Therapies that promote progressive multifocal leukoencephalopathy (PML)

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August 23, 2019 – Progressive multifocal leukoencephalopathy (PML) is a rare and often fatal viral disease characterized by progressive damage or inflammation of the white matter of the brain at multiple locations (i.e., multifocal). It is caused by the JC virus, after the initials of the person from whose tissue the virus was first successfully cultured (i.e. John Cunningham) and which is normally present and kept under control by the immune system. The JC virus is harmless except in cases of weakened immune systems. In general, PML has a mortality rate of 30–50% in the first few months, and those who survive can be left with varying degrees of neurological disabilities.

PML occurs almost exclusively in patients with severe immune deficiency, most commonly among patients with acquired immune deficiency syndrome (AIDS), but people on chronic immunosuppressive medications including chemotherapy are also at increased risk of PML, such as patients with transplants, Hodgkin’s lymphoma, multiple sclerosis, psoriasis, and other autoimmune diseases

The cause of PML is a type of polyomavirus called the JC virus (JCV). Recent publications indicate 39 to 58% of the general population are seropositive for antibodies to JCV, indicating current or previous infection with the virus. Other publications put the percentage as high as at 70 to 90% of the general population. JCV causes persistent asymptomatic infection in about one-third of the adult population, based on viral shedding into the urine from the site of asymptomatic infection in the kidney. Fortunately, the virus causes disease, including PML, only when the immune system has been severely weakened. And, as for PML, even under these conditions of weakened immune system function, PML is very rare.

Nevertheless, drugs such as Natalizumab (Tysabri), Rituximab (Rituxan), Alemtuzumab (Campath, or Lemtrada),, Ofatumumab (Arzerra), Carfizumab (Kyprolis), as well as the 2009 in the EU and the US from the market withdrawn Efalizumab (Raptiva),  all of whose pharmacological mode of action involves fiddling with the patients immune system (mostly selective immunosuppression) are associated with cases of PML occurring in patients.

From recent review articles and in VigiAccess, which is sourced from VigiBase, the World Health Organization’s (WHO) global database for adverse drug reactions (ADRs), maintained by the Uppsala Monitoring Centre (the UMC), it becomes evident that the list of drugs who in one way or the other suppress the immune system, either selectively by interaction with target molecules within the immune system, or more indirectly, is much longer and also includes Infliximab (Remicade), Adalimumab (Humira), Bevacizumab (Avastin), Basiliximab (Simulect), Cetuximab (Erbitux), Belimumab (Benlista), Obinutuzumab (Gazyva), Brentuximab vedotin (Adectris), Ibritumomab tiuxetan (Zevalin), Muromonab‐CD3 (Orthoclone OKT3), Etanercept (Enbrel), and Abatacept (Orencia).

It comes as no surprise that in indications where the immune system has to be suppressed in order to achieve a therapeutic response, you find the therapies hat most often cause PML. Such indications would include transplantation, HIV, rheumatoid arthritis (RA), systemic lupus erythematous (SLE),  and multiple sclerosis (MS). Particularly in the latter indication MS, there are, interestingly, some non-antibody yet immuno-suppresive agents such as Dimethyl Fumarate (Tecfidera) and Fingolimod (Gilenya) associated with PML.

While generally patients with PML had a rather dire future (often with untimely and premature death), it remains to be seen, how the new cancer therapies based on immune checkpoint inhibitors (ICI) such as Nivolumab (Opdivo), Pembrolizumab (Keytruda), Cemiplimab (Libtayo), Atezolizumab (Tecentriq), Avelumab (Bavencio), and Durvalumab (Imfinzi) might fare as a treatment option for patients afflicted with PML. If successful, this would be an excellent example of repurposing therapies (i.e., drugs) for successfull use in other than the original indication.

See here a short sequence on PML from an affected patient’s point of view. Note the person in the sequence died from it (PML) not to long after recording this video. So, the person speaks about real life:

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About the Author
thassodotcom Ph.D.; Professor in Pharmacology and Toxicology. Senior expert in theragenomic and personalized medicine and individualized drug safety. Senior expert in pharmaco- and toxicogenetics. Senior expert in human safety of drugs, chemicals, environmental pollutants, and dietary ingredients.

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