Progressive multifocal leukoencephalopathy risk increases with longer natalizumab exposure

Forty-two cases of progressive multifocal leukoencephalopathy (PML) in patients receiving the humanized monoclonal antibody natalizumab have been documented since 2006 from MedWatch reports.

Key Points

Forty-two cases of progressive multifocal leukoencephalopathy (PML) in patients receiving the humanized monoclonal antibody natalizumab have been documented since 2006 from MedWatch reports.

The incidence of natalizumab-associated PML increases "with duration of [natalizumab] exposure during the first 3 years, after which it appears to stabilize," said David B. Clifford, MD, at the 62nd annual meeting of the American Academy of Neurology, Toronto.

To characterize the PML presenting in natalizumab-treated patients with multiple sclerosis (MS), he reviewed 24 cases from MedWatch records, published reports, and contacted many of the treating physicians involved. To estimate risk, data on the population exposed to natalizumab were obtained from Biogen Idec.

The risk of PML increased with duration of exposure through the first 3 years of treatment: the incidence was .035/1,000 patients with 1 to 12 infusions, increasing to 0.34/1,000 with 13 to 24 infusions, and 1.34/1,000 with 25 to 36 infusions.

Of the 42 cases of PML documented since 2006, 64% have occurred in Europe and 36% in the United States. The reasons for this difference are unknown, although it may be related to differences in prior therapies, Dr Clifford said. About 50% of PML cases had prior chemotherapy exposure both in the United States and Europe.

Ten of the 42 patients who developed PML as a result of natalizumab have died to date. Immune reconstitution with plasma exchange is the only effective treatment for natalizumab-associated PML, given natalizumab's long half-life, but plasma exchange comes at a cost of immune reconstitution inflammatory syndrome (IRIS), which is recognized by progression of MS symptoms and signs, and evolution of MS lesions.

As evidence of lesion evolution as a part of IRIS, "natalizumab-associated PML lesions had Gd+ enhancement on T1 images in 15 of the 42 cases at diagnosis," making it difficult to distinguish PML from exacerbations of MS, said Dr Clifford.