Monday, 16 November 2015

ClinicSpeak: more on PML and lymphopaenia

More musings on PML #ClinicSpeak #MSBlog #MSResearch

"I have been asked to comment on the fourth case of DMF-related PML. I have nothing new to say, but have tried to pull together information from some of my previous posts on the topic. I have found that repetition helps with getting the message across. Do you remember the 500 vs 800 debate, the differential lymphocyte post,  or my recent predictions, to highlight a few?

1. JCV: PML is caused by a mutant strain of the John Cunningham, or JC, virus (JCV). JCV belongs to the family of viruses called human polyoma viruses. To get PML you first need to be infected with the JCV. Please note we have not identified a symptomatic human infection due to primary JCV infection. In other words when you become infected with JCV you won't be aware of it. As we detect JCV in urine and saliva we think the virus is transmitted via contact with urine and/or saliva from a person who is shedding the virus. Please note not all people who are JCV seropositive 
(have antibodies in their blood to JCV) shed the virus. Whether JCV non-shedders are still infected with the virus is unknown at present. We assume that all MSers who are JCV seropositive are infected with the virus.

3. Mutant JCV: To cause PML, the JC virus has to mutate and be able to infect the brain of MSers. On average the virus acquires 4-5 mutations in its surface, or coat protein, and several mutations in its regulatory region. These mutations allow the virus to become neurotrophic, i.e. acquire the ability to infect the brain and cause PML, and to escape recognition by the immune system. The antibody against JCV that is found in blood of MSers with PML does not recognise the JC virus in their brains, this tells us that the PML mutant strain of JCV is an escape mutant and is not been recognised by the immune system. I suspect that in MSers on natalizumab who develop PML the virus is able to hide from the immune system in the brain; hidden behind a blood-brain-barrier that is sealed off from immune cells that would normally find the virus and destroy it. This is almost certainly why the risk of getting PML on natalizumab is orders higher than on other drugs and this included dimethyl fumarate (DMF, Tecfidera). 

4. Immunosuppression: It is clear that JCV is more likely to mutate and cause PML if you are immunocompromised. Being immunocompromised increases the chance of the JCV mutating, escaping immune detection and elimination, by the immune system. It is clear that virus takes months to years  to become pathogenic, i.e. being able to cause PML, which is why there is carryover risk of PML when you switch from an immunosuppressive drug onto natalizumab. Similarly, it is likely that there is a similar carryover risk when you switch from natalizumab to another immunosuppressive drug. It is highly unlikely that the pre-PML mutant strains disappear when you switch from natalizumab to another DMT. This is why it is particularly risky when you switch from natalizumab to an immunosuppressive DMT. In the fourth DMF PML case presented below, I am convinced the prior natalizumab treatment is relevant. I suspect the virus had already started mutating whilst the person was on natalizumab and completed its evolution on DMF. 

5. Lymphopaenia: Lymphopaenia is a risk factor for PML, but is a relative risk factor. The lower you lymphocyte count the greater the chance of you getting PML. I am saddened, but not surprised, that the case presented below developed PML on DMF with a total lymphocyte count above 500/mm3 (WHO grade 2/3 boundary); I predicted this several months back based on the psoriasis literature. Two people with psoriasis developed PML on other formulations of fumarates with moderate lymphopaenia (counts > 500/mm3). This is why we at Barts-MS use a lymphocyte cutoff of 800/mm3, for dose interruption or stopping DMF, and not the  500/mm3 cut-off as recommended by several regulatory agencies. It is clear the latter is now inappropriate particularly in MSers who are older (see below) or who have other risk factors, including prior natalizumab treatment. 

6. Age: Interestingly, this patient (61-years) and the two psoriasis cases (69-year old male and a 64-year old woman) were relatively old . In addition, all the patients with de novo PML, without an identifiable risk factor, I have personally seen have all be old (>60 years). Therefore, I strongly suspect that age-related immune dysfunction, or immunosenescence, is a risk factor for PML. 

7. Mode of action: DMF's mode of action may have a role to play in causing PML. We have yet to fully delineate how DMF works and its role in the development of PML. At present lymphopaenia appears to be the most modifiable risk factor associated with DMF, but other risk factors specific to DMF may emerge with time. The papers on DMF being an anti-trafficking agent, previously discussed on this blog, need confirmation. If DMF is does have an anti-trafficking mode of action we will see a steady rise in number of cases over time; this will occur as more MSers have been on the drug 2-years or more. 

8. JCV serology: What about JCV serology in monitoring the risk of PML on DMF? At present knowing your serostatus at baseline would be useful, however, outside of this I would not like to speculate about the utility of the JCV antibody index or whether a rising index is meaningful. Unlike natalizumab, DMF is likely to be a generalised immunosuppressive drug and hence it may affect the antibody response to JCV. Therefore, I would advise against using the JCV antibody index as part of any risk stratification strategy at present. Hopefully, Biogen will do the necessary research using their serum banks, from their DMF trials, to assess how DMF affects the JCV antibody index. 

I would also like to put things in perspective; at present there are about 170,000 MSers on DMF worldwide and only 4 cases of PML in DMF-treated MSers. All these cases were associated with lymphopaenia, with lymphocyte counts below 800/mm3. Therefore, we need to monitor lymphocyte counts and stop DMF in those patients who have counts persistently below 800/mm3. A more liberal cut-off may be applicable to those MSers who are JCV seronegative. However, we would still need to be vigilant for other opportunistic infections, and complications, associated with lymphopaenia in these people. Please note PML is not the only complication associated with persistent lymphopaenia. 

In summary (1) previous immunosuppressive treatment (including natalizumab treatment), (2) duration of immunosuppression, (3) level of lymphopaenia, (4) JCV serostatus, (5) level of JCV antibody index (natalizumab-treatment only), (6) genetic (HLA), (7) immunological factors (L-selectin, lymphocyte subset function), (8) viral factors, (9) mode of action of drug and (10) age play a role in the pathogenesis of PML. 

I have said before that I don't think PML is an intractable problem. All we need is targeted R&D to solve the problem. I envisage a future in which we will be able to treat every JCV positive person with a course of an anti-viral drug that will clear them of JCV and put them in the very low risk group of getting PML. Now wouldn't that be wonderful? I hope this all makes sense."

Kristina Fiore. Will 4th PML Case Change Tecfidera Risk Profile? Medscape NEUROLOGY 11.13.2015.


...... Biogen has reported a fourth case of PML with Tecfidera -- this one in a patient with only moderate lymphopenia -- to U.S. and European regulators, raising new questions about the drug's safety......

....... The latest case occurred in a 61-year-old female with relapsing-remitting multiple sclerosis, who'd been taking Tecfidera for 22 months before being diagnosed with PML. She had grade 2 lymphopenia, at 600 cells/mm3, for 6 months before developing symptoms of PML, which included left arm weakness and apraxia....

...... The patient had previously taken natalizumab (Tysabri) for 6 years and 4 months, but the company said that prior exposure wasn't considered a confounder in this case......

...... This is not the first case of a patient with moderate lymphopenia developing PML while taking a dimethyl fumarate product. Last April, researchers reported in the New England Journal of Medicine the case of a 64-year-old female patient who died from PML after 2 years on a compounded formulation of dimethyl fumarate for psoriasis (Psorinovo). Her lowest lymphocyte count was 792 cells/mm3.....

...... A 69-year-old man taking Biogen's Fumaderm dimethyl fumarate brand for psoriasis developed PML with only moderate grade 2 lymphopenia at a range of 724 to 738 cells/mm3. The case was reported in Neurology Neuroimmunology and Neuroinflammation.....

...... Although questions remain about the best way to use lymphopenia to determine PML risk with Tecfidera, some experts have raised concerns about the interval of lymphocyte screening on the drug's label.....

...... Tecfidera's label calls for a baseline lymphocyte count, followed by another check-in after 6 months and then regular checks every 6 to 12 months thereafter. Physicians should consider stopping therapy in those whose levels stay below 500 cells/mm3 for 6 months......

....... However, European regulators recently recommended checking lymphocyte counts every 3 months, and reconsidering treatment in patients who maintain grade 3 lymphopenia for longer than 6 months.......

CoI: multiple


  1. PML in a Patient Treated with Dimethyl Fumarate from a Compounding Pharmacy- 42-year-old woman

  2. " I envisage a future in which we will be able to treat every JCV positive person with a course of an anti-viral drug that will clear them of JCV and put them in the very low risk group of getting PML. "

    Anyone doing serious work on a JCV vaccine or treatment?

    1. Not to my knowledge...

    2. Look for CMX001 from Chimerix

      Tony Fonda

  3. This comment has been removed by a blog administrator.

    1. Re: "....statement that antibodies to JCV and the mutant JCV..."

      The antibodies in the blood recognise wild-type virus, but not the mutant PML strain. In other words the PML strain has escaped neutralization by the immune system. It doesn't matter whether or not the anti-JCV antibodies cross the blood-brain-barrier as they won't neutralise the PML variant.

    2. I see, thanks for clearing that up. Why do we measure JCV antibodies in of tysabri then? Are you just using that as a marker as to whether someone has the wild-type virus (and therefore the possibility for it to mutate)? Does increased viral load just mean more chance of a mutant variant forming?

  4. Thank you so much. This clearly explains the risks involved. I'm someone who did just one dose of tysabri 6 years ago and had a reaction and wasn't able to continue. I did do 2 years of Gilenya, and came off it when my lymphocytes started to drop. When they rose I went onto DMF, but came off after two years when I started to get repeated infections, and I'm now on Aubagio... not so patiently wait info for ocrelizumab. I have a combination of relapsing and progressing features to my ms. The DMDs have done a good job at managing my relapsing part, but obviously the progressive part marches on.

    Having read this, I now have a clearer understanding of not only the risk points, but also the cumulative effect of some DMDs.

    Thank you

  5. Exactly right. Whilst I am not a researcher I have done a fair share of reading on PML. According to research most folks immune systems are just do not "see" JCV. When it becomes active the immune system has no problems knocking it off. I believe it is was in Australia (I think) where they basically injected immune cells into CSF via lumbar puncture and in 4 or 5 cases of PML knocked it out in no time flat. It was a matter of a few days and patients felt better and within a short time PML was gone.

  6. But your right... Pharma needs to collectively pool some resources, get PML beat. It suits the patients at risk across many disorders and also their bottom lines so incidents of PML do not send fear throughout patient populations and stock markets. When one takes a look at the financial hits taken by Biogen due to PML its astonishing. While other Pharma may benefit due to that they too are just as much at risk. Again, my fear is something like Ocrelizumab with all the hype towards its efficacy and RRMS/PPMS would be clinical incidents there and another round of stock market hammering. That would send a clear message off to BioPharma that maybe its not worthwhile to pursue such meds and research and that is a real risk for everyone with MS. Biogen's 400+ something per share value dumping into the low 200's in many respects tied to PML is more money lost that Tecfidera probably stands to make.

  7. "These mutations allow the virus to become neurotrophic, i.e. acquire the ability to infect the brain and cause PML, and to escape recognition by the immune system."

    Why do you assume this? I think a normal healthy person has immune cells that can cross the BBB to deal with the JCV. Do all cases of PML show the existence of a mutated virus or a non mutated virus in the CNS? What evidence is there that the unmutated JVC cannot cross the BBB?


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