Saturday, 13 July 2013

Natalizumab PML Update: June 2013

June 2013 PML update. How many MSers have died from PML? #MSBlog #MSResearch

"The following are the latest risk figures for PML on natalizumab. Please note that the slideshow at the bottom is for professional eyes only. I embed this slideshow for my colleagues who inform me that they are now using this blog for their monthly update."

"As of 4th June 2013 there have been 372 cases of natalizumab-associated PML; 85 (23%) MSers have died from PML and 287 (77%) are alive. Please note that the majority of those surviving have a poor functional outcome."

"The following figure captures all the necessary information in one slide."



IS = previous immunosuppression
Anti-JCV = antibodies detected against JC virus



Conflicts: multiple

9 comments:

  1. My doctor has suggested moving to a 5 or 6 week infusion interval now that I'm past 24 months. Seeing the new higher risk numbers for people in that category I think I might try 5 weeks and see how things go.

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    1. Not sure that increasing the gap between infusions will do anything for the risk of MS. It takes about 3 months or natalizumab to wash-out of the body.

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    2. But Tysabri doesn't cause PML, lack of white blood vessels to the brain causes PML.

      Theory: One could imagine with each infusion that a Tysabri "saturation index" rises, allowing less and less white cells to patrol the brain and prevent PML. Eventually, this leads to actual PML once there is such low white cell activity that this doesn't happen. This of course happens much faster with people who've had prior IS use and have less PML effective white cells to begin with.

      But with prior IS use and without, we see that each successive infusion probably comes with greater PML risk. So the idea is that if things are going well MS wise, try giving that extra week or two for Tysabri to diminish somewhat and let enough white cells through to prevent PML.

      Patients refer to what is called a Tysabri "slump week" before their next infusion which may indicate that Tysabri has cycles of effectiveness. Obviously this is not scientifically backed yet, but since we know Tysabri is removed from the blood over time, the idea isn't too controversial.

      So, without hard scientific evidence, we have a choice between two theories:

      The "all or nothing" theory: Tysabri must be completely removed from the blood to reduce PML risk in any way.

      The "reduction" theory: Tysabri can be administered less frequently to reduce PML risk.

      I think most people, and even most scientists would agree that the "reduction" theory, in the absence of hard evidence, is a theory that's both more likely to be true, and more practical to MSers on Tysabri that would like to try something to lower their PML risk.

      I hope my tone hasn't come off offensive or combative, but I am trying to extract from you scientific evidence for or against the "reduction" theory. I want to engage you in useful "debate". Right now, I think I have provided logic as to how the "all or nothing" theory, to which you referred, is probably unlikely to be true, but I know that your science is way better than mine, so I'd like to hear any information you have as to reason you may feel the "reduction" theory is still impossible or impractical for MSers.

      Unfortunately for MSers on Tysabri, we're at a point where we have to make decisions not based on hard science to prevent something drastic from happening in our lives. We should still use logic, though, so please help us with this.

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    3. Since opportunities are limited many of us are extremely interested in any possibility to decrease risk of PML. We read in Clinical Neurology News 4/4/13 Quote “Thinner multiple sclerosis patients may be at higher risk for natalizumab-induced progressive multifocal leukoencephalopathy, according to researchers from the Rocky Mountain Multiple Sclerosis Research Group in Salt Lake City.

      The risk may derive from the drug’s higher mean plasma concentrations and the greater saturation of lymphocyte receptors in such patients, lead investigator Dr. John Foley suggested.

      At 60 kg or less, "there is a striking elevation in PML cases. [The] incidence definitely trends towards patients with lower body weights," said Dr. Foley, founder of the clinic.

      … patients weighing less than 75 kg tend to develop higher plasma concentrations of the monoclonal antibody over time and are more likely to saturate 95% or more of the lymphocyte receptors that natalizumab targets, exceeding the saturation goal of about 85%.
      We think there’s a link between serum concentration and saturation of lymphocytes in general, and that excessive saturation leads to near-complete stoppage of [lymphocyte] trafficking from blood vessels into brain parenchyma." Perhaps "we reach a threshold where we not only impede the cells that are programmed to cause MS, but also the trafficking of the cells that are programmed to kill viruses. We need to figure out what the optimal balance is," he said in an interview.

      For now, "how we are approaching this is [by] dose-extending high-risk, JC virus antibody–positive populations out to 5-6 weeks, instead of dosing every 4 weeks," as the natalizumab label indicates. It "reduces concentrations in the last few weeks, and saturations decline. It may well be a viable approach for PML risk reduction," Dr. Foley said. End Quote

      If there is no proof of harm rational doctors and patients will likely employ dose extension. If it has the potential to save lives why would it not be used? Any treatment regimen not harmful and having potential to avoid PML understandably will be utilized. Like Matt, we all are hopeful to learn of any reason why dose extension should be avoided.

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  2. Just wondering if anyone has developed PML who was not JCV positive and their blood tests continually showed they were JCV negative.

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    1. There has been one case that was JCV negative who developed PML 9 months after the test Whether that MSer converted to being positive before developing PML cannot be determined as there were no blood tests done.

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  3. A negative test is just a view at the particular moment the test was done. You can get a JC-infection just a second after the test. That's why you need to repeat it almost every half a year.

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  4. Naive question here. Since PML symptoms are neurological, when they show up in MS patients, does that make it hard to diagnose quickly?

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  5. change risk in JC negatives dropped from 1 in 14,000 down to 1 in 10,000 and JC positive imunosuppression positive 2 years plus risk below 1 in 90.

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