Confirmed PML

[Myoak]

Lots of people are benefiting from Tecfidera; many do very, very well on it w/o major problems. 2% to 5% (depending on who you read) of the people on Tecfidera experience lymphopenia; that means 95% to 98% don’t. As RingpOP mentioned there are few meds without risks.

Unfortunately, Biogen doesn’t exactly instill confidence when they put out a statement like: “It is not yet clear whether dimethyl fumarate was directly responsible or whether other factors caused this case of PML.” Pretty weak reasoning, IMO.

PML is caused by the JC virus. Period. PML isn’t caused by Tecfidera any more than PML is caused by Tysabri. The article linked by RingpOP states, “PML is a known side effect of another disease modifying treatment, natalizumab (Tysabri).”

Tysabri diminishes immune surveillance blocking white blood cells from crossing the blood brain barrier. White blood cells patrolling the brain normally keep JC virus from becoming a problem. But if enough aren't getting in there JCV can become a problem.

Tecfidera diminishes white blood cells; in the brain and in the blood outside the brain. The recent patient taking Tecfidera got PML and died from pneumonia, Biogen said. Evidently, this person had insufficient white blood cells in the brain to prevent JCV from causing PML and insufficient white blood cells to prevent or recover from pneumonia. Indeed, Biogen has already stated the patient had lymphopenia (low white blood cells).

If PML is a known side effect of Tysabri it’s difficult to believe it is not a side effect of Tecfidera. Neither medicine directly causes PML. JCV directly causes PML. But both meds deplete white blood cells and that depletion allows the mutation of JC virus into a harmful form causing PML.

The argument of whether Tecfidera causes PML directly is a spurious one, IMO. Does a particular medicine, in this case Tecfidera, allow JCV to cause PML? That is the real question. It will be tough for Biogen to argue it didn’t.

It appears this particular medicine allowed JCV to cause PML in one person.

IMO, it is pound your head on the wall stupid for anyone to discontinue Tecfidera based on one person out of 100,000.

MS is a terrible disease. Please don’t stop treatment w/o consulting your doctor. I know people on Tysabri who accept a 1 in 87 risk of PML because they know what MS does to them. A 1 in 100,000 risk certainly ought to be tolerable. Don’t allow fear to take advantage of you by discontinuing Tecfidera because of one case.

Overall, Tecfidera has a good safety profile. It is a very valuable medicine for MS.

Pipes, Agate is spot on with the immunosuppressant info. It is correct that steroids for flares are not considered (in the risk for PML) as prior use of immunosuppressants.

Best.

[Nico Blue]

I'm a little concerned because I had to stop taking Tysabri in May after taking it for 2.5 years because my JC Virus bloodwork counts kept going up. I'm supposed to be starting Tecfidera next week. Now what?!

[rsinger]

PML

Good question Nico Blue. I am also positive for JC Virus. Have been taking tecfidera since July. WBC count is still good. Haven't talked to my doctor yet about what he is planning for his patients like me.
I think they will not take people off tecfidera because of this incident. Keep in mind this individual was taking tecfidera for 4 1/2 years of which 3 1/2 he or she had severe low WBC count. This is an extreme situation. The verdict is still not out on how this will effect people like us.
I am curious to see how your doctor will handle this.
Keep us posted.

[Myoak]

Hi Nico,

The PML was caused by lymphopenia. Do you have lymphopenia? Very likely not. You had a blood test to qualify for Tecfidera; you should have a copy of the results or you can call your doctor and ask the results. No lymphopenia, no problem; same with the other 200 million people in America who are JCV+. And, keep in mind this tragic death was not from PML; it was from pneumonia, they said.

People on Tysabri, Gilenya, Rituximab, Fumaderm, Tecfidera and other meds have gotten PML. As have immunosuppressed cancer patients, HIV patients and many others. All occurred because white blood cells were inadequate to fight off infection of JC virus. But even with lymphopenia PML is still very rare and it seems when it does occur the cases often involve a lengthy period of lymphopenia.

Will you get lymphopenia on Tecfidera? About a 2% to 5% chance which is why you will have a blood test every few months. If WBCs gets to a level your doctor considers too low you can always stop treatment and build back to a higher level.

Will there ever be another case of PML in someone taking Tecfidera? I believe so, but if people with lymphopenia are taking off until WBC are built back higher then it may be a very long time, if ever, before we see another case.

Most people with lymphopenia will never get PML but it is a risk factor. I don’t to mean to be flippant but life is a risk. Living involves risk. All medicines involve risks. But we must keep a proper perspective. Mortality-wise if this one death gets attributed to tecfidera (IMO, it should) then tecfidera is still about 1000 times safer than driving your car to the grocery store over a lifetime. According to the National Safety Council the chances of dying in a motor vehicle incident is 1 in 108.

http://www.nsc.org/nsc_library/Docum...02013%20ed.pdf

[JerryD]

Thanks for the very clear post, Myoak. Your answer is in line with the answer that my neurologist gave me, when I asked him about PML. So it is a risk but a very slim one. One I am willing to take.

[rsinger]

PML

Great post Myoak. Eloquently put. MS is a serious disease that requires serious medications. There will always be some risk involved. Getting blood work every few months and listening to your body are key to staying healthy.

Thanks for your input.

[Nico Blue]

Thanks Mayoak!

I guess I'm more concerned because my titers (sp?) are already elevated so I don't have much wiggle room if they go up from what they are at now. I was doing so well on Tysabri and had to be pulled off of it suddenly because the titer increase so it was a big disapointment. My bloodwork was fine to start Tecfidera. I'm hoping Tec works just as well, or even better, than Tysabri.

[Marco]

JCV+ and on Tecfidera

There were 4 people that contracted PML while on Fumaderm and in all 4 cases the patients had additional medical complications. Fumaderm is chemically similar to Tecfidera, but they are not identical. The Tecfidera patient had lymphopenia for over three years prior to succumbing to PML/pneumonia.

This patient and their neurologist knew the patient had lymphopenia and decided to remain on therapy for 3+ years.

• The medications we take can have serious, even lethal, complications. As a patient you need to be aware of the risks and take responsibility for your healthcare decisions.
• When you get sick, have a car accident or have any major health you should contact your neurologist. For example: this summer I contracted shingles and I immediately contacted the neurologists after-hours number (it was a Sunday). My neurologist immediately pulled me off Tecfidera until the shingles cleared or we could make an informed decision.
  
• Likewise, as patients with a chronic, progressive disease we must be advocates for our own health. The "ostrich" or "ignorance is bliss" methods do not work.
  
• Do not skip your monitoring blood tests as they have an important purpose. Get copies of and ensure you understand the reports. If any of your blood tests are abnormal ask about it and ensure you check that value on your next step. If any of your counts continue to decline then ask your neurologist. If they won't talk to you, go see your PCP and consider changing neurologists.
  
• Maintain a symptom list and track changes. The early symptoms of PML may be mistaken for a flare up with weakness, vision loss, speech issues, paralysis, etc. Call your neurologist and let them know what is going on.

My heart goes out to the family and friends of this patient. I am not blaming the patient, but I regret someone, anyone, had interceded and at least temporarily stopped Tecfidera therapy. I'm sorry if you are offended by the tone of this post, but another MS patient has died prematurely.

It takes time for PML to develop as the presence of JCV increases, mutates and eventually causes the onset of PML. It's similar to being HIV+, but not having full-blown AIDS. Fortunately, Tecfidera clears your body rapidly without the need for a medical procedure like aubagio (activated charcoal) or Tysabri (plasmaphersis). Other treatments like Lemtrada have no process to undo the changes. That's why being informed is so important.

The patient had lymphopenia, which is specifically addressed in the Tecfidera prescribing information. In fact, lymphopenia is the first warning given in the Tecfidera information as seen here:

5 WARNINGS AND PRECAUTIONS
5.1 Lymphopenia
TECFIDERA may decrease lymphocyte counts [see Adverse Reactions(6.1)]. In the MS placebo controlled trials, mean lymphocyte counts decreased by approximately 30% during the first year of treatment with TECFIDERA and then remained stable. Four weeks after stopping TECFIDERA, mean lymphocyte counts increased but did not return to baseline. Six percent (6%) of TEDFIDERA patients and <1% of placebo patients experienced lymphocyte counts <0.5x109/L (lower limit of normal 0.91x109/L). The incidence of infections (60% vs 58%) and serious infections (2% vs 2%) was similar in patients treated with TECFIDERA or placebo, respectively. There was no increased incidence of serious infections observed in patients with lymphocyte counts <0.8x109/L or 0.5x109/L.

Before initiating treatment with TECFIDERA, a recent CBC (i.e., within 6 months) should be available. A CBC is recommended annually, and as clinically indicated. Withholding treatment should be considered in patients with serious infections until the infection(s) is resolved. TECFIDERA has not been studied in patients with pre-existing low lymphocyte counts.

As always, I wish each of you well. I want nothing more than for each of you to live a prosperous and blessed life. Be strong and courageous ... and keep up the fight.

[rsinger]

PML

Always good to hear from Marco. He is well educated and level headed. I do agree that as patients we need to take control of our health. Always ask doctors questions and keep good records. And please if you are not happy with your doctor find another one.
We wait to hear more information from Biogen regarding this unfortunate incident. We don't know all the facts of this case yet. I think from what Marco said in his post is that both the patient and the doctor knew exactly what the risks were but this disease can be so hard on some patients that taking risks out weighs the potential for serious disability.
Thank you Marco for your input.

[Myoak]

My apologizes for being lengthy. The nuances of lymphopenia are more than can be tackled briefly. Indeed, if prohibited from making general statements little discussion is even possible on the subject.

I am giving this topic one more shot to please the mods or anyone else demanding more specificity and dropping it hereafter.

I am now, and as always, expressing my opinion. In my opinion, between 2% and 5% will experience lymphopenia on Tecfidera. The 2% figure came from here: http://www.rxlist.com/tecfidera-side...rug-center.htm and the 5% came from the difference between 6% and 1% as found in the last paragraph on page 7 of this document: http://www.ema.europa.eu/docs/en_GB/...C500162069.pdf

That paragraph on page 7 says 6% of those treated with Tecfidera had lymphocyte count of under 500 and as did 1% of placebo.

There are different grades of lymphopenia according to the World Health Organization.

Normal > 1200/mm3 or 1.2x10**9/L

Grade 1 = 800-1200/mm3 or 0.8–1.2x10**9/L

Grade 2 = 500-800/mm3 or 0.5–0.8x10**9/L

Grade 3 = 200-500/mm3 or 0.3–0.5x10**9/L

Grade 4 < 200/mm3 or 0.2x10**9/L

Grade 3 is considered severe lymphopenia, by many, including the WHO. That is the standard I used to form my opinion. There is no consensus among doctors on what level constitutes "too low" a level.

There are considerations which have to do with the type of medicine involved, whether upper levels can be restored on any particular med and a host of other factors. What level is “too low” is the source of argument and that level varies among individual doctors.

Literature on Tecfidera states that there was a mean reduction of 30% in lymphocytes. Hey, wait a minute, isn’t a 30% reduction of lymphocytes considered lymphopenia? Yes, some people do. I don’t. Why? Because with tecfidera the 30% reduction resulted in no serious infections in the phase 3 trials. Lymphopenia which makes a difference in health is what interests me in the Tecfidera issue.

Let’s read about that from the above EMA link. I list three page references.

Page 4 Infections

“In phase III placebo-controlled studies, the incidence of infections (60% vs 58%) and serious infections (2% vs 2%) was similar in patients treated with Tecfidera or placebo, respectively. There was no increased incidence of serious infections observed in patients with lymphocyte counts <0.8x109/L or <0.5x109/L. During treatment with Tecfidera in the MS placebo controlled trials, mean lymphocyte counts decreased by approximately 30% from baseline at one year and then plateaued (see section 4.8). Mean lymphocyte counts remained within normal limits. If a patient develops a serious infection, suspending treatment with Tecfidera should be considered and the benefits and risks should be reassessed prior to re-initiation of therapy. Patients receiving Tecfidera should be instructed to report symptoms of infections to a physician. Patients with serious infections should not start treatment with Tecfidera until the infection(s) is resolved.” End of Quote.

Ok, let’s consider what was said. The incidence of infection was 60% on Tecfidera and 58% on placebo. Therefore, we can say the risk of infection was 2% greater on Tecfidera than placebo.

Now, even though lymphocyte count was reduced by approximately 30% that reduction did not result in serious infections. Remember what they said, “there was no increased incidence of serious infections observed in patients with lymphocyte counts <0.8x109/L (800) or <0.5x109/L (500)”.

Serious infection on Tecfidera was 2% and serious infection on placebo was 2%; therefore, no difference.

The phase 3 trials indicate 30% of the MSers on Tecfidera will experience a reduction of lymphocytes. For some, this reduction meets their parameters for lymphopenia. Others, like me, care about levels low enough to make a difference in health and define that as lymphopenia.

Page 22 … “ In Phase 3 studies, upon treatment with Tecfidera mean lymphocyte counts decreased on average by approximately 30% of their baseline value over the first year with a subsequent plateau.

Page 46 … “Common side effects, which may show up in your blood or urine tests
- low levels of white blood cells (lymphopenia, leucopenia) in the blood. Reduced white blood cells could mean your body is less able to fight an infection. If you have a serious infection (such as pneumonia), talk to your doctor immediately.” End Quotes.


I hope everyone on Tecfidera will take time to read the EMA link. Europe is usually where I find comprehensive information. The Pharmas seem to have a death grip on information in the US. Europe demands and gets more openness from Pharma; I often find more complete info overseas. In my opinion, of course.

This issue is complex so there will always be plenty of room for disagreement. Doctors disagree about it so it is not surprising others do, also.

At what level of lymphocytes will your doctor take action? Ask him/her, if concerned. Always talk with your doctor on every issue of concern.

I understand clarity is important but proving every expression with scientific reference to satisfy the mods is more than I signed on for. Last post on this topic for me. I’m sure it is way too long… if not for you, it is for me.

I understand and have no hard feelings. I believe the mods do a great job overall. Thanks for your time and dedication. Time is the chief standard of value you and you guys/gals contribute your own time graciously. You really are appreciated and don’t get thanked often enough. Without you the site would not be possible.

PS, poppydaring, if thoughts and prayers can send a hug, you are receiving one; so concerned about you, how are you doing?

Best.

[KSeraSera]

The patient who had been on Tecfidera for 4 years,

How can this be when it was only approved for MS treatment last March, 2013? Doesn't make sense to me. Is this a typo? Is the rest of the information valid?

[agate]

Yes, it's correct. The patient was in clinical trials, and some reports say it was for 4.5 years.

[KSeraSera]

All medications, whether for MS or another condition, have serious and even potentially fatal side effects. Most are rare, but still possible. To me, the key is having a doctor that is willing to take them seriously and do their due diligence in monitoring. And that is a tall order. In my experience, most play down the side effects. I've had nurses at an MS clinic tell me my side effects weren't possible, they had never heard of it (on Copaxone) despite it being in the literature. I've had neuros willing to prescribe without blood work first. I've been given antibiotics where the serious side effects were almost identical to MS symptoms, so how would I know if I had them?

We would like to believe that our doctors know a great deal about medications before they prescribe them, but that is simply not the case. There are too many, and remember, most of their info comes from the drug company reps who want them to prescribe them. Docs know what to give for what condition, but what else it might do to you can be a mystery to them. And how it might effect you personally and with other conditions you may have an even bigger one.

I am my own advocate when it comes to meds. I read everything, ask my pharmacist who knows the meds better the questions I have, and ask my doc to see if they are well-versed about them or clueless. I apply the info to my own body and then decide. Needless to say, some docs aren't pleased, last my previous neuro who didn't see why I needed to know so much. He said I should just take it so I won't end up in a wheelchair, that's all that mattered. Now you know why he's my previous neuro.

[Myoak]

You are welcome rsinger, nicoblue and Jerry. I was neglectful of acknowledging your appreciation and feel as though the tone of my last post was not pleasant so my apologies for that.

I have been getting flak for some of my recent posts and overreacted.

KSeraSera, your post is spot on. You are right on track. Congrats on choosing to be an informed patient. Your life and health will be greatly enhanced because of it.

Biogen would love to spin this PML case as the fault of the physician/patient but the reality is that the patient was on Tecfidera and got PML. They can blame the doctor, patient, lymphopenia, JC virus or whatever but Tecfidera’s involvement is the real issue.

Best

[Marco]

Biogen would love to spin this PML case as the fault of the physician/patient but the reality is that the patient was on Tecfidera and got PML. They can blame the doctor, patient, lymphopenia, JC virus or whatever but Tecfidera’s involvement is the real issue.

Myoak,
I always enjoy reading your posts and appreciate your wit & wisdom. Tecfidera is absolutely part of the patient's unfortunate story, but there were red flags, orange cones and a whole series of warning signs that were also bypassed. There's no reason to respond. I completely concur with your position and believe your statement to be 100% correct. I just hope we all can learn from this example and pay attention to whatever "warning signs" that may confront us.

I have RRMS. I am JCV+. I am on Tecfidera. I realize that Tecfidera has potential side effects, up to and including death. I realize that there are certain conditions, including lymphopenia, that may increase my risk factors. I voluntarily receive quarterly blood checks to help understand my risk factors....

This thread has been wonderful and I understand and appreciate everyone's perspectives and opinions, I wish you all well.