Tuesday, October 8, 2013

Test May Suggest Tysabri for More MS Patients

October 7, 2013

COPENHAGEN -- A blood test for L-selectin expression on circulating immune cells may identify multiple sclerosis patients who could safely receive natalizumab (Tysabri) despite past exposure to the JC virus, a small study presented here suggested.
All MS patients taking natalizumab who developed the rare but life-threatening brain inflammation called progressive multifocal leukoencephalopathy (PML) in the study had very low levels of L-selectin expression, which was not seen in other patients who did not develop PML or in controls, said Heinz Wiendl, MD, of the University of Muenster in Germany.
He and his colleagues at the Muenster MS clinic have begun to implement the test in patients, he told attendees at the European Committee for Treatment and Research in Multiple Sclerosis annual meeting, using a cutoff of 30% of circulating T cells positive for L-selectin (also known as CD62L).
So far, 10 patients had levels consistently below the cutoff in repeat testing. Four stopped natalizumab after counseling, Wiendl said. One developed PML, and five others are still taking the drug but with no sign of PML so far.
A larger validating study is now underway, with 342 patients accrued so far, Wiendl said.
PML results from reactivation of latent infection with the JC virus, which is common in the general population. It has been a particular problem with natalizumab, appearing shortly after the drug was approved in 2004 and forcing it off the U.S. market until its manufacturer implemented a strict risk evaluation and mitigation strategy.
Current recommendations call for JC virus serological testing in patients prior to starting natalizumab and periodically while on the drug to detect new infections. Although a positive test is not an absolute contraindication for the drug -- it remains the standard of care for patients showing aggressive MS activity in patients taking first-line therapies -- it is to be prescribed cautiously.
PML risk in patients with JC virus infection is increased with prior immunosuppressive therapy and duration of natalizumab treatment beyond 2 years.
Natalizumab mainly targets the alpha-4 integrin protein, an adhesion molecule, as is L-selectin. Studies of T cells in blood and cerebrospinal fluid (CSF) taken from 381 patients treated at the Muenster clinics showed that alpha-4 integrin expression in CSF T cells was essentially nil in natalizumab-treated patients.
But because some type of adhesion molecule action is necessary for T cells to enter CSF, Wiendl said, the finding indicated that an alternative pathway must exist, prompting the attention to L-selectin.
Among patients with long-term natalizumab therapy who did not develop PML, a mean of 40.2% of their peripheral blood CD4-positive T cells expressed L-selectin, whereas in the eight patients who later developed PML and for whom pre-PML blood samples were available, the average was 4.6% (P<0.0001), Wiendl said.
He told MedPage Today that the most obvious use of an L-selectin test would be to identify patients with past JC virus exposure on natalizumab with relatively high T-cell expression of L-selectin, since so far they appear to be at low risk for PML.
But he noted that JC virus-negative patients could benefit as well, because their risk of PML is not zero. JC virus serology tests may miss patients with recent infection or may simply be wrong; and the condition can be caused by other viruses.
Currently, he said, the group is beginning to test patients when they have received 18 natalizumab infusions, and then every 6 months. (He said the test "is very laborious.") In patients with L-selectin positivity in less than 30% of CD4-positive T cells, a switch to other therapies is considered.


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