Confirmed PML

[subekal]

Grade 3 Lymphopenia

I posted a new thread regarding this before seeing this one. My Lymphocyte count is 300. It was 400 in August. My Neuro says Tecfidera doesn't have a clear course of action regarding Lymphopenia. At what level should a patient stop therapy? There is no answer. I love Tecfidera and have been on it since April of last year. My current thinking is to stay on it since, as has been stated before, even with Lymphopenia there has not been a substantial increase in serious infections. Yet still nervous...
Has anyone else had any experience with low Lymphocyte count and being taken off Tecfidera, or continuing therapy?

[Marco]

subekal,
After an initial dip, all of my numbers are better. Even the liver damage done by interferon therapy has greatly improved. I would ask your doctor what #s he believes are too low. That will let you gauge if they are really on top of things. The second thing I would do is request more frequent, even monthly, monitoring. That would allow you to more closely look at what's going on and if you continue to dip a decision then would be easier to make.

I wish you well and hope you find the right therapy for your health & well-being.

[sheli18]

low WBC

Started Tec in Nov. '13, WBC normal and stayed that way until around June or July. Dropped to 2.0, then back up to 4 something, almost 5. Got a call today that WBC is 0.6, and JC virus is now + which has been checked multiple times and always negative. Have an EMERGENCY appt. with neuro tomorrow (he is coming in at 7:30 in the am just to see me) to discuss further options. Am terrified about PML. Talked with nurse at Tecfidera today, no link to tecfidera she says, only Tysabri she says. I don't believe a word they say! The patient with PML died of pneumonia she says, does she not know aspiration pneumonia is often related to neurological problems. She was reading everything from a book. Big bucks at the patient's expense.

[Marco]

I completely understand your concerns about PML. Due to the seriousness of your situation, I want to be cautious about posting information. I did however want you to know that I read your post and my wife and I are hoping and praying for you.

Thankfully, you and your doctor are monitoring the situation. The good news is PML, unlike the JCV, does not just switch from on to off. There are a number of transformations that take place before the onset of PML. My understanding is, if you abort the process during any of these transformations it can prevent PML. I would imagine that a spinal tap and MRI might be in your near future. Hopefully, you are not exhibiting any increased PML symptoms. I hope you will keep us informed of your progress. I wish you well!

[Marco]

I am not trying to argue or debate Tecfidera and PML. It is absolutely true that a patient taking Tecfidera passed away after contracting PML. I personally take Tecfidera and I am JCV+, so this hits close to home. There are some additional facts besides, "a Tecfidera patient died after contracting PML," that I believe are important to consider:

• the patient had been taking Tecfidera for 4.5 years
• the patient had had severe and prolonged lymphophenia for 3.5 years and continued taking the drug
• the patient that died contracted pneumonia
• pneumonia is listed as the cause of death
• over 100,000 patients are taking Tecfidera
• up to 5% of Tecfidera users may develop lymphophenia
• when starting Tecfidera, it is normal for your wbc to dip
• that people with lymphopenia may not have enough lymphocytes to fight off or prevent infections
• routine blood monitoring (i.e complete blood count or CBC) can determine your white blood count (wbc)
• you and your doctor should track your wbc

Please have your blood drawn regularly and monitor your wbc levels. If you dip below normal wbc levels, you should talk to your neurologist about your situation. If you continue to have below normal wbc levels, you have a chance of developing lymphopenia. If you are JCV+ and have lymphopenia, and you continue to take Tecfidera you begin running the risk of developing PML.The longer you have lymphopenia and stay on Tecfidera the greater the odds you have of developing PML. PML takes time to develop and that process can be interrupted. Once you stop Tecfidera, your wbc numbers should begin to normalize over weeks or months. You should contact your neurologist if you are taking Tecfidera and develop an infection.

I hope the first Tecfidera case of PML will be the last, but with over 100,000+ patients taking Tecfidera there will undoubtedly be more. Please ensure it isn't you, but routinely getting your blood drawn and analyzed. This summer I developed shingles and called my neurologist. My neuro discontinued Tecfidera until the shingles passed. During this time, we did multiple blood draws to ensure my WBC numbers remained in a healthy range.

We all need to take a lesson from sheli18 and be proactive with our care, especially when taking a medication that has life and death consequences.

[rsinger]

low WBC count

No postings from sheli18 since her last one regarding very low WBC count. Hope you are okay and just busy with Thanksgiving. Just wanted to check in and see how you appointment with your neurologist went.
Keep us posted on your situation.

[agate]

I hate to bring unwelcome news in here on a major holiday.

The FDA has issued a safety alert on Tecfidera for MS, based on this case.

http://www.fda.gov/Safety/MedWatch/S.../ucm424752.htm

They don't know much about what caused this person's PML but they're not taking any chances. At least that's how it looks to me, FWIW.

[22cyclist]

UGH! I was afraid this would happen. There were little warnings here and there in medical journals. GOOD GRIEF.

God bless the poor soul who passed.

Lisa

[rsinger]

FDA report for tecfidera

I knew this would be coming. Now what? How will the neurologists treat their patients who are JC virus positive? Should we be watched more closely with more frequent blood work? I am very concerned about this.

[onlyairfare]

The report says the patient had been taking Tecfidera for over four years, and was known to have a low lymphocyte count for some time before developing PML.

The prescribing instructions say to check a CBC before beginning Tec (to be sure the lymphocyte count is normal), and annually thereafter, unless symptoms suggest to check it sooner. It seems to me it might be prudent now to be sure to have those regular CBC checks, perhaps more often than once a year - maybe every 3 - 6 months? Maybe check every MSer for JCV, not just those going on Ty?

The challenge is that the FDA says as a remedy, doctors should tell patients of the risk and instruct them to call for problems such as new weakness, eye problems, tremor, etc. All of those are typical flare symptoms as well as potential problems of PML. The problems of MS are the same as the signs of a problem with Tecfidera.

[Marco]

Sorry about typos, this all upsets me so much

The FDA has issued a safety alert on Tecfidera for MS, based on this case.
http://www.fda.gov/Safety/MedWatch/S.../ucm424752.htm

I don't see anything alarming about the FDA safety alert. I also do not see new monitoring requirements. The alert basically says, "one person, taking Tecfidera, died of PML. "PML is a rare and serious brain infection caused by the John Cunningham (JC) virus. The JC virus is a common virus that is harmless in most people but can cause PML in some patients who have weakened immune systems."

The FDA then gave 3 recommendations:

1. Tell patients to call their neurologist if they have PML symptoms
2. Immediately stop taking Tecfidera if you develop signs of PML
3. Blood should be monitored for lymphocyte counts (get regular blood tests)

In this case, the weakend immune system took form of Lymphopenia. Lymphopenia is where a patients white blood cell or lymphocyte count is reduced below a healthy level. Tecfidera normally causes a drop in lymphocyte counts, and MS patients normally want this to happen. A nominal reduction in lymphocytes may help to reduce the MS immune response and be beneficial to MS patients. Too large of reduction in lymphocytes may result in lymphopenia (too few lymphocytes). Lymphopenia is a known risk factor in developing PML. Approximately six percent of patients develop lymphopenia while on Tecfidera. Once a patient's lymphocyte count drops too low, the patient should be closely monitored, and/or Tecfidera therapy should be stopped. Lymphocytes levels below the normal range, make make the patient more vulnerable to opportunistic infections. If Tecfidera is stopped, lymphocyte levels quickly begin to increase, but do not generally regenerate to normal levels within a four week period.

Directly from the prescribing information:

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 TECFIDERA 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.

Biogen Blood Testing
I talked to Biogen late this summer and was surprised to find out that routine blood monitoring for Tysabri patients was not mandatory. I was told that blood testing was highly recommended, but not a requirement. This may not be a requirement to accommodate religious viewpoints. I'd personally like to see it mandatory for all patients, with an opt-out feature for patients with specific requirements.
For starting Tecfidera, Biogen recommends having a CBC test within 6 months and then recommends another CBC test annually. These recommendations may be inadequate to properly screen patients for lymphopenia.

Personally, I'd like to see an actual REQUIREMENT of a CBC test within 90 days of starting Tecfidera. A JCV test within 6 months and a quarterly CBC test REQUIREMENT during the first year. Afterwards, CBC tests would be required for any patients with less than a 1,000 lymphocytes/mL3. For patients over 1,000 lymphocytes/mL3, a CBC and JCV test would be required annually. For JCV+ individuals, the JCV titer value would be a REQUIREMENT. This would increase the cost to deliver Tecfidera, but they are charging $6,000/month for the drug -and- they stand to lose a ton of money with every confirmed case of PML.

Going back to Fumaderm
Fumaderm (pre-Tecfidera and pre-BG12) is a medication used to treat Psoriasis in Germany and other parts of the European Union. Fumaderm has been in use since 1993, and is generally considered safe with over 190,000 patient hours. Fumaderm is made up of dimethyl fumarate + 3 other closely-related chemicals. Tecfidera is made up of dimethyl fumarate without the 3 other chemicals. Fumaderm and Tecfidera both depress white blood cell counts. MS patients should actually WANT this to happen so our MS immune response is reduced. The problem is when lymphocytes get too low, patients become vulnerable to opportunistic infections, including the JCV. Once the JCV is reactivated the process that leads to PML begins.
Interestingly enough, Teva, the manufacturer of Copaxone, sent the FDA a letter discussing potential safety issues with BG12. The original complaint did not cite PML as a concern, but it suspected that Teva also introduced the Fumaderm/PML issue into the discussion. Without a doubt, Teva had a vested interest in slowing or preventing the FDA approval of BG12. Teva fiercely defends their marketshare and the approval of BG12 would siphon off Copaxone users. The good news is Teva's efforts brought legitimate safety concerns to the BG12 discussion.


When you review the four PML cases you will find:

1. The first patient was on topical steroids and methotrexate, a drug known to cause PML, prior to starting Fumaderm. This patient was diagnosed with lymphopenia, that also increases your PML risks, within the first year of starting Fumaderm. This condition prevents the patient from producing an adequate number of lymphocytes. Severe lymphopenia is a known risk factor for PML. The prescribing information called for more frequent blood monitoring than either patient received. The manufacturers recommended protocol to remove a patient with severe lymphopenia was missed or outright ignored.
2. The second patient had been taking dimethyl fumarate + other chemicals, made by a compounding pharmacy (not fumaderm), to treat psoriasis. The compounding pharmacy also used copper gluconate as an additive that may also increase your PML risks. This patient had been experiencing lymphopenia for five years prior to being diagnosed with PML.
3. The third patient had sarcoidosis, cancer and psoriasis. The patient was on Efalizumab, a drug, known to cause PML. The patient stopped Efalizumab, began Fumaderm and was diagnosed one month later.
4. The fourth patient had a history of sarcoidosis and psoriasis. This patient had previously used methotrexate, another drug known to cause PML. This patient was believed to also have Multiple Sclerosis had a recent round of intravenous steroids to treat MS, just prior to PML diagnosis.

In summary, in all four cases of dimethyl fumarate-related PML, each patient had significant other medical issues and/or increased risk factors for developing PML. This is why patients must be aware of what their individual risk factors are, and how other medical conditions or medications affect them.
Rant: As I said earlier, I believe blood monitoring should be a requirement (not optional), but my soap box sags from overuse. Had the lymphopenia been found and properly responded to it's likely that several of these patients would not have contracted PML.


Back to Tecfidera and PML
The Tecfidera patient in question had lymphopenia for three years prior to contracting PML. Both the patient and the physician were aware of this condition. Again, lymphopenia is a severe reduction in lymphocytes, or white blood cells, a key component of the immune system to fight infections. This makes the patient vulnerable or more susceptible to opportunistic infections, like JCV. Despite the increased susceptibility, the patient remained on Tecfidera for three additional years and eventually got pneumonia. So a patient with a weakened immune system contracted pneumonia (further reducing their immune system) prior to the reactivation of the JCV and the development of PML.
Had either the patient or physician stopped the Tecfidera, until the lymphopenia was resolved, the patient would most likely be alive today. Had either the patient of the physician adhered to the manufacturer's prescribing information, the patient would most likely be alive today. If Biogen REQUIRED these tests and helped monitor patients for increased PML risk factors, the patient would most likely be alive today. I am bewildered (and infuriated), that we know the primary PML risk factors for MS patients and yet we are still regularly burying patients with PML.

Please talk to your doctor's about your individual risk factors for developing PML. For some patients the risk should be 0%, but for some patients the risk may be less greater than 1%. This conversation should repeat itself every time you switch to a different MS drug. I'd rather your neurologist look at you crazy, than to be writing about you in the future.

Here is an abbreviated list of risk factors:

• If you have prior or current immunosuppressants use your PML risk factors is increased. Immunosuppressant drugs suppress or reduce the body’s immune system. This includes if you are on Tysabri, Rituximab, Gilenya, Aubagio, Tecfidera, Methotrexate or any number of other immunosuppressants. Immunosuppressant use is common for patients with Crohn's disease, Multiple Sclerosis, Cancer/Oncology, Psoriasis, Rheumatoid Arthritis, and Organ Transplant Recipients.
• Generally speaking, the longer you are on an immunosuppressant, past or present, your risk factors for developing PML are increased. Remaining on a therapy that causes PML for longer than recommended is not a badge of honor. I'm sorry, I love all you long-term Tysabri patients, but I do fear for your safety after a certain point
  
• If you are JCV+, you are at an increased risk of developing PML. This is why I hope Biogen begins to require the JCV prior to taking Tysabri or Tecfiera. This should also apply to other manufacturers of medications that increases patient risks of developing PML. If you are currently JCV-, you can still become JCV+ in the future. Your JCV- test could also be a false negative. This is why repeating the JCV test is necessary and should be a requirement.
• If you have an altered or weakened immune system, you are at an increased risk of developing PML. You are a greater risk of developing PML, if you have long-term diseases like HIV/AIDS, Leukemia, Hodgkin's disease, Lupus, etc. You are at a greater risk of developing PML, if you get a temporary infection like shingles, pneumonia, etc.

Please do not be the next victim of PML. Even though the survival rate has increased, survivors of PML may have a significantly reduced quality of life. Please become your own advocate, especially when the consequences can be terminal.

[onlyairfare]

I don't blame you for being upset Marco.

Maybe medical malpractice liability plays a role in the prescribing information verbiage. While it would certainly be prudent from a risk reduction viewpoint to test regularly for JCV status as well as lymphocyte count, perhaps BioGen doesn't want to dictate specific requirements as "standard of care." A double edged sword.

It does boggle my mind to think of a patient going for years on any prescription medication without any lab work, let alone not checking a CBC when a patient is known to be taking a med that lowers lymphocyte count and increases the risk for PML. My own PCP checks my CBC and CMP chemistries at least annually, and I am on Copaxone, not Ty or Tec.

When the risk is potentially a fatal illness such as PML, better to be safe than sorry. Check and recheck the CBC and JCV status/titer, hold the Tec during acute infections, and see the patient if there are symptoms that could be PML. Even if they could also be typical MS symptoms, the doc may want to change meds if there are increased relapses.

[agate]

Marco, one point about your post. When you say

Despite the increased susceptibility, the patient remained on Tecfidera for three additional years and eventually got pneumonia. So a patient with a weakened immune system contracted pneumonia (further reducing their immune system) prior to the reactivation of the JCV and the development of PML.

I'm fairly sure that the patient was diagnosed with PML first, then got pneumonia and died (with pneumonia the cause of death). According to this:

The infection, progressive multifocal leukoencephalopathy (PML) struck a European patient who had been taking Tecfidera for four years, Biogen said. The patient, who started on Tecfidera during clinical trials, then died of pneumonia.

(from a FiercePharma article, October 22)

http://www.fiercepharma.com/story/bi...ase/2014-10-22

[Marco]

agate - I'm completely willing to cede the point. The patient never should have been on Tecfidera, especially after 3 years after being diagnosed with lymphopenia

[agate]

I agree, Marco.

A person can get desperate. The patient may have insisted on taking the risk in spite of warnings from medical providers, who yielded.