PML With mAbs Reviewed
This month’s issue of Lancet Oncology provides a reasonably comprehensive and up-to-date review of progressive multifocal leukoencephalopathy (PML) in the context of monoclonal-antibody (mAb) therapy. The authors draw on data from Northwestern’s Research on Adverse Drug Events and Reports (RADAR) project.
Perhaps most surprising is the total number of PML cases that have been reported to date with rituximab treatment—76. Although it’s important to remember that the mAb has been on the market for more than 10 years, with greater than 1 million patient exposures (at least according to the drug’s web site). By contrast, the latest incidence of PML with natalizumab treatment has been calculated at about 1.2 in 10,000.
A supplemented synopsis of PML with rituximab, natalizumab, or efalizumab therapy is provided here:
Rituximab (Rituxan; Genentech/Biogen IDEC): As of July 29, 2009, a total of 76 cases of PML have been reported in rituximab-treated patients. These cases include 69 oncology patients, 1 patient with autoimmune hemolytic anemia, 5 patients with autoimmune disorders (eg, SLE), and 1 patient whose primary condition is described as unknown. Median time to death is 2 months. Survival in patients with non-Hodgkin’s lymphoma is higher in those who develop PML after hemoatopoietic stem-cell transplantation (eg, 38% vs 10%). Rituximab is proposed to increase the risk of PML by indirectly expanding the population of pre-B cells that harbor JC virus.
Natalizumab (Tysabri; Biogen IDEC/Elan): As of July 24, 2009, there have been a total of 11 PML cases in natalizumab-treated patients since the drug’s relaunch in July 2006 (multiple sclerosis, 10; Crohn’s disease, 1). The risk of PML with natalizumab appears to be increased by the concomitant use of interferon beta and extended monotherapy (eg, ~2 years). Natalizumab may cause PML by enhancing the migration of JC virus-infected CD34+ cells into the CNS.
Efalizumab (Raptiva; Genentech): Four cases of PML were reported with the use of efalizumab, a mAb that was indicated for the treatment of psoriasis. Consequently efalizumab was withdrawn from the US market on June 8, 2009.
Treatment of PML, which is due to the activation (or reactivation) of latent JC* virus in the CNS, has been chiefly informed by experience with PML in patients with AIDS. Therapy requires reconstitution of the immune system (and, in the case of mAb treatment, the discontinuation of the mAb). In patients with AIDS, HAART reduces the severity of PML, but its use in HIV-negative patients is unproven. Treatment with cytarabine is supported by case studies, say the authors. There is also 1 ongoing, international, company-sponsored study of the antimalarial drug mefloquine in PML; however, the outcomes do not include survival endpoints.
AIDS = acquired immunodeficiency syndrome; CNS = central nervous system; HAART = highly active antiretroviral therapy; HIV = human immunodeficiency virus; SLE = systemic lupus erythematosus.
* JC = John Cunningham, a patient with PML (see Padgett BL et al. Lancet. 1971;1:1257-1260.).