Correspondence

More on Melanoma with Transdifferentiation

N Engl J Med 2008; 359:99-100July 3, 2008

Article

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December 2007 do not indicate an increased risk of melanoma among more than 21,000 patients who received natalizumab (unpublished data).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 α₄β₁–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 α₄-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

5 References

1. 1

   Mullen JT, Vartanian TK, Atkins MB. Melanoma complicating treatment with natalizumab for multiple sclerosis. N Engl J Med 2008;358:647-648
   Full Text | Web of Science | Medline

2. 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
   Web of Science | Medline

3. 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 | Web of Science | Medline

4. 4

   TYSABRI. South San Francisco, CA: Elan Pharmaceuticals, 2007 (package insert).
   

5. 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
   Full Text | Web of Science | Medline

Author/Editor Response

Though we agree with Panzara et al. that α₄β₁ 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 α₄β₁ 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 α₄β₁ 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 α₄ integrins at different stages in the cascade. Perhaps α₄ 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

3 References

1. 1

   Johnson JP. Cell adhesion molecules in the development and progression of malignant melanoma. Cancer Metastasis Rev 1999;18:345-357
   CrossRef | Web of Science | Medline

2. 2

   Bauer R, Humphries M, Fassler R, Winklmeier A, Craig SE, Bosserhoff AK. Regulation of integrin activity by MIA. J Biol Chem 2006;281:11669-11677
   CrossRef | Web of Science | Medline

3. 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 | Web of Science | Medline

Citing Articles (7)

Citing Articles

1. 1

   Henrik Gensicke, David Leppert, Özgür Yaldizli, Raija L.P. Lindberg, Matthias Mehling, Ludwig Kappos, Jens Kuhle. (2012) Monoclonal Antibodies and Recombinant Immunoglobulins for the Treatment of Multiple Sclerosis. CNS Drugs 26:1, 11-37
   CrossRef

2. 2

   Ludwig Kappos, David Bates, Gilles Edan, Mefkûre Eraksoy, Antonio Garcia-Merino, Nikolaos Grigoriadis, Hans-Peter Hartung, Eva Havrdová, Jan Hillert, Reinhard Hohlfeld, Marcelo Kremenchutzky, Olivier Lyon-Caen, Ariel Miller, Carlo Pozzilli, Mads Ravnborg, Takahiko Saida, Christian Sindic, Karl Vass, David B Clifford, Stephen Hauser, Eugene O Major, Paul W O'Connor, Howard L Weiner, Michel Clanet, Ralf Gold, Hans H Hirsch, Ernst-Wilhelm Radü, Per Soelberg Sørensen, John King. (2011) Natalizumab treatment for multiple sclerosis: updated recommendations for patient selection and monitoring. The Lancet Neurology 10:8, 745-758
   CrossRef

3. 3

   Christine Lebrun, Patrick Vermersch, David Brassat, Gilles Defer, Lucien Rumbach, Pierre Clavelou, Marc Debouverie, Jérôme Seze, Sandrine Wiertlevsky, Olivier Heinzlef, Ayman Tourbah, Agnes Fromont, Marc Frenay. (2011) Cancer and multiple sclerosis in the era of disease-modifying treatments. Journal of Neurology 258:7, 1304-1311
   CrossRef

4. 4

   A. Laroni, M. Bedognetti, A. Uccelli, E. Capello, G. L. Mancardi. (2011) Association of melanoma and natalizumab therapy in the Italian MS population: a second case report. Neurological Sciences 32:1, 181-182
   CrossRef

5. 5

   Azza Ismail, Julie Kemp, Basil Sharrack. (2009) Melanoma complicating treatment with Natalizumab (Tysabri) for multiple sclerosis. Journal of Neurology 256:10, 1771-1772
   CrossRef

6. 6

   Ö. Yaldizli, P. Baumberger, N. Putzki. (2009) Natalizumab et nævus atypiques : commentaires sur la note de pharmacovigilance de J.-L. Schmutz et al.. Annales de Dermatologie et de Vénéréologie 136:5, 450-451
   CrossRef

7. 7

   A. A. Pace, J. P. Zajicek. (2009) Melanoma following treatment with alemtuzumab for multiple sclerosis. European Journal of Neurology 16:4, e70-e71
   CrossRef