label tabulates postmarketing incidence rates of PML by level of exposure to the product

As reported by Medscape Medical News, FDA noted that the incidence of PML per 1000 patients is 0.3 in those receiving fewer than 25 infusions, 1.5 in those receiving 25 to 36 infusions, and 0.9 in those receiving 37 to 48 infusions.

In their current report in Neurology, Dr. Richman and colleagues summarize observations for the first 35 postmarketing cases of natalizumab-associated PML, with a focus on clinical outcomes and predictors of survival. "The report is the product of assessments from treating clinicians, organized by the company that markets natalizumab," Dr. Clifford notes in his commentary.

Patients included 10 men and 25 women, aged 27 to 59 years (mean age, 43.7 years), who had MS for an average of 12.5 years. Eleven patients were from the United States and 24 from Europe.

At the time of PML diagnosis, patients had had between 12 and 44 infusions of natalizumab (mean, 26.6 infusions). At the time of the analysis, after a mean follow-up of 6.8 months, 25 patients (71%) were still alive.

"This survival rate is higher than what you see in other PML populations in the literature," Dr. Richman points out. For example, transplant patients with PML have about a 30% survival rate; HIV patients with PML had a 10% survival rate, before the era of highly active antiretroviral therapy (HAART). With HAART, they have about a 50% survival rate.

Worse Outcomes in Older, Sicker Patients

Compared with fatal cases of natalizumab-associated PML, nonfatal cases occurred in younger (mean age, 40.7 vs 51.1 years) patients who had less disability before diagnosis (mean pre-PML Expanded Disability Status Scale score, 3.9 vs 4.9).

These patients also had a shorter time from symptom onset to diagnosis (mean, 44.2 vs 62.8 days), and they had more localized disease on brain magnetic resonance imaging (MRI), suggesting earlier diagnosis.

Brain MRI results at the time of diagnosis were available for 31 patients. Most of the patients who survived (86%) had unilobar or multilobar disease (2 or more contiguous lobes) on brain MRI at diagnosis, whereas most of the patients with fatal cases (70%) had widespread disease (2 or more noncontiguous lobes or disease in both hemispheres), the study team notes.

The investigators say there were no significant differences between patients with fatal and nonfatal disease in sex, MS duration, natalizumab exposure, prior immunosuppressant use, and cerebrospinal fluid (CSF) JC viral load at diagnosis.

Most patients were treated with rapid removal of natalizumab from the circulation using plasma exchange or immunoadsorption. Nearly all of the patients (91%) developed immune reconstitution inflammatory syndrome (IRIS) and were treated with corticosteroids.

IRIS presented as new or worsening neurologic symptoms, tended to be severe, and usually occurred within days or weeks after rapid removal of natalizumab, the investigators note. "By 6 months post diagnosis, most of these patients had either recovered from IRIS or had started to recover from IRIS," Dr. Richman added.

Of the survivors followed up for at least 6 months from the time of PML diagnosis, one-third had mild disability, one-third had moderate disability, and one-third had severe disability, based on physician-reported Karnofsky scores. However, the investigators urge caution in interpreting the residual disability data, which were "probably confounded by disability attributable to underlying MS."

'Extensive' Natalizumab Education Seen Helpful

"The extensive education on PML that is provided to prescribers, patients, and relatives as part of global risk-management programs for natalizumab has probably resulted in earlier detection of PML, and prompt restoration of immune surveillance has contributed to better clinical outcomes," Dr. Richman and colleagues note in their report.

John R. Scagnelli, MD, of the University of Virginia in Charlottesville, who was not involved in the study, agrees that increased education of clinicians has helped.

"Having managed patients on natalizumab, there definitely is a high level of surveillance for patients receiving it both by the clinicians and the infusion centers," he notes in the Neurology podcast.

One limitation of the current analysis, the investigators say, is a lack of long-term follow-up of PML survivors. They note, however, that from the time the first postmarketing case of natalizumab-associated PML was reported in 2008 to the time of the current analysis, the proportion of survivors has remained near 70%. Even looking at more recent data (not in the article), the survival rate has been maintained at this level, Dr. Richman points out.

More detailed and standardized long-term data collection of PML survivors is needed to better characterize functional status and to reassess predictors of disability, the investigators say.

'Time is Brain' for Infections Too

Dr. Richman says it's important to give patients a "balanced" view of natalizumab, noting that PML remains "an infrequent consequence of natalizumab therapy but that we are also noting a high survival rate in the data that we have."

The description of outcomes of PML from this report will help neurologists and patients realistically frame the risk of natalizumab therapy. Neither exaggeration nor minimization of the risks of this complication will serve our patients well.

Dr. Clifford agrees. "Where patients face life with a disabling disease while effective therapies are available, much good can be done by assuming calculated and real risks," he writes. "The description of outcomes of PML from this report will help neurologists and patients realistically frame the risk of natalizumab therapy. Neither exaggeration nor minimization of the risks of this complication will serve our patients well."

Dr. Clifford also notes in his commentary that neurologists might well apply the "time is brain" mantra to natalizumab-associated PML, as well as to vascular disease, and strive for prompt clinical assessment and MRI of the brain to determine whether PML is possible, followed by CSF analysis with an ultrasensitive polymerase chain reaction assay for JC viral DNA to confirm the diagnosis.

Dr. Richman and 2 coauthors are employees of Biogen Idec Inc. Several other authors have financial relationships with Biogen. A complete list of author disclosures is published with the original article. Dr. Clifford serves or has served on the scientific advisory boards for Biogen Idec, Elan Corporation, and several other pharmaceutical companies. A complete list is published with his editorial.

Neurology. 2011;76:1697-1704, 1688-1689. Abstract Editorial