Immune System Activation Induced by Filgrastim Likely Beneficial for Patients with Tysabri-associated PML, Study Says

Immune System Activation Induced by Filgrastim Likely Beneficial for Patients with Tysabri-associated PML, Study Says

Immune system activation induced by filgrastim may be beneficial for patients with progressive multifocal leukoencephalopathy associated with the use of Tysabri (natalizumab), without worsening multiple sclerosis (MS) progression, a study says.

The study with that finding, “Treatment of natalizumab‐associated PML with filgrastim,” was published in the journal Annals of Clinical and Translational Neurology.

Biogen‘s Tysabri is a monoclonal antibody designed to bind to alpha‐4 integrin, preventing the entry of immune cells in the brain and minimizing inflammation. It has been approved for treating relapsing-remitting multiple sclerosis (RRMS) and Crohn’s disease in both the U.S. and Europe.

Unfortunately, Tysabri is known to increase the risk of a rare type of brain infection called progressive multifocal leukoencephalopathy (PML), caused by the John Cunningham Virus (JCV). PML is more frequent among individuals who have a weakened immune system, either due to illness (e.g., AIDS/HIV), or due to the use of immunosuppressants (like Tysabri).

“As of 5 December 2018, there have been 801 confirmed Nz [natalizumab]‐associated PML (Nz‐PML) cases in MS patients. There are a few reports regarding the outcome of Nz‐PML, but the management of Nz‐PML remains a matter of debate,” the investigators wrote.

According to the team, filgrastim “is used widely to promote and restore the immune system after intense immunosuppression and chemotherapy. We hypothesized that filgrastim would induce a rise in [immune cells] that could enter the brain, despite the blocking effect of Nz [natalizumab], thereby achieving immune recovery faster and more effectively than through simple Nz withdrawal,” they wrote.

To test their hypothesis, researchers analyzed the clinical outcomes of MS patients who had PML associated with the use of Tysabri, and were treated with filgrastim to stimulate the activation of their immune system in order to eliminate JCV as fast as possible.

The retrospective study involved a total of 17 MS patients who were recruited from a tertiary referral center between 2010 and 2017. Patients’ symptoms, diagnostic methods, survival, and clinical outcomes after treatment were reviewed in all study participants.

Data showed that on average, patients developed PML after having received 49 infusions of Tysabri.

To accelerate immune system recovery and hasten JCV elimination, all patients were treated with filgrastim administered through a subcutaneous (under the skin) injection after being diagnosed with PML, and stopped treatment with Tysabri.

Results showed that in most patients (88.2%) immune reconstitution inflammatory syndrome (IRIS, a condition in which the immune system responds to a previous infection with an overwhelming inflammatory response) occurred earlier than previously reported, approximately 57.4 days after the last Tysabri administration.

After developing PML-IRIS, patients were treated with intravenous (IV) methylprednisolone for three to five days, followed by an oral corticoid taper (descending dose of steroids) for two to four weeks.

Seven (41%) patients recovered from PML-IRIS, and no deaths associated with PML-IRIS were reported in the course of the study.

From the 17 patients participating in the study, three (18%) experienced MS relapses within one year after developing PML, and five (29%) more than one year after the onset of PML, which was lower than expected for patients with active MS.

Eight (47.1%) patients started treatment with other disease-modifying therapies after developing Tysabri-associated PML, on average about 26 months after Tysabri discontinuation.

“Our findings indicate that immunoactivation with filgrastim during PML, and careful management of subsequent IRIS is likely beneficial in patients with Nz‐PML, without worsening MS,” the researchers wrote.

“Further research is warranted as it may contribute to better understanding and treatment of autoimmune diseases and opportunistic infections. Prospective controlled studies, including larger number of patients are needed to confirm these findings,” they added.

Joana is currently completing her PhD in Biomedicine and Clinical Research at Universidade de Lisboa. She also holds a BSc in Biology and an MSc in Evolutionary and Developmental Biology from Universidade de Lisboa. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that make up the lining of blood vessels — found in the umbilical cord of newborns.
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Joana is currently completing her PhD in Biomedicine and Clinical Research at Universidade de Lisboa. She also holds a BSc in Biology and an MSc in Evolutionary and Developmental Biology from Universidade de Lisboa. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that make up the lining of blood vessels — found in the umbilical cord of newborns.
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