Friday, 24 October 2014

ClinicSpeak: PML and dimethyl fumarate (Tecfidera)

How should we deal with the PML risk in patients on Tecfidera? #ClinicSpeak #MSBlog #MSResearch

"Progressive multifocal leukoencephalopathy or PML is classed as an opportunistic infection and typically occurs in patients who are immunosuppressed as a result of cancers, in particular haematological malignancies, immunosuppression from medication, or specific diseases such as HIV that are associated with immune suppression."

"The fact that Biogen-Idec reported a case of PML on their formulation of dimethyl fumarate or DMF (Tecfidera) two days ago appears to have triggered a panic response. My email inbox is full of queries from anxious patients and colleagues about what we should do."

"I have noted a spike in Google Trends when using the search terms ‘Tecfidera and PML’. The questions I have been asked are:

1. Should we treat the risk of PML on DMF in the same way do the risk on natalizumab?

Obviously not; we need to take a step back and think rationally about things. DMF has been around for decades as a treatment for psoriasis. If DMF was a major risk factor for PML we would have seen far more cases in patients with psoriasis. I have posted on the latter before and we got Professor Gold, who looked after one of the psoriasis PML cases to comment as well. In summary and to the best of my knowledge there have been 5 PML reports in patients with psoriasis on DMF. All but one of the cases had been on multiple immunosuppressive therapies that are known risk factors for PML. The one patient who developed PML on DMF monotherapy has a very low lymphocyte count for several years (5 years) before developing PML. The latter seems to be the same as the reported patient with MS. This patient had been on DMF as part of the clinical trial programme for 4-and-a-half years and had a persistent lymphopaenia for 3-years before developing PML. The questions I have asked Biogen-Idec to answer are: (1) how severe was that lymphopaenia?; (2) why was he/she left on DMF; (3) when DMF was stopped did the lymphocyte counts recover; (4) were there any other risk factors for PML, for example previous use of immunosuppressants? Until we have more information it would be foolish to speculate. What is clear is that PML on DMF is likely to be rare considering the psoriasis data set. The one proviso is that the dermatologists tend not to use DMF as a continuous long-term therapy in psoriasis so the situation in MS may be different. Therefore in the short-term what we need to do is be more vigilant about lymphopaenia and if someone on DMF develops a persistently low lymphocyte count the drug will need to be stopped. Until we get more data I would suggest anyone with a lymphocyte count less than 800/mm3, or 0.8x10**9/L, takes a drug holiday for several weeks until their lymphocyte counts recover above 1200/mm3, or 1.2x10**9/L; if the lymphocyte counts don’t recover, or drop below this proposed threshold on restarting DMF the drug will need to be stopped. Please note that a threshold or cut-off of 800 (WHO grade 1/2 lymphopaenia boundary) is conservative and we may be able in the future to set the cut-off at 500 (WHO grade 2/3 lymphopaenia boundary). Setting cut-offs like this will need to be data driven and does not take into account lymphocyte function."

"We will also need to be more vigilant about screening for lymphopenia in patients on DMF. The EMA summary of product characteristics states: ‘Tecfidera may decrease lymphocyte counts (see section 4.8). Tecfidera has not beenstudied in patients with pre-existing low lymphocyte counts and caution shouldbe exercised when treating these patients. Prior to initiating treatment withTecfidera, a recent complete blood count (i.e. within 6 months) should beavailable. Assessments of complete bloodcounts are also recommended after 6 months of treatment and every 6 to 12months thereafter and as clinically indicated’. I would suggest that we now institute 6 monthly monitoring as we do for patients on interferon-beta."

2. Should we stop DMF in patients who are JCV positive?

"Clearly not. The main risk factor for PML appears to be lymphopaenia. Therefore if you are JCV positive on DMF and have a normal lymphocyte count there is probably nothing to worry about. There is some data from the psoriasis literature suggesting that DMF may have a mode of action in addition to lymphopaenia, that may add to the PML risk; it seems to interfere with adhesion of leukocytes to blood vessels and reduce trafficking of cells. This situation is not too dissimilar to natalizumab in which we know that the PML risk is linked to the mode of action of natalizumab, i.e. its stops trafficking of lymphocytes into the brain and reduces immune surveillance for infections."

3. Should we start routine JCV testing in patients about to start DMF or who are on DMF?

"No I don’t think this is necessary. The only situation I envisage this happening in, is if someone is doing well on DMF and has a lymphopaenia and wants to stay on the drug. Being JCV seronegative may give this person and their clinician more confidence in leaving them on DMF."



4. Should we not start someone on DMF if they already have a lymphopaenia?

"This will depend on the cause of the lymphopaenia. If for example they are switching from fingolimod, that causes a reversible lymphopaenia, it would seem reasonable to check lymphocyte counts after 8 weeks to make sure they have recovered. If the cause of lymphopaenia is due to previous immunosuppression, for example secondary to corticosteroids, cladribine, alemtuzumab, mitoxantrone, teriflunomide, etc. I would be more careful. In this situation a decision will need to be made after considering the level of lymphopaenia and how active the patient's MS is. This may be one situation were a JCV serology may help. Please note that prior immunosuppressive therapies is in itself a major risk factor for PML ; therefore if the patient is JCV seropositive you will need to be more careful."

5. Is there something specific about DMF that causes PML?

"As I have alluded to above there DMF may affect cell trafficking into the brain and spinal cord that can increase PML risk independent to lymphopaenia. We need more data on this in relation to MS. Please note that almost every drug that affects the immune system has been associated with cases of PML."

"We mustn’t get distracted from the fact that this is a personal tragedy. Someone with MS has died as a direct result of a treatment for MS. My condolences go out to the family and friends of this patient. From my perspective as an MSologist this complication may have been preventable, which is the main reason for this post. We must also not forget that this patient participated in the DMF clinical trial programme and without his/her participation other MSers would not be benefiting from DMF. I suggest we all pause to reflect on this tragedy.“


CoI: multiple

29 comments:

  1. ProfG If you go on a drug holiday do you think that MS will return?

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    1. Re: "ProfG If you go on a drug holiday do you think that MS will return?"

      Yes, why should DMF be any different from natalizumab or fingolimod. If you off the drug for several months your disease is likely to return. DMF is a maintenance, and not an induction, therapy.

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  2. Thanks a lot ProfG !!
    I'am supposed to start Tecfidera in few weeks and your
    post take me out from panic I was experiencing since yesterday....

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    1. There is no need to panic; this is one case of PML with over 100,000 patients on the drug. How many of the 100,000 patients are JCV positive and how many have prolonged lymphopaenia and how many have been on the drug for longer than 2-years? That is the risk profile: JCV+ve and prolonged lymphopaenia. Therefore there is no need to panic.

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  3. MouseDoctor, I am not prof G but I would say yes - return of the lymphocytes would probably mark the point when the drug is out of the system and the risk for MS attack goes up.

    And here is another question: Gilenya also causes lymphopenia, are patients on fingolimod and lymphopenia at risk for PML? So far so good, but the drug has not been used for that long and it usually takes some years for PML to show up its ugly head.
    J

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    1. Hi J
      There has been one reported case of PML in an MSer treated with Gilenya so far. again let's hope this is an isolated case rather than what is seen with Tysabri.
      http://multiple-sclerosis-research.blogspot.com/2013/07/first-case-of-pml-that-may-be.html

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    2. At ACTRIMS/ECTRIMS Novartis presented 11 cases of PML on fingolimod; 10 cases appeared to be carry-over PML from natalizumab and 1 case was occurred soon after starting fingolimod. When the latter case was reviewed in detail it seems that the patient may have had PML from the beginning. At present there does not appear to be a PML risk with fingolimod itself. The lymphopaenia on fingolimod is different to other lymphopaenias; i.e. the lymphocytes are still present just trapped in lymph nodes. In the fingolimod trial programme the lymphocyte count was not associated with side effects or for that matter efficacy of the drug.

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    3. Re: "return of lymphocyte counts"

      Yes, in withdrawal of DMF (Tecfidera) and return of the lymphocyte count towards normal would indicated that the drug effect is out of the system. Whether or not this means the lymphocyte function is back to normal is difficult to say. I am not aware of any studies looking at this aspect of lymphocyte function, but it needs to be done. Please note that it is not the DMF itself, by the immune effects of a low lymphocyte count, and function, that is critical.

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  4. "Obviously not; we need to take a step back and think rationally about things. DMF has been around for decades as a treatment for psoriasis. If DMF was a major risk factor for PML we would have seen far more cases in patients with psoriasis."

    There is a big difference that you seem to overlook. DMF treatment for Psoriasis is short term (< 6 months typically). DMF treatment for MS is indefinite.

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    1. Re: "There is a big difference that you seem to overlook. DMF treatment for Psoriasis is short term (< 6 months typically). DMF treatment for MS is indefinite."

      No I didn't overlook this I state: "The one proviso is that the dermatologists tend not to use DMF as a continuous long-term therapy in psoriasis so the situation in MS may be different."

      You may be interested to know that the case with psoriasis that developed PML had been on the drug for 5 years:

      http://www.nejm.org/doi/full/10.1056/NEJMc1215357

      "On November 5, 2012, a 42-year-old woman who reported having progressive right-sided hemiparesis since May consulted us for a second opinion. She had been given a diagnosis of possible multiple sclerosis in September and at that time received 3000 mg of intravenous methylprednisolone over 3 days, without effect. Her medical history was notable for psoriasis, for which she had been taking 420 mg of Psorinovo per day since 2007, supplemented by 1000 mg of calcium ascorbate per day and EPA-1000 fish oil capsules (EPA denotes the omega-3 fatty acid eicosapentaenoic acid)."

      So the answer is yes and no; clearly some dermatologists use DMF for longer than 6 months. The issue is not the length of time the drug is used, but the lymphopaenia. This lady had a count of 200.

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  5. Methinks there once was the first case on Tysabri, too :-))). We are less panicky now than we were in 2006, but still.
    Having said that, PML occurs in situations when immunity is impaired ( untreated AIDS, treatment with rituximab, Raptiva, in hematological malignancies, post-transplant etc), but can also occur spontaneously ( rare) without a good explanation.
    J

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    1. I agree; PML is not always an opportunistic infection and I have seen two patients in my career with biopsy proven PML who developed it spontaneously. Interestingly, both these patients made spontaneous recoveries from PML, but, unfortunately, have been left with persistent disability.

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  6. How long does it take for PML to develop?

    I discontinued Tecfidera 12 months ago and had last MRI 6 months ago which showed no PML - my white blood cells are normal but on the lower end of the spectrum.

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    1. I think it unlikely if you stopped Tecfidera 12 months ago.

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    2. Re: "How long does it take for PML to develop?"

      I suspect it takes many months and possibly years to develop PML. The virus has to undergo several mutations and acquire the ability to infect the brain. The natalizumab data suggest this process takes at least a year and on average several years. In addition, PML must have a period of time when it is asymptomatic, hence the carry-over cases from natalizumab onto other drugs. The one case of carry-over PML on fingolinod only appeared at 6 months on treatment.

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  7. Apologies about the formatting of this post; a problem with using Blogger in Arabia.

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  8. I think Biogen-Idec need to get ready for the second case of PML; it is bound to happen.

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    1. Re: "I think Biogen-Idec need to get ready for the second case of PML; it is bound to happen."

      Yes, I agree it is bound to happen. It is a numbers game; if you leave enough high-risk people on the drug and someone will develop PML. It is all about education. Biogen-Idec have learnt a lot from natalizumab and I have no doubt they will make the community aware of the risk of prolonged lymphopaenia and get people off the drug.

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  9. Query for Dr. Giovannoni:

    Should we narrow the group of patients whom we treat with tecfidera given that tecfidera failed to beat copaxone in a head to head trial and is clearly more deleterious?

    The only indication for tecfidera (it seems to me) is someone with relatively mild MS who is doing well on GA/IFN who has severe injection fatigue/site reactions or other contraindications to first line therapy and is will to take additional risk for equal benefit and better tolerability.

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    1. Re: "Should we narrow the group of patients whom we treat with tecfidera given that tecfidera failed to beat copaxone in a head to head trial and is clearly more deleterious?"

      I am not aware of any head-2-head between DMF and GA. I assume you are referring to the open-label comparator group in the CONFIRM study; this was added at the request of the EMA. The GA group was not blinded and the study was not powered for efficacy.

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    2. Re: "The only indication for tecfidera (it seems to me) is someone with relatively mild MS who is doing well on GA/IFN who has severe injection fatigue/site reactions or other contraindications to first line therapy and is will to take additional risk for equal benefit and better tolerability."

      In correct, the best efficacy data was in the naive population rather the switchers. So I think DMF is probably going to remain the 1st-line drug of choice. To date none of my new patients have chosen an injectable over an oral when given the choice. On the other hand if you are on an injectable and are NEDA-3 why change? It is horses for courses that fact that you are responding to one drug does not mean to say you will respond to the next drug.

      GA has life in it yet; it seems to have a good safety profile in pregnancy hence it will be the drug of choice in woman who have active MS who to start or extend their families.

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    3. Prof G you shouldn't take the bait, Anonymous (Friday, October 24, 2014 11:17:00 pm) either works for TEVA or is an analyst. You should be more frank and tell him that it is only downhill from now for the injectables. Not to mention the impact biosimilars will have on the market.

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    4. Prof G is a gentleman answering to Anonymous (Friday, October 24, 2014 11:17:00 pm)
      Anonymous is probably trolling (this seems more probable) or confounding Aubagio efficacy with Tecfidera.

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    5. I hope AnonymousFriday, October 24, 2014 11:17:00 pm replies with information that they are referring to. Not everyone who questions the Mantra of Team G is a representative for Teva, yet for some reason Team G taints this blog with this perception.

      Yes Tecfedera has shown to be quicker at reducing relapse rate at initiation of treatment, but there is no proof it is any more effective at more important endpoints (to me) such as slowing or stabilizing longterm progression. I guess the ability of Tecfedera to be able to quickly suppress the chance of a second attack after starting treatment is an affect of it's immunosuppressive properties. I guess the question for the family and friends of the person who died from PML was if it was worth it.

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  10. Prof G this is pretty reasonable summary based on the current state of knowledge. However, I would urge you to use your influence to get Biogen-Idec to do detailed functional T-cell studies in people on Tecfidera. I agree that the risk may not necessarily be linked to total lymphocyte counts alone, but may relate to lymphocyte function.

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  11. A quick update; I was at a meeting yesterday when all the specific details about this case was presented. As I am under a NDA (non-disclosure agreement) I can't discuss specifics. Nothing really changes regarding my post. I suspect there will be some debate about what cut-off to use for the lymphopaenia to stop DMF. I am proposing the 800 boundary, others for example in Germany are stating 750, and others will be comfortable with 500. For example with interferon-beta I have am comfortable with the 500 level as it reversible and the lymphopaenias are often transient. Until we know how reversible the lymphopaenia is post DMF I would prefer recommending the more conservative level of 800 (i.e. the boundary between grade 1 and grade 2 lymphopaenia).

    Biogen-Idec are committed to making all the necessary information about this case public and will be taking action to try and prevent this scenario from occurring again.

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  12. Hi
    I'm b12 deficient and currently taking injections @8 weekly intervals to increase blood serum levels.
    I'm about to embark on Tecfidera and I was thinking would I be better off increasing B12 to perhaps 4 weekly?
    Thanks.

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  13. Hello, I am for positive for the JCV and have been taking Tecfidera for 8 months. I have a routine monthly test for my white blood count which has been within normal limits. I did have a b12 deficiency and was prescribed to take a 1 ml injection once a week along with 500mcg tab daily. The end of Aug I began to have break through seizures, anxiety, disoriented, migraines, vomiting and severe mood swings. I feel like my brain is in overdrive times 10. I was prescribed two different meds for seizures and had allergic reactions to both. I asked my Dr. to do a complete blood work up and an MRI to see if the tecfidera was working. No major changes were on the MRI but my B12 level is 1747. Would this be an indication that I need to be tested for PML? How can I level off my B12 quicky? Besides the obvious to stop taking it. Thanks for any help you can give.

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  14. JCV Positive. On Tecfidera for 10 months. Blood work done in March, August and September: Lympocytes down from 1874 to 785 to 598. My Absolute CD3+ (1512 to 587 to 418), CD4+( 928 to 405 to 294), CD8+ (602 to 166 to 121) and CD19+ (96 to 73 to 62). Told to stop Tecfidera and am waiting for repeat lab work results. Is there any data available on people whose labs dropped, recovered and then started back on the drug? Neuro is saying going back on Tecfidera is not an option but I have tolerated it really well and the potential side effects of the alternative drugs are causing me pause. I am considering a "take nothing" strategy if I can't go back on the Tecfidera. Follow up visit in January. Appreciate any data you can share that can help me with this important decision.

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