The 57-year-old lawyer in New York had handily completed the New York Times' Saturday crossword puzzle - the hardest of the week - for years. But one Saturday morning, suddenly he couldn't retrieve the words to fill in the squares.
In Chicago, an 83-year-old woman began parroting the same phrases over and over. When her doctor asked her how she was, she replied, "I am fine. I am fine. I am fine."
The symptoms of the New York lawyer and the Chicago woman could have been mistaken for early dementia. But an MRI brain scan and biopsy revealed something surprising. It looked like their brains had been eaten away. A brain biopsy and a spinal tap confirmed the diagnosis of a swiftly moving and often fatal viral brain infection called progressive multifocal leukoencephalitis (PML) that attacks the brain's white matter. Both had lymphoma and had been taking the popular cancer drug rituximab (brand name Rituxan) before they developed the brain infection.
The two patients are part of a new study from the Northwestern University Feinberg School of Medicine RADAR project, led by Charles Bennett, M.D., that links rituximab to PML. Rituximab is the most important and widely used cancer drug for lymphoma. It is also approved for treatment of rheumatoid arthritis and is widely used off-label to treat multiple sclerosis, lupus erythematosus and autoimmune anemias.
Bennett reports on 57 cases from 1997 to 2008 in which patients with anemia, rheumatoid arthritis or lymphoma developed the fatal brain disease after taking rituximab. They died an average of two months after being diagnosed. The study was published in the May 14 issue of the journal Blood.
"Rituximab is one of the most prominent drugs in a new class called monoclonal antibodies. It's now the third monoclonal antibody that is associated with PML," said Bennett, the A.C. Buehler Professor in Economics and Aging at Northwestern's Feinberg School and a hematologist and oncologist at the Jesse Brown VA Medical Center in Chicago.
One of the other two drugs, Raptiva, was taken off the market in April of this year because of the PML risk. The other drug, Tysabri, was removed from the market for 1½ years because of similar concerns.
Bennett said the brain infection is often overlooked and undiagnosed because it is so subtle at first. "People may think it's early Alzheimer's disease or depression," he said. "Many of these patients have cancer and when they die, people assume it's the cancer that killed them."
It is not yet known how rituximab is connected to the brain virus and who may be at risk. Bennett notes that the best information on the frequency of PML is among patients with lupus with an estimated rate of 1 in 4,000 patients developing PML.
Monoclonal antibodies target one particular protein found on the surface of cells. In lymphoma, rituximab targets a protein called CD20 on the outside of B-cell lymphomas. The antibody binds to the protein, leading to the destruction of the cancerous cell.
"In non-Hodgkin's lymphoma, it turned out to be a home run," Bennett said of the drug. "It's been a magic bullet."
But concerns about the drug's association with PML first surfaced in 2006 when two patients with lupus developed the illness after taking rituximab and other immunosuppressive treatments. In 2008, Bennett said, the manufacturers of the drug, Genentech and Biogen Idec, sent letters to doctors alerting them that a patient with rheumatoid arthritis who had been taking rituximab also died from the brain infection. The companies asked whether physicians had detected this illness among cancer patients who were taking the drug.
Bennett said it was known that a small number of patients with lymphoma get the infection regardless of the drug. "But it was atypical for lupus and rheumatoid arthritis patients to get it," he said. "It was especially unusual for patients with autoimmune anemia-like illnesses who have not received a large number of other drugs."
Then Steve Rosen, M.D., director of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, noticed that the 83-year-old woman was repeating the same phrases over and over. After a brain biopsy identified the infection, Rosen alerted Bennett.
"I told him a serious abnormality was uncovered and the RADAR program needs to pursue it in the manner that he has investigated all other severe adverse drug problems," Rosen said.
Bennett's RADAR project (Research on Adverse Drug Events and Reports) is an international consortium of physicians that collaborate to identify adverse reactions to medications and devices.
Bennett met with Genentech executives, offering to help them gather what thus far had been elusive information on the drug's connection to the brain infection. Doctors had been reticent to report PML in their patients who had been taking rituximab.
"It's a lot of work to produce these reports," Bennett explained about doctors' reticence.
To offset this concern, Bennett called 12 major cancer centers around the country, asked doctors to share their information and offered to produce the reports for them. He discovered an additional 22 cases beyond what had previously been reported.
The study results illustrate a need for caution in prescribing rituximab, Bennett said.
"The drug has tremendous usefulness in lymphoma, but as its use expands to diseases that are not cancer, we might have to reconsider the risk benefit," Bennett said. "Some cancer patients take this drug chronically for non-fatal chronic leukemia where the risk-benefit calculations differ from lymphoma."
The next step, Bennett said, is to determine the risk factors for the disease in people who take rituximab.
"We need to learn more about this, " he said. "People have to think about the pros and cons in settings where it is being used for nonmalignant diseases. People have been lulled into a false sense of security that this drug is harmless and that it only does good things. No drug is perfect."
If people on rituximab develop any strange neurological symptoms such as forgetfulness, disorientation or mood changes, their doctors should be alerted, Bennett said.
Source:
Marla Paul
Northwestern University
September 2008
IMPORTANT DRUG WARNING NEW SAFETY INFORMATION
Dear Healthcare Professional:
Genentech, Inc. and Biogen Idec, Inc. would like to inform you of important new safety information regarding Rituxan® (rituximab).
• A case of progressive multifocal leukoencephalopathy (PML) leading to death has been reported in a patient with rheumatoid arthritis (RA) who received Rituxan in a long-term safety extension clinical study. This is the first reported case of PML in a Rituxan-treated patient with RA
The case of JC virus infection with resultant PML and death was reported in an RA patient treated with Rituxan and was diagnosed approximately 18 months after the last dose of Rituxan. This case was confounded by the patient’s development
of oropharyngeal cancer, which was treated with chemotherapy (a platinum
containing regimen) and radiation therapy 9 months prior to the development of PML. The patient had longstanding RA treated with immunosuppressants and a complex medical and rheumatologic history including Sjogren’s syndrome and undetectable complement C4 levels. Treatment for RA included methotrexate, steroids, and a TNF antagonist prior to Rituxan therapy; and methotrexate and
steroids during and after Rituxan therapy.
The Rituxan package insert WARNING section on PML has previously noted reports of PML in patients with hematologic malignancies and autoimmune diseases for which Rituxan is not approved. It has been updated to reflect the case of PML in an RA patient treated with Rituxan and is enclosed for your reference [See WARNINGS and PRECAUTIONS: 5.4 Progressive Multifocal Leukoencephalopathy (PML)].
Physicians treating patients with Rituxan should consider PML in any patient presenting with new onset neurologic manifestations. Consultation with a neurologist, brain MRI and lumbar puncture should be considered as
clinically indicated.
In patients who develop PML, Rituxan should be discontinued and reductions or discontinuation in concomitant immunosuppressive therapy and appropriate treatment including antiviral therapy should be considered. There are no known interventions that can reliably prevent PML or adequately treat PML if it occurs.
PML has been reported in the literature in populations such as: HIV-positive
patients, immunosuppressed cancer patients (including those with hematologic malignancies), organ transplant patients, and patients with autoimmune disease
who were not receiving Rituxan.
Rituxan is indicated for the treatment of patients with relapsed or refractory,
low-grade or follicular, CD20-positive, B-cell, non-Hodgkin’s lymphoma (NHL) as a single agent, and for the treatment of previously untreated follicular, CD20positive, B-cell NHL in combination with CVP chemotherapy. Rituxan is indicated for the treatment of nonprogressing (including stable disease), low-grade, CD20positive, B-cell NHL, as a single agent, following first-line treatment with CVP chemotherapy. Rituxan is also indicated for previously untreated diffuse large B-cell, CD20-positive, NHL in combination with CHOP or other anthracycline
based chemotherapy regimens. Rituxan in combination with methotrexate is also indicated to reduce signs and symptoms and slow the progression of structural
damage in adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies.
Rituxan has been associated with fatal infusion reactions, tumor lysis
syndrome (TLS), severe mucocutaneous reactions and progressive multifocal leukoencephalopathy (PML). Hepatitis B reactivation and cardiac arrhythmias and angina have also been observed. Patients should be closely observed for signs of infection if biologic agents and/or DMARDs other than methotrexate are used concomitantly. Common adverse reactions: hypertension, nausea, upper
respiratory tract infection, arthralgia, pruritus, and pyrexia.
Health care professionals should report any serious adverse events possibly associated with the use of Rituxan to Genentech Drug Safety at 1-888-835-2555. Alternatively, this information may be reported to the FDA’s MedWatch reporting system by phone (1-800-FDA-1088), facsimile (1-800-FDA-1078) or the Med Watch website at www.fda.gov/medwatch or mailed to MedWatch, HF-2, 5600 Fishers Lane, Rockville, MD 20852-9787.
If you have any questions regarding the use of Rituxan, please call Genentech Medical Information/communications Department toll free at 1-800-821-8590.
Hal Barron, M.D. Senior Vice President, Development Chief Medical Officer
Genentech, Inc.
David Hagerty, MD Vice President, CMO Rheumatology
Biogen Idec
Just a little additional information. So far, I have not been able to find any other deaths. I would appreciate it if anyone having anymore info would post it
It was the first PML-associated death of a patient taking rituximab for RA, according to Genentech and Biogen Idec in a letter to clinicians. The patient, who developed a JC virus infection leading to PML, had been taking the drug in a long-term safety extension clinical study.
"This case was confounded by the patient's development of oropharyngeal cancer, which was treated with chemotherapy (a platinum-containing regimen) and radiation therapy nine months prior to the development of PML," said the letter.
"The patient had longstanding RA treated with immunosuppressants and a complex medical and rheumatologic history including Sjogren's syndrome and undetectable complement C4 levels. Treatment for RA included methotrexate, steroids, and a TNF antagonist prior to Rituxan therapy, and methotrexate and steroids during and after Rituxan therapy."
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