Tysabri (natalizumab), PML (progressive multifocal leukoencephalopathy), and Ongoing Research

  • Of the available disease-modifying treatments for multiple sclerosis, Tysabri (natalizumab) has arguably been the most controversial to date.  The reason for this controversy is a condition called progressive multifocal leukoencephalopathy or PML.  Any patient who is trying to decide whether Tysabri is the right medication for personal use, she/he must balance the risks and benefits and how those might fit into his lifestyle or circumstances.


    Of the 79 Tysabri patients who developed PML, 16 patients have died to date.


    The number of Tysabri patients who have developed PML (progressive multifocal leukoencephalopathy) has reached 79* as of December 17, 2010 says Biogen Idec, Inc.  The company also reports that an additional death among Tysabri/PML patients has occurred, bringing that total number of cases to sixteen. (*updated Dec 17, 2010)

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    "The number of PML cases is important because if the infection rate climbs too high, the drug's sales growth may drop. Regulators have said that they watch the cases, but have concluded that the benefits of the medicine to MS patients outweigh the risks.  The overall global PML rate is about 0.96 per 1,000 patients, a company spokeswoman said, which still falls within the 1-in-1,000 rate previously seen in clinical trials and implied on the drug's label. But the rate has been rising, and multiple Wall Street analysts raised concern about the trend on Wednesday as the MS market is becoming increasingly competitive."


    Biogen reports that as of Sept. 30, 2010, there are 55,100 patients using the drug around the world and that approximately 75,500 patients have used the drug since its launch.  Of the 79 total cases of PML, 34 cases were in the United States, 40 cases were in the European Union, and 5 cases were in other areas.


    "The most recent data update translates to a rate of 1.54 cases per 1,000 for patients on the drug for a year or longer, but rises to 2.05 per 1,000 for those on the drug for two years or longer.  Looked at another way, the rate is about 1.48 cases per 1,000 patients on the drug for between two and three years. The incidence is about 0.38 case per 1,000 patients in those using it for one to two years, and it is essentially nonexistent in patients using it for less than a year."


    According to these growing numbers, the death rate of Tysabri/PML patients is at 20%.  I wish that we knew the condition of the other 80% of PML-affected patients.  It would be helpful to know how much PML has permanently disabled them.  Reports are limited.  The chart below shows the number of reported PML cases in patients using Tysabri, where they live, how many have died, and the percentage of deaths among Tysabri-PML patients.



    What is PML?


    Progressive Multifocal Leukoencephalopathy (PML) is a rare disease that damages myelin, the fatty substance which protects nerves in the white matter of the brain.  It is caused by an infection or reactivation of the JC virus in patients who have weakened immune systems due to disease (ie. HIV, Hodgkin’s disease, lymphoma), use of immunosuppressants (such as in transplant patients), certain kinds of chemotherapy, or medications for multiple sclerosis (ie. Tysabri/natalizumab), rheumatoid arthritis (ie. Rituxan/rituximab), or psoriasis (ie. Raptiva/efalizumab).


    As PML is a demyelinating disease, the symptoms very closely resemble those of MS.  Loss of coordination, weakness of the legs or arms, disorientation, seizures, vision loss, impaired speech, and cognitive deterioration.  The development of PML may be difficult to distinguish from an MS relapse.  If new symptoms develop at any time, it is very important to contact your neurologist, especially if you are using Tysabri or some other powerful immunosuppressant.


    It is important to note that concurrent or previous use of powerful immunosuppressants (such as methotrexate, cytoxan, imuran, etc) may further increase the risk of developing PML.  When PML is suspected, patients undergo a lumbar puncture to test the cerebrospinal fluid for the JC virus.  Patients should also undergo MRI imaging to look for multifocal non-enhancing lesions in the cortical white matter.    Unfortunately, PML can be difficult to diagnosis.

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    Can PML be treated?


    Several case reports have been published in the past 16 years regarding patients diagnosed with PML.  Researchers have been investigating possible treatments for decades and as a result survival rates in HIV/AIDS patients have increased dramatically.  A common approach used in AIDS-PML patients is high active antiretroviral therapy (HAART).  In transplant patients, stopping immune-suppressing medications improves clinical outcomes.  However, at present there is no known cure.


    The only effective treatment for PML at this time is to quickly restore the immune system.  One method to restore the immune system which has been proposed in Tysabri-treated patients is plasma exchange (PLEX) or plasmapheresis.  In plasma exchange, whole blood is withdrawn from the patient then plasma is removed from the blood.  Donor plasma (or saline and albumin) replaces the removed plasma, then blood is transfused back into the patient.  This removes Tysabri from the patient’s blood faster than it would dissipate on its own.


    Following treatment, some patients experience immune reconstitution inflammatory syndrome (IRIS), a condition in which the recovering immune system produces an intense inflammatory response against the JC virus, thus making symptoms worse. If IRIS develops, MRI images may show contrast-enhancing lesions and significant cerebral edema.  Steroids may be helpful in combating IRIS.


    Biogen Idec (makers of Tysabri) is funding trials which are underway to test other potential PML treatments such as the antimalaria drug mefloquine mefloquine hydrochloride.  Research is also underway to develop an accurate test to predict a patient’s risk of developing PML based on detecting anti-JCV antibodies.


    To Continue or Discontinue Tysabri Treatment?


    This is a decision which must be made between the patient and his/her neurologist.  Some doctors are suggesting “treatment holidays” for patients who have had more than 24 infusions of Tysabri.  It is at the two-year mark that PML risk has shown to be increased in patients treated with natalizumab.


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    Researchers at Beth Israel Deaconess Medical Center have reported on thirty-two of their patients who had received at least 12 consecutive Tysabri infusions and experienced relapses or new gadolinium-inhanced lesions.  These patients discontinued Tysabri.  The interesting observation seen in the report is that patients who had more inflammatory disease before the start of treatment experience more significant IRIS after stopping Tysabri.  Very interesting observation which should help patients and their doctors decide what treatment strategies to undertake.


    In Real Life


    Here at HealthCentral, we have not had many in-depth discussions of Tysabri by patients who are actually using it, have used it, or are considering it.  If you fit into any one of those categories, I invite you to share your experiences with us.  Please comment below or create a Sharepost of your own to begin the discussion.






    FDA Drug Safety Communication: Risk of Progressive Multifocal Leukoencephalopathy (PML) with the use of Tysabri (natalizumab)


    Multiple Sclerosis Resource Centre and The Wall Street Journal Copyright (c) 2010 Dow Jones & Company, Inc. (17/12/10)


    Progressive Multifocal Leukoencephalopathy on MedlinePlus


    Progressive Multifocal Leukoencephalopathy (PML): Brain Infections on Merck Manual Professional


    Warnke C, Menge T; et al.  Natalizumab and Progressive Multifocal Leukoencephalopathy: What Are the Causal Factors and Can It Be Avoided?  Arch Neurol. 2010;67(8):923-930.


    Stüve O, Marra CM, Cravens PD; et al. Potential Risk of Progressive Multifocal Leukoencephalopathy With Natalizumab Therapy: Potential InterventionsArch Neurol. 2007;64(2):169-176.


    Miravelle A, Jensen R, Kinkel RP.  Immune Reconstitution Inflammatory Syndrome in Patients With Multiple Sclerosis Following Cessation of Natalizumab TherapyArch Neurol. Published online October 11, 2010. doi:10.1001/archneurol.2010.257


    Lisa Emrich is author of the blog Brass and Ivory: Life with MS and RA and founder of the Carnival of MS Bloggers.

Published On: December 16, 2010