Early Detection of PML With Natalizumab Improves Outcome

Megan Brooks

March 13, 2013

Detecting progressive multifocal leukoencephalopathy (PML) associated with natalizumab (Tysabri, Biogen Idec/Elan) before symptoms appear may improve survival and decrease disability, according to a retrospective study of 319 cases.

The study was released March 10, ahead of presentation at the American Academy of Neurology (AAN) 65th Annual Meeting, to be held March 16 to 23 in San Diego, California.

The findings suggest that the consequences of natalizumab-associated PML infection "can be mitigated by early detection of the disease," Tuan Dong-Si, MD, medical director, Biogen Idec and principal investigator for the study, said in a statement.

Dr. Dong-Si told Medscape Medical News these preliminary data are "important" but "not sufficient for inclusion in our label or to warrant revised routine monitoring recommendations at this time."

  "We know that some physicians do use MRI screening in their practices to monitor multiple sclerosis [MS] patients receiving Tysabri, however we cannot recommend this practice at this time. We continue to collect additional data and support clinical studies in order to better understand the utility of MRI screening," Dr. Dong-Si added.

Mitigation Strategy?

The researchers evaluated outcomes in all 319 natalizumab-associated PML cases confirmed as of January 1, 2013.

At diagnosis, 21 patients were asymptomatic, having been diagnosed by MRI findings and JC virus (JCV) DNA–positive cerebrospinal fluid (CSF). Their mean age was 45.1 years, 66.7% were women, and they had been exposed to a median of 38 doses of natalizumab. It's known that positivity for antibodies to JCV is associated with increased risk for PML.

The remaining 298 patients were symptomatic at diagnosis. Their mean age was 45.8 years, 70.5% were women, and they had also received a median of 38 doses of natalizumab.

In asymptomatic and symptomatic cases, PML lesions on MRI were unilobar in 76% and 36%, multilobar in 14% and 25%, and widespread in 10% and 39%, respectively.

In both groups, frontal lesions predominated. Ten of the 21 patients asymptomatic at diagnosis had symptoms an average of 13.8 weeks after diagnosis; 5 of these patients had cognitive deficits and/or behavioral changes.

Patients who were asymptomatic at diagnosis had an average disability score on the Karnofsky Performance Scale (KPS) of 67, while those with symptoms at diagnosis had a score of 54.

A KPS score of 70 indicates that the individual may be able to care for him- or herself but may be unable to carry on normal activities or do active work. A KPS score of 50 indicates that a person may require considerable assistance and frequent medical care. A score less than 50 indicates that the individual may be unable to care for him- or herself and may require institutional care or the equivalent.

One year after PML diagnosis, the average KPS score in the group asymptomatic at diagnosis was 70, compared with 47 for those with symptoms at diagnosis.

As of January 1, 2013, all 21 patients asymptomatic at diagnosis were living, compared with 77% of those with symptoms at the time of diagnosis, the researchers say.

Clinical Implications

Reached for comment, Mark Freedman, MD, professor of medicine (neurology) at the University of Ottawa and director of the Multiple Sclerosis Research Unit, Ontario, Canada,  said, "It's always nice to have retrospective data to help us perhaps understand how better to deal with PML."

"The bottom line," he said, "is that less than 10% of PML is detected asymptomatically and probably doesn't warrant doing monthly MRI scans. Even the asymptomatic ones get symptomatic within a month or so, indicating that there is little one can do but stop the drug. I'm not sure this makes me any more comfortable using Tysabri."

But Mary Rensel, MD, staff physician in the Cleveland Clinic Mellen Center, Ohio, told Medscape Medical News she feels this study helps "confirm that it is indeed important to monitor the patients on natalizumab with brain MRIs."

She noted that "the mean length of time on natalizumab for the patients with PML was 3 years. The ability to find the PML without symptoms seems to increase the survival and the level of disability in the long run. The amount of the brain affected with PML was less if it was found without symptoms. It is difficult to find the symptoms of PML as they can be cognitive dysfunction and if the patient is living alone then this can be missed."

"This study suggests that periodic monitoring [with] brain MRI while on natalizumab is important, with or without symptoms," Dr. Rensel concluded.

The study was funded by Biogen Idec and Elan Pharmaceuticals. Dr. Don-Si is an employee of Biogen Idec. Dr. Freedman reports he has received grants for clinical research from Bayer HealthCare Pharmaceuticals and Genzyme Corporation and has served as an advisor or consultant for Bayer HealthCare Pharmaceuticals, Biogen Idec Inc, EMD Serono Inc, Novartis Pharmaceuticals, sanofi-aventis, and Teva Neuroscience Inc. He is also an uncompensated member of the editorial advisory board of Medscape Neurology. Dr. Rensel has disclosed no relevant financial relationships.

American Academy of Neurology (AAN) 65th Annual Meeting. Abstract P04.268. March 16-23, 2013.