PML cases associated with rituximab resulted in 90% case-fatality rate

Rituximab is one of three monoclonal antibodies associated with PML.

In a series of progressive multifocal leukoencephalopathy cases among HIV-negative patients treated with rituximab, researchers found a 90% case-fatality rate, with a 100% case-fatality rate among those patients diagnosed with PML within three months after the last dose of rituximab.

Researchers from the Research on Adverse Drug Events and Reports (RADAR) project examined the link between the monoclonal antibody rituximab (Rituxan, Genentech/Biogen Idec) and progressive multifocal leukoencephalopathy (PML) in patients with anemia, rheumatoid arthritis and lymphoma. The report, published in Blood, included 57 cases of rituximab-associated PML.

“These patients presented with an inability to do crossword puzzles, had problems speaking and had difficult word-finding; these are not obvious presentations and may be overlooked in many people,” Charles Bennett, MD, A.C. Buehler professor in economics and aging at Northwestern’s Feinberg School and hematologist and oncologist at the Jesse Brown VA Medical Center in Chicago, told HemOnc Today.

Rituximab is one of three monoclonal antibodies associated with a risk for PML. Natalizumab (Tysabri, Biogen Idec) was removed from the market for a year and a half, and efalizumab (Raptiva, Genentech) was also recently removed due to cases of PML associated with the drug. According to Bennett, more attention should be paid to the link between rituximab and PML.

Using data from the FDA, the drug manufacturer, physicians and a literature review from 1997 to 2008, Bennett and colleagues reviewed cases of PML that occurred in patients treated with rituximab. The median patient age was 61, and all patients were HIV-negative.

The researchers identified 52 cases of PML in patients with B-cell lymphoproliferative disorders, two in patients with systemic lupus erythematosus, one patient with rheumatoid arthritis, one with autoimmune pancytopenia and one with immune thrombocytopenic purpura. Aside from treatment with rituximab, other treatments included hematopoietic stem cell transplantation, purine analogs or alkylating agents.

According to the data, PML occurred in one patient with an autoimmune hemolytic anemia after treatment with corticosteroids and rituximab and one patient with an autoimmune pancytopenia after treatment with corticosteroids, azathioprine and rituximab.

Patients with PML received a median of six rituximab doses prior to diagnosis; the median time from last rituximab dose to PML diagnosis was 5.5 months. Patients presented with confusion/disorientation, motor weakness/hemiparesis, poor motor coordination and speech or vision changes. Most cases were identified with MRI and JC virus detection in the cerebrospinal fluid or by brain biopsy or autopsy.

The fatality rate among PML cases diagnosed within three months of last rituximab dose was 100% compared with 84% among PML cases diagnosed more than three months after last rituximab dose, yielding a case-fatality rate of 90%.

“It’s important that both patients and doctors know of the link between PML and rituximab. As rituximab therapy diffuses outside of oncology to nonmalignant or noncancer fields, doctors will be less familiar with rituximab and PML, so there is a good chance there will be an important educational and safety need for this very important drug,” Bennett said.

The RADAR project began in 1998 and is comprised of a multidisciplinary team based at Northwestern University, though the group is connected internationally. Their goal is to identify, understand and report on hematology/oncology–related near-fatal adverse drug reactions. According to Bennett, this is particularly difficult in oncology due to the toxic nature of most cancer treatments and requires a high level of expertise and physician know-how.

Currently, Bennett and his colleagues at the RADAR project are working to help Genentech further explore the association between rituximab and PML. They hope to complete a large, international, prospective, case-control, epidemiologic study to identify risk factors for PML. – by Stacey L. Adams

Carson KR. Blood. 2009;113:4834-4840.