PML Reported in Europe with Fumarate

[MSer102]

Basically, from my understanding, is that there is no link saying that people got PML due to Tecfidera, but because they had Psoriasis.

I don't think your understanding that quite right. Psoriasis doesn't cause PML. PML comes from a virus and nobody would say that psoriasis causes a disease that's caused by a virus. That's like saying that MS causes PML and we know that isn't true!

The articles don't say that the people got PML from Tecfidera because none of them were taking Tecfidera. The articles are saying that there is a link to the medications the people were taking and they were taking medicines that are similar to Tecfidera and some had also taken immunosuppressant medicines.

PML doesn't have anything to do with psoriasis except that it was the condition the people were taking the medicines for. The link is the medicines not the disease - the same way Tysabri is the link to PML in the people who took it for Crohn's disease and the same way people with other diseases who take other immunosuppressant medicines get PML.

[Sunshine]

Thanks Ringer! I am a firm believer the Knowlege is Power! As one who is hoping to start Tecf. Soon, I feel more at ease knowing that the MS Socity is on top of this issue!

Katie (and anyone else have feedback)
Just curious about how long does you doc recommend the washout period to be after having steriod for your flare? And if you have another flare (heaven forbid) will your doc continue to use steriod while taking Tecfidera?

[durgastiger]

Just got my tecfidera

Starting first dose of 120mg for 1 week then 240mg for 3 weeks.

look out liver and kidneys here it comes!

[KatieAgain]

My neuro is waiting 30 days and we are going to get another baseline CBC to make sure it is normal. Dang flare...had not had one that required steroids in 3 years.

We are going to do monthly CBCs after I go on the drug to monitor my WBC just like the trials apparently did. No one in the trials got PML because they were pulled if their WBC went too low. Therefore, there is at this time no correlation between Tecfidera and PML.

One of the above posters is correct neither psoriasis or MS causes PML. It has been noted, although extremely rare, that a derivative drug Fumaderm caused 4 cases of PML. Given that Tecfidera is similar and it can cause a significant decrease in WBC's, it seems logical, at least to me, that blood testing should be done on a more frequent basis than yearly, as was done in the trials.

I am like a few of the other posters who said no to Tysabri, even though I was JCV-...it was not an option for me. I am more comfortable with Tecfidera, I hope it lives up to all the hype and claims, but I feel that simple precautions should be taken with this new drug or any new drug. Precautions that ensure a safer experience for all of us. In my humble opinion, I don't think Biogen did that. But, I am only one person with an opinion, and I am lucky to have a Neuro that is going to closely monitor me.

I also agree with the poster that Teva started all this, but I am glad they did. I am a big believer in transparency. Big Pharma does not do that...and that is why it is important to have a good relationship with your doctor.

All-in-all, I think Tecfidera is going to be a good drug. This has not scared me off...I am going to take it...just going to have it monitored a little more closely than recommended.

I anxiously await to read about your experiences and I will share mine as well. Hopefully, we will all have good things to report.

Katie

[Myoak]

All three of the researchers mentioned in this thread Fox, Schulz, and principal investigator Giovannoni agree that the four cases of PML related to dimethylfumarate depended on prolonged lymphocytopenia [low white blood cell counts].

All four PML cases were with Fumaderm (dimethylfumarate plus ethylhydrogenfumarate) not Tecfidera which is dimethylfumarate minus ethylhydrogenfumarate. Unfortunately, it doesn’t matter whether a patient takes Fumaderm or Tecfidera; taking dimethylfumarate resulting in low white blood cell count is the problem. MSer102 is correct, the very first warning listed in the prescribing information says, “Tecfidera may decrease lymphocyte counts” (lymphocytopenia). Remember, all 3 researchers mentioned agree this is the condition which led to the 4 PML cases.

AnonyMS clarified further by posting “About 3 percent of patients in the Tecfidera trials were taken off the medication when their white blood cell counts dropped too low, said Dr. Robert Fox, a staff neurologist at the Mellen Center for Multiple Sclerosis at the Cleveland Clinic in Ohio.

"The intensive monitoring of the clinical trial may have been what helped to prevent PML," said Fox.

Katie posted that blood counts were taken monthly during the trial at Cleveland Clinic. Biogen recommends it be done yearly. There are a lot of doctors who closely follow recommendations so if you want a blood count done more often, ask.

There are numerous good posts in this thread worth reading again. One misunderstanding was made by Ringer who does such a great job overall that it can be easily excused. “Basically, from my understanding, is that there is no link saying that people got PML due to Tecfidera, but because they had Psoriasis.” MSer102 is right again, no one gets PML because of Psoriasis. The med is the problem.

A few (only 4) Psoriasis sufferers got PML because they were taking Fumaderm which contains dimethylfumarate (the chemical in Tecfidera) which caused lymphocytopenia which lead to PML, in the opinion of several highly qualified researchers.

No one taking Tecfidera has gotten PML but then those most likely to were taken off during trials. If the most likely (those with very low white blood cell counts) are taken off during treatment then perhaps, no one will develop PML post trials, either. Keep in mind Tecfidera often lowers white blood cell counts but it is the dramatic and prolonged lowering which has potential to cause a problem.

No MS medicine is perfect. Tecfidera is likely to be a very good one, comparably. IMO.

Again, the great info and opinion by a number of people in this thread is well worth reviewing.

[shalimar]

how low is low?

I know that normal white blood cell count is between 4.4 and 10.4 CMM, but what would be the lowest acceptable count? Anybody know?

[MSer102]

I think that "acceptable" depends on how brave your doctor is and how much risk you want to take on in comparison to how much risk your under from MS. I think that these newer medicines took a long time in coming because the risk of dying from an infection was greater than the risk of dying from MS. People with RA and lupus on other medicines die from PML all the time but we just don't hear about it. My doctor took me off a medicine when my cell count hit 2.2.

[Kimba22]

My wbc went down to 2.3 when I was on Gilenya. I got a UTI that turned into sepsis within 24 hours, which went directly to my heart and caused endocarditis. Long story, but turned out results of my bloodwork weren't being sent to my MS Specialist (different hospitals). He would have pulled me off the drug much sooner.

[Myoak]

Perspective from the 3/27/13 FDA News Release announcing approval of Tecfidera:

“Tecfidera may decrease a person’s white blood cell count (lymphocytes). Lymphocytes help protect the body from infection and low counts can raise the risk of infection, although no significant increase in infections was seen in patients taking Tecfidera in clinical trials. Before starting treatment, and annually thereafter, the FDA recommends that the patient’s white blood cell count be assessed by their health care provider.

Flushing (warmth and redness) and stomach problems (nausea, vomiting, and diarrhea) were the most common adverse reactions reported by patients receiving Tecfidera in clinical trials, especially at the start of therapy. These side effects may decrease over time.” End Quote.


Keep in mind after “About 3 percent of patients in the Tecfidera trials were taken off the medication when their white blood cell counts dropped too low” that “no significant increase in infections was seen in patients taking Tecfidera in clinical trials.”

I believe there were 14 serious infections reported during the two phase 3 trials which involved a total of 2664 patients. Apparently, only 14 out of 2664 permits the statistical statement, “no significant increase was seen”.

It is not unreasonable to conclude some patients on Tecfidera will see a decrease in their white blood cell count, and 3 or 4% may experience a substantial decrease in WBC. Ask your doctor to monitor more than once a year, if it will lessen worry and stress. No medicine is perfect. 97% of patients trying this particular med have opportunity for great success, IMO.

No one in the trials taking Tecfidera got PML.

PS… Shalimar asked a good question which everyone concerned should ask of their doctor.

[Sunbeam91500]

Also concerned about PML..

I should be receiving my pills sometime this week and have to say was not comfortable hearing that PML had reared it's ugly head in yet another MS med, although that's not absolutely accurate, it was the compound for psoriasis.

I just wondered why, to be on the safe side, as well as getting liver counts and CBC done prior to taking Tecfidera, that it has not been recommended to have the test for JC, as I believe the Tysabri patients are required to do. Perhaps because it hasn't been found in Tecfidera patients in the studies, but I do find it a little disconcerting..... I'm almost thinking I should stick with the devil I know and live with easily, Rebif 22mcg, than the devil I don't, Tecfidera!!

[Myoak]

Hi Sunbeam,

You made a good comment wondering about why prospective Tecfidera patients aren’t given a JC virus test. I’m sure most are aware PML is not caused by Tysabri, Tecfidera, or Fumaderm; PML is caused by JC virus which has activated (perhaps the better word is mutated) into a life-threatening form.

Various estimates suggest that a little over 50% of the general population have JC virus, and the overwhelming majority of those will never have a problem or even know they have it.

JC virus has mutated into a life-threatening form in some individuals who have a weakened immune system. The last figures I’ve seen for Tysabri was 347 PML causes out of about 108,000 who have taken Tysabri. There have been 4 cases of PML reported in patients taking Fumaderm for psoriasis; I don’t know how psoriasis many patients have taken Fumaderm.

One thing to keep in mind is that Fumaderm for psoriasis is usually a short-term treatment not lasting years. Tysabri is taken for years and most often PML has shown up after two years. Would more cases of PML show up in Fumaderm patients if they took it for years? There is no way of knowing.

There were no cases of PML in the Tecfidera trials even though Fumaderm and Tecfidera both contain dimethylfumarate, a compound which weakens the immune system by decreasing white blood cells. A weakened immune system is the condition which allows the mutation of JC virus into a dangerous form causing PML. It doesn’t happen often but is pretty ugly when it does.

MS can be pretty ugly, too; making treatment decisions very, very difficult. We all want a med without risk but there is no FDA approved med for MS like that. The best we can do is soberly assess risk. Please forgive me for what I’m about to say but from my perspective the greatest need I’ve seen in people using this site is the need for realistic risk assessment.

For example, I have heard people who are JC virus negative say that Tysabri scares them. Taking Tysabri they have virtually zero chance of getting PML if JC virus is absent and over 33% chance of being free of disease activity but PML scares them more than MS! My God! Fear should never rule over reason.

Be sober about risk. PML happens only occasionally even in those with seriously compromised immune systems. If you opt for Tecfidera and your white blood cells don’t drop to a dangerously low level for a long period of time there is no evidence Tecfidera will weaken your immune system enough to make you vulnerable to PML. Around 3000 people taking Tecfidera for 2 years plus and no cases of PML. Yes, dropped from the trials were about 3% whose white blood cells had dropped to very low levels. But none of those developed PML.

Monitor for white blood cell counts on Tecfidera and from everything shown so far there will be extremely small opportunity (zero up to now) for JC virus to mutate into PML, if you even have JC virus. Be realistic, everyone has a different risk profile but please think soberly.

[Marco]

Sorry, I am showing up very late to this game.

Patient #1
He had previously taken methotrexate and had lymphocytopenia (very low white blood count) prior to developing PML

Patient #2
Her medication was made at a compounding pharmacy and also had lymphocytopenia prior to developing PML

Patient #3
Patient treated with methotrexate and then diagnosed with PML one month after starting fumaderm.

Patient #4
Was treated efalizumab that was pulled from the market in 2009 due to PML concerns. The patient had also been diagnosed with cancer before starting Fumaderm.


To me the most significant takeaways are:
- First year lymphocyte monitoring is key since lymphocyte production may be reduced by up to 1/3rd the first year of Tecfidera usage. After the first year, lymphocyte counts begin to return to normal and annual screening is suggested.

- Along with being JCV+, lymphocytopenia should be considered a risk factor for PML.

- Patients that have previous exposure to certain medications may be at a higher risk than others. Prior immunosuppressant usage, prior cancer treatments.


I am personally JCV+ and I have taken my Tecfidera today and I will be taken it tomorrow as well.

I am grateful that I have a proactive neurologist that I can trust. My next appointment is in July and you can "bet your boots" I will be getting ANOTHER lymphocyte test so we can monitor exactly where my counts are.

I understand that as an early adopter I am taking more risks that others. I have had open and honest conversations with my neurologist about my personal risk factors and what to look out for.

There are other wonderful Tecfidera threads that you should read. Be as informed as possible before making medication decisions and when in doubt you can always get a second opinion. I'd rather wait a month or two and get a second opinion form another neurologist than rush into a medication I wasn't sure about.

I still believe Tecfidera can revolutionize the DMT landscape for MS patients, but there will be some curves along the way.

Godspeed -- one and all --

[Torn]

My take, and understanding on the matter...

I have had low lymphocytes for over a year. This has kept me from being able to be on most effective dmds. CRAB drugs didn't work for me. When tecfidera was approved I called my nuero the first day. Signed papers ect. When I went in for my appt before starting, my doctor said he had bad news, my lymphocytes were really low and he didn't think it was a good idea. Needless to say, I was upset. He decided to send me to oncology for there opinion. They said it was ok to try the lower dose with monthly blood work to see how it affects me. Not everyone had low lymphs from this drug. My doc said anytime you have low lymphs you are at risk for pml. This is true with tecfidera and tysabri amongst other meds. So, my understanding is if you have low lymphs before or during you are at risk for pml. Higher if you are jc+.

At this point, any immune suppressants I go on will put me at risk. My ms is progressing so rapidly that I feel I have to try something. With close monitoring I feel I'm pretty safe. Hoping I understand all of this correctly and that I will be able to stay on this drug. Also praying that it works. I'm also looking into the stem cell transplant as a last resort but it is really scary to me.

[feathertat]

leukocyte vs lymphocyte

Hi all,

Getting ready to start Tec myself. Reading thru this thread got me concerned that some folks may be unclear on the WBC count thing. I've been a lab tech for over 30 years so just had to speak up.
Leukocytopenia is Low white blood cells (all of the types together, ie...neutrophils, lymphocytes, monocytes, eosinophils, basophils, etc)
Lymphocytopenia is low lymphocytes which are a type of wbc.
A person can have a low WBC count which is total cells and still have a normal ratio of lymphocytes.
The Tecfidera package insert says "Lymphocytopenia"

I tend to run a total WBC count of around 4,000 (4.0) sometimes a little above which is low normal to a little below which is abnormal. However my ratio of lymphocytes to other cells is perfectly normal. I am also JVC+. Will I monitor my WBC count...sure I will,,,but because I don't have low lymphocytes, I'm not going to get too worried about it.

[Sunshine]

Thanks for the explanation! I think its important to compare apples to apples, not apples to oranges.