Off-label treatment with natalizumab (Tysabri) for 20 children with severe multiple sclerosis reduced relapses and brain lesions seen on MRI scans, a retrospective analysis found.
The mean annualized relapse rate while on natalizumab in these patients was 0.4, compared with 3.77 before starting the drug (P<0.001), according to Barbara Kornek, MD, of Austria's Medical University of Vienna, and colleagues.
Also, new T2/fluid attenuated inversion recovery (FLAIR) lesions declined from a mean of 7.8 before natalizumab to 0.5 on the drug (P=0.001), the researchers reported online in JAMA Neurology.
But the treatment was not without adverse events, Kornek and colleagues noted. Half the patients experienced some type of clinical event, including one case each of severe asthenia, laryngeal edema, and anaphylaxis. Two had recurrent infections, although it was not clear that natalizumab was responsible.
Eight of the children also exhibited laboratory abnormalities. Four developed mild anemia, two showed transient elevations in liver enzymes, and two developed hyperbilirubinemia.
In addition, two patients developed high levels of neutralizing antibodies to natalizumab that led to withdrawal of the drug. Three other patients stopped natalizumab after tests showed the presence of antibodies to the JC virus, a strong risk factor for development of progressive multifocal leukoencephalopathy (PML), which can be fatal.
One patient had tested positive for JC virus antibodies before starting natalizumab, but the decision was made to use the drug anyway because of a "highly active disease course." Overall, the researchers found, five of 13 patients tested for JC virus antibodies were positive.
Natalizumab is not currently approved for pediatric use in the U.S. or Europe, but it is sometimes used anyway in children with very severe disease or who do not respond to more conventional disease-modifying treatments.
The 20 children Kornek and colleagues reported on were mostly teenagers and were receiving the drug in 11 clinics in Germany and Austria. In addition to the standard outcomes of relapse rates and MRI lesions, the researchers paid particular attention to development of neutralizing anti-drug antibodies and JC virus antibody status, as these had not previously been studied in a pediatric population.
Mean age at disease onset in these patients was 15.2 (SD 1.3) and the mean age when natalizumab was started was 16.7 (SD 1.1). All but four were girls.
One patient started on natalizumab as first-line treatment, 15 had previously received one disease-modifying treatment, and four had received two.
With a mean of 18 months of disease duration before starting natalizumab, the average number of relapses was 4.3, with 3.1 occurring in the previous year -- numbers that signify highly active disease.
Four of the patients had undergone plasma exchange for a severe, prolonged relapse event.
The mean number of T2/FLAIR brain lesions at pre-natalizumab baseline was 30 (SD 17), with a mean of 2 gadolinium-enhancing lesions.
Mean treatment duration for natalizumab in the analysis was 20 months, during which time 14 of the 20 patients remained relapse-free. Among seven patients on the drug for 2 years or more, four stayed relapse-free.
Only two patients did not show a significant reduction in relapse frequency with natalizumab.
In an analysis combining clinical and MRI results, six of 13 patients with adequate data were deemed to be free of disease activity with natalizumab, insofar as they had no relapses, did not develop new MRI lesions, or show disability progression.
Among 10 patients with complete data for at least 1 year, four were disease-free throughout follow-up.
Most of the patients actually showed some lessening of disability, with a median change in EDSS score of -0.25 points (interquartile range -1.25 to 0.00) relative to baseline, when the group median was 2.0 points.
Kornek and colleagues also looked at the clinical course of patients who had stopped natalizumab either permanently or temporarily. After excluding two who were lost to follow-up after stopping the drug and one who had stopped temporarily during pregnancy, there were nine patients available for this analysis, including eight followed for at least 6 months.
Among those eight, six developed relapses in the first 6 months off natalizumab. The annualized relapse rate among all nine patients showed a strong trend toward increase (mean difference 1.47, 95% CI -0.04 to 2.98, P=0.06).
Overall, Kornek and colleagues concluded that natalizumab "may be safe and effective against MS in pediatric patients with breakthrough disease," but they cautioned that controlled trials are needed to confirm a favorable benefit-risk balance.
The study had no external funding.
Study authors reported relationships with Biogen Idec, Merck Serono, Teva, Bayer Schering, Novartis, Sanofi, UCB, Orion, Solvay, Mundipharma, and Ipsen.
- Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner