ABSTRACT & COMMENTARY
Utility of Anti-JC Virus Antibody Index to Assess the Risk of PML in Natalizumab-Treated MS Patients
By Jai S. Perumal, MD
Assistant Professor of Neurology, Weill Cornell Medical College
Dr. Perumal is on the speakers bureau for Biogen Idec, Teva Pharmaceuticals, Genzyme Corp., and Acorda Therapeutics.
Synopsis: This study suggests that we may further define the risk of progressive multifocal leukoencephalopathy associated with natalizumab treatment based on individual anti-JC virus antibody index values rather than anti-JC virus antibody-positive or -negative status alone.
Source: Plavina T, et al. Anti-JC virus antibody levels in serum or plasma further define risk of natalizumab-associated progressive multifocal leukoencephalopathy. Ann Neurol 2014; Oct 1. Doi: 10.1002/ana.24286.
Natalizumab is a monoclonal antibody that is FDA-approved for the treatment of relapsing-remitting multiple sclerosis (MS). Among the available options to treat MS, it is one of the most effective. The greatest concern with natalizumab treatment is the risk of developing progressive multifocal leukoencephalopathy (PML). The factors known to increase the risk of PML in natalizumab-treated patients include positive JC virus antibody status, longer duration of treatment, and prior immunosuppressive therapy use; the most significant among these is JC virus antibody status. Table 1, taken from the manufacturer prescribing information for natalizumab, provides estimated risk based on known risk factors.
When it was initially investigated, the results of the JC virus antibody test were reported simply as positive or negative, and risk assessments were based on positive or negative status alone, as noted in Table 1. More recently, risk has been quantified using an anti-JC virus index value, calculated from a two-step ELISA antibody assay of serum/plasma. An index of < 0.2 is designated as negative, > 0.4 positive, and a value > 0.2 but < 0.4 is designated as "indeterminate" and further evaluated by a confirmatory test.
The purpose of this study was to determine if the risk of PML associated with natalizumb can be further defined based on index values, and not merely by JC virus antibody, negative vs positive, status alone. A total of 2522 patients who were on natalizumab and who were JC virus antibody-positive and did not have PML, and 71 natalizumab-treated patients who were JC virus antibody-positive and who developed PML were included in the study. The subjects were either participants from the clinical trials of natalizumab or post-marketing use. For the analysis, subjects were divided into a test data set of 1039 non-PML and 45 PML patients and a validation set of 1488 non-PML and 26 PML patients. Integrated analysis of the combined data set of 2522 non-PML patients and 71 PML patients was also performed. In PML patients only, samples that were collected at least 6 months prior to the PML diagnosis were included.
The analysis showed that patients who developed PML had significantly higher JV antibody index than non-PML patients in the test data set (median = 2.4 vs 1.4, P < 0.0001) and the validation test set (median = 2.3 vs 1.9, P = 0.0199). Using predicted probabilities for JC virus antibody-positive patients with no prior immune suppression, with an antibody index of 0.9 to 1.5, the risk of PML was about 0.1 per 1000 from 25 to 48 months and 1.3 per 1000 from months 49 to 72. For JC virus antibody-positive patients with no prior immune suppression who have a JC virus antibody index of
> 1.5, the risk of PML was about 1 per 1000 from 25 to 48 months and ranged from 8.1 to 8.4 per 1000 from months 25 to 72. The association of higher index values with higher risk of PML was not significant for patients who were treated with prior immune suppression, and did not appear to help determine PML risk based on index values in this group. There was no association between the index value and duration on natalizumab treatment or prior immunosuppression. Long-term stability of the index values for an individual patient was assessed over a period of 18 months. Eighty-seven percent of those who were JC virus antibody-negative at baseline remained negative during the entire 18 months. Ninety-six percent to 97% (each data set respectively) of patients who were negative at baseline either remained negative, or if they converted, were below an index value of 1.5.
Commentary
This study helps further define the risk of natalizumab-associated PML based on JC virus antibody index values. The risk appears to be highest in patients with an index value > 1.5. For those patients who have an index value < 0.9, risk appears to be similar to that of a JC virus antibody-negative patient. The study also demonstrates that the index value remains stable over a duration of 18 months. This risk stratification, based on index values, does not appear to be helpful in patients with prior immune suppression.
Limitations of this study include the relatively small number of patients with PML, the lack of association between the index and patients with prior immune suppression, and the short duration of follow up. However despite these limitations, the index value provides another tool to better stratify the risk of PML associated with natalizumab treatment. These findings should be further corroborated with a larger number of patients and longer duration of follow up.
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