BOSTON — A new test seems to be able to stratify patients at risk for progressive multifocal leukoencephalopathy (PML) while receiving the multiple sclerosis (MS) drug natalizumab more effectively than anything available at present.

The test is based on observations that patients who develop PML appear to have very low levels of L-selectin (CD62L) on CD4+ T cells in the months or years before they develop the condition.

"We believe that very low levels of L-selectin is a predictive test for the future risk of PML on natalizumab," stated Dr. Heinz Wiendl, University of Münster, Germany.

He presented the data at the recent MS Boston 2014, the 2014 Joint Americas and European Committees for Treatment and Research in Multiple Sclerosis (ACTRIMS/ECTRIMS) meeting.

Dr. Wiendl explained that he and his colleagues noticed that some patients receiving long-term natalizumab had reductions in levels of L-selectin. "In particular patients who developed PML tended to have very low levels of L-selectin, so we thought it might be a good biomarker," he said.

They therefore went back and analyzed blood samples from a larger group of natalizumab recipients. "We now have data on 1000 patients treated with the drug, of whom 15 have developed PML," he reported.

"Of these 15 patients, 14 showed very low levels of L-selectin (less than 21.6) in samples of peripheral blood taken months or years before PML developed."

Asked for comment on these findings, Robert J. Fox, MD, Mellen Center for Multiple Sclerosis at Cleveland Clinic in Ohio, said he thought this was one of the "most exciting developments" presented during the meeting.

Dr. Wiendl told Medscape Medical News that he is now testing all patients after 18 months of natalizumab and then every 6 months thereafter. "If one value is low then the patient is at significant risk of PML and we stop the drug."

Dr. Wiendl believes that L-selectin is far more selective than JC virus V (JCV) antibodies for identifying patients at risk for PML.

"About half of patients test positive for JCV antibodies, but only about 10% of patients have low levels of L-selectin," he noted. "JCV positivity puts patients at a risk of about 1 in 100 of developing PML, but with low L-selectin levels the risk is more like 1 in 10," he estimated.

The L-selectin test is also more reliable in patients who have had previous immunosuppression, he added.

Synergistic With JCV Antibody Status

Dr. Wiendl is not advocating that L-selectin replace the JCV antibody test but rather that they be used together. "I see it as a combined effort, as the 2 markers appear to be synergistic," he said.

The problem, however, is that the L-selectin test is not easy to perform. It involves purifying and isolating mononuclear cells and then performing multicolor flow cytometry. "At the moment our L-selectin test is just at the transition from academic to clinical," he noted. It is now undergoing validation in different cohorts in France and Spain.

Dr. Wiendl's team is offering the test to centers in Germany, Austria, Switzerland, and Benelux (Belgium, the Netherlands, and Luxembourg) at present and is open to the idea of expanding the service to other countries. However, there is a logistical issue in that the blood has to be processed within 24 to 36 hours so the mononuclear cells are still viable, which limits long travel distances to the laboratory. Dr. Wiendl is looking at ways to commercialize the test to enable more widespread use.

Dr. Fox emphasized the importance of risk stratification for complications such as PML. "With these complications what we try to do is risk-stratify and risk-mitigate," he told Medscape Medical News. "We want to stratify patients to understand their risk, and then mitigate that risk as best we can. This test promises to help us do just that."

He said the sensitivity and specificity of the L-selectin test were reported to be about 90%, "which is very encouraging."

"I would be eager to have the test available for general clinical use so that we can use that to help guide patients regarding their risk, and not just predicting the risk but also perhaps identifying those that are in the early stages of having developed PML," he added.

More information about the tests can be obtained from contacting Dr. Wiendl through the hospital's Web site.

Dr. Wiendl reports honoraria and consultation fees from Bayer HealthCare, Biogen Idec, Fresenius Medical Care, GlaxoSmithKline, GW Pharmaceuticals, Merck Serono, Novartis, Sanofi-Genzyme BioVentures, and Teva Pharmaceutical Industries; grants and contracts with Bayer HealthCare, Biogen Idec, the German Ministry for Education and Research, Deutsche Forschungsgesellschaft, the Else Kröner Fresenius Foundation, the Fresenius Foundation, the Hertie Foundation, Merck Serono, Novartis, the NRW Ministry of Education and Research, the Interdisciplinary Center for Clinical Studies in Münster, Germany, the RE Children's Foundation, sanofi-aventis/Genzyme, and Teva Pharmaceutical Industries. Dr. Fox reports he has received personal consulting fees from Novartis, Biogen Idec, GlaxoSmithKline, MedDay, Questcor, Teva, and XenoPort; has served on advisory committees for Biogen Idec and Novartis; and received research grant funding from Novartis.

MS Boston 2014: 2014 Joint Americas and European Committees for Treatment and Research in Multiple Sclerosis (ACTRIMS/ECTRIMS). Abstract PS6.5. Presented September 11, 2014.


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