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Doctors report 2 cases of the deadly skin cancer developing in patients taking Tysabri

By Amanda Gardner
Posted 2/6/08

WEDNESDAY, Feb. 6 (HealthDay News) -- Almost immediately after a 46-year-old woman with multiple sclerosis received her first dose of the drug Tysabri, a mole that had been on her shoulder for years suddenly took on a dangerous new character. It turned out to be a melanoma that spread like wildfire. The woman now has just a few months to live.

At almost the same time, a 45-year-old woman who also has multiple sclerosis developed melanoma in her retina after receiving several doses of Tysabri. She had a family history of melanoma and also had atypical moles on her body; the mole on her retina went back at least nine years.

Although these are just two -- albeit dramatic -- examples, the authors of a letter in the Feb. 7 issue of the New England Journal of Medicine are cautioning doctors who care for MS patients to keep this potential risk in mind.

"Neurologists who have patients who report a family history of melanoma or have funny moles should send them to a dermatologist first. Don't just start them on drugs [Tysabri]," said Dr. John Thomas Mullen, co-author of the letter and a surgical oncologist with Beth Israel Deaconess Medical Center, in Boston.

"I can't say it's cause-and-effect definitively because it's just an observation, but the first patient had had that mole forever. She took the drug and almost instantaneously the lesion changed," added Mullen, who saw both patients.

"We don't know if the two are related right now," said Patricia O'Looney, vice president of biomedical research at the National Multiple Sclerosis Society. "There are so many people taking Tysabri, we should go forward with caution... One should always consult with their doctor and go over their personal family history and decide what is best."

Tysabri (natalizumab), a monoclonal antibody that helps treat autoimmune disorders such as MS and Crohn's disease, has had a clouded history. It first received U.S. Food and Drug Administration approval in November 2004, only to be pulled from the market three months later after several patients in clinical trials developed a rare but deadly viral infection of the brain called progressive multifocal leukoencephalopathy.

In June 2006, the FDA allowed the drug back on the market but with strict conditions governing its use.

Just last month, the FDA approved Tysabri to treat people with a moderate to severe form of Crohn's disease.

But there is basic science to support Mullen's observations.

One of the participants in an earlier study of Tysabri had developed (and subsequently died of) a metastatic melanoma that appeared as soon as he got his first dose of the drug, Mullen said.

And in a study done before Tysabri received FDA approval, melanomas in mice that were given the drug had an increased tendency to detach from the primary tumor and spread.

Tysabari may have a dampening effect on the immune system that encourages the formation of the potentially deadly skin cancer, the letter stated.

And now that Tysabri has been approved for people with Crohn's disease, more people may be at risk, although those with no family history of melanoma and no moles probably don't need to worry, Mullen said.

"Doctors should ask for a family history of melanoma and do a quick skin check," he said. "Tysabri isn't the only drug in our arsenal. You could give the patient something else if you were concerned about that."

I'm sure Harry will not be surprised by this and it has me concerned what else they are not passing on.

http://www.medindia.net/news/Multiple-S ... 2749-2.htm

Shannon Altimari, a spokesperson for Biogen Idec Inc., which in partnership with Elan Corp. markets Tysabri, has confirmed that another MS patient, a man who received treatment in clinical trials prior to the drug’s FDA approval, has also developed melanoma.

However, according to him, the manufacturers of the drug have no current plans of putting the caution notice on Tysabri's label warning doctors and patients of the possible risk of melanoma in patients with atypical moles or a family history of melanoma.

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Surprised...No...saddened...Yes!

A couple of people involved with MS research that I've met over the years in dealing with this lousy disease, told me that it would be highly likely that this kind of problem with Tysabri would surface over time. After all, we are dealing with a very powerful drug that alters the way the immune system works.

What makes me sad about this is that MS patients have again been subject to the roller coaster ride of yet another promising drug which has been over promoted as being great for MS but slowly becoming associated with other problems. I saw what this did to my wife Marg while she was alive and it made her totally skeptical to the MS world of medicine.

While these two cases are just observations so far, it makes you wonder what else has gone unreported with those who are using Tysabri. Biogen, like all drug companies, are loathe to report this kind of information because it can have a very negative effect on potential sales.

Let's hope that this recent problem is a very isolated situation....MS patients don't need more bad news!

Harry

Bob,

I'm not sure that the people involved with the report are trying to prove anything other than what they have discovered. The very way that Biogen/Elan promoted Tysabri, introduced it and then had to pull it off the market for a period of time, has resulted in it coming under the microscope. I wouldn't be a bit surprised if Biogen's competitors in MS drugs are behind this because there is a bitter rivalry among them. In normal circumstances, we probably wouldn't have even heard about these two melanoma cases but with Tysabri's current situation, everything happening with this drug is going to be reported. Perhaps not necessarily fair but a reality, nonetheless.

Harry

This caught my eye, because my husband has had several basal cell sites removed since his dx last year (no melanoma), and beginning treatment with Copaxone. Perhaps it's just because of the scrutiny Tysabri is receiving that the connection has been made with melanoma. Would be curious to know what the data is on all CRABs patients with melanoma.

In any event, I think it would be wise for all MSers on CRABs with moles and skin anamalies to be vigilant and see the dermatologist. Immune modulation can affect many things.

interesting,
AC

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dx dual jugular vein stenosis (CCSVI) 4/09
dual stents placed 5/09
CCSVI in MS

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It is more than obvious that Tysabri in one way or another does dampen a humans body's defense outside of the brain and spinal cord in order to preserve the wellness of the neurological tissue from inflammations (attacks).

Therefore, unfortunately for all us who take Tysabri, we must be extra careful

1) of our family history for any type on body 'malfunctions' ...
2) that we lead and preserve a very healthy life so that we dont promote any 'malfunctions' ourselves!

It is the nature of the drug to lower the immune' s system capabilities and therefore I would say there is no side of story etc etc,

POSSIBLE or it is a POSSIBILITY describes perfectly this new drug, due to the fact that you had 2.000.000 knights fighting for you ... and now you have about say 500.000 defending the nation. However, we have seen in the past 300 (Leonidas and his heroes from Thermopylae) defend the country against millions of enemies !!!

It is the best commercial TREATMENT out for R-R MS patients to lead a normal life, but that certainly does not come without its costs .... so being extra careful and maintaining a healthy and happy spirit will certainly breed these 300 to defend you from anything and anyone!

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an action brings..... a reaction !

I know of another case that may be somehow related to Tysabri. A good thing to consider would be, how many cases of melanoma in the general population?

That being said, I just had my 10th infusion, and so far, so good. After hearing this news though, I did schedule my first baseline dermatology checkup for Feb 20th which I had been overdue for anyway. I have several moles I'd like to be checked out just to be sure they aren't bad ones.

My Mom had skin cancerous moles removed, but I think they may have been squamous cell? I have to see if my sister remembers.

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Take care, Ewizabeth Previously Avonex, Rebif & Copaxone RRMS ~Tysabri, 31 infusions, ended 9/09. Starting Copaxone 12/09, waiting for Cladribine to be approved in 2010.

Interesting reading, all of your comments! I would like to say thankx Lauren for your possitive words, as you may remember I am about to start Tysabri & I can tell you I am terrified So the I guess the night before I go to my Neuro isnt really a good time to be getting on this site & reading all this stuff because I am already worried, but we do have to be informed as much as possible so thanks to you all again!

There was an update on the nmss site. For those who are intereasted http://www.nationalmssociety.org/news/n ... px?nid=256

This is the text, and the original authors reply.

To the Editor: Mullen et al. (Feb. 7 issue)1 report on two cases of melanoma in patients with multiple sclerosis who received natalizumab. Their letter shows the limited interpretability of individual case reports in establishing cause-and-effect relationships. In response to this letter, we performed a meta-analysis of safety data from clinical trials of natalizumab. The incidence of melanoma was similar among patients who received natalizumab (3 of 4250 [0.07%]) as compared with those who received placebo (2 of 2059 [0.10%]). Rates of melanoma followed a similar pattern: 0.419 per 1000 patient-years among persons who received natalizumab versus 0.823 per 1000 patient-years among persons who received placebo. In addition, postmarketing surveillance data as of December 2007 do not indicate an increased risk of melanoma among more than 21,000 patients who received natalizumab (unpublished data).

Studies suggest that {alpha}4β1–vascular-cell adhesion molecule 1 interactions are important for the metastatic capacity of melanoma cells and that blockade may prevent metastasis.2,3 In addition, natalizumab at saturating levels had no effect on tumor growth or metastasis in a xenograft model involving an {alpha}4-integrin–positive human melanoma tumor line implanted in nude mice.4

The conclusion by Mullen and colleagues that patients with a personal or family history of melanoma or atypical moles should not receive natalizumab is not supported by the evidence from studies in animals, controlled clinical trials,5 and postmarketing surveillance.


Michael A. Panzara, M.D., M.P.H.
Carmen Bozic, M.D.
Alfred W. Sandrock, M.D., Ph.D.
Biogen Idec
Cambridge, MA 02142

References

1. Mullen JT, Vartanian TK, Atkins MB. Melanoma complicating treatment with natalizumab for multiple sclerosis. N Engl J Med 2008;358:647-648. [Free Full Text]
2. Garofalo A, Chirivi RG, Foglieni C, et al. Involvement of the very late antigen 4 integrin on melanoma in interleukin 1-augmented experimental metastases. Cancer Res 1995;55:414-419. [Free Full Text]
3. Klemke M, Weschenfelder T, Konstandin MH, Samstag Y. High affinity interaction of integrin alpha4beta1 (VLA-4) and vascular cell adhesion molecule 1 (VCAM-1) enhances migration of human melanoma cells across activated endothelial cell layers. J Cell Physiol 2007;212:368-374. [CrossRef][ISI][Medline]
4. TYSABRI. South San Francisco, CA: Elan Pharmaceuticals, 2007 (package insert).
5. Polman CH, O'Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006;354:899-910. [Free Full Text]


The authors reply: Though we agree with Panzara et al. that {alpha}4β1 expression may play a role in melanoma-cell extravasation and metastasis formation,1 equally strong data show that small-molecule (melanoma inhibitory activity)2 and antibody blockade of {alpha}4β1 may play a role in melanoma tumor invasion and spread by mediating tumor-cell detachment from other melanoma cells and the extracellular matrix.3 Moreover, it is no surprise that natalizumab had no effect on tumor growth or metastasis in their mouse model of melanoma, since multiple melanoma cell lines have widely differing metastatic capacities independent of their {alpha}4β1 expression levels.3 We conclude that the process of melanoma tumor growth and metastasis is a complex, multistep cascade that is probably influenced by the variable expression of {alpha}4 integrins at different stages in the cascade. Perhaps {alpha}4 expression is protective of melanoma-cell detachment early in the cascade but harmful later by promoting metastasis. Regardless, we recommend that clinicians strongly consider alternative therapies or, at a minimum, surveillance strategies for patients at high risk for melanoma for whom natalizumab therapy is planned, at least until further data are available.


John T. Mullen, M.D.
Timothy K. Vartanian, M.D.
Michael B. Atkins, M.D.
Beth Israel Deaconess Medical Center
Boston, MA 02115
jtmullen@bidmc.harvard.edu

References

1. Johnson JP. Cell adhesion molecules in the development and progression of malignant melanoma. Cancer Metastasis Rev 1999;18:345-357. [CrossRef][ISI][Medline]
2. Bauer R, Humphries M, Fässler R, Winklmeier A, Craig SE, Bosserhoff AK. Regulation of integrin activity by MIA. J Biol Chem 2006;281:11669-11677. [Free Full Text]
3. Qian F, Vaux DL, Weissman IL. Expression of the integrin alpha 4 beta 1 on melanoma cells can inhibit the invasive stage of metastasis formation. Cell 1994;77:335-347. [CrossRef][ISI][Medline]

It's all interesting, but has anyone just shown a simple percentage of "normal" people who get melanoma vs. MS'ers on Tysabri? I'd be interested in only that. One thing we all need to always remember is that just because we have MS doesn't mean we won't get cancer or anything else that we may have gotten had we not got MS. If it's a higher percentage, I think we should be concerned. But until that comes out, we should all be smart and pay attention to our moles and skin just as we should if we didn't have MS. Maybe I'm being a little flip here, but there seems to be a prediliction (sp?) to knee jerk to anything that happens to a Tysabri patient since there are scary things that we KNOW are linked to Tysabri use. I suppose we ought to err on the side of caution however, so I'd like to have someone show the percentage vs. the general population before I, personally, will worry about it. With this drug there is already enough to worry about and I, for one, want to enjoy the quality of life that Tysabri hopefully gives me. I hate the way this disease and it's treatments make me "overly self aware"; almost hypochondriacal if you will. I'd love to just not freaking think about it for a couple of hours a day. Maybe that's why I like my MJ. I mean self reflection and observation can of course be a good thing. But too much of it just makes me hate this shit even more. I think one thing that I will watch for is to not get too self absorbed. It's hard not to, but I'm really hating my MS right now, so sorry if I come off like an Eeyore.

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Well, the population of the US in 2007 was estimated at just over 301,000,000. The American Cancer Society estimated that about 60,000 people would get Melanoma in the same year. That gives approx .2% of the population.

So how many Tysabri patients have contracted Melanoma? We really don't know yet because the drug has only been out there for general use for about 2 years now.

The reason why the doc reported his two cases of Melanoma to Biogen was because these patients appeared to be fine until they started on Tysabri. Does that mean that Tysabri was the problem? Who knows? But because the drug is under the microscope due to its past history, everything that surrounds it is going to make the medical news.

Let's hope that these cases of Melanoma had nothing to do with Tysabri...MS patients don't need more problems than they already have.

Harry

amen to that.

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