Correspondence

Melanoma Complicating Treatment with Natalizumab for Multiple Sclerosis

N Engl J Med 2008; 358:647-648February 7, 2008

Article

To the Editor:

We report on two cases of melanoma in women with multiple sclerosis who were treated with natalizumab (Tysabri, Biogen Idec and Elan Pharmaceuticals), a humanized monoclonal antibody against α₄ integrins. Patient 1 was a 46-year-old woman who, shortly after receiving her first dose of natalizumab, noticed a rapidly changing mole on her shoulder; on evaluation, it proved to be a thick, nonulcerated melanoma with metastatic disease in the regional lymph nodes. Patient 2 was a 45-year-old woman who had a long-standing ocular nevus that developed into an ocular melanoma after the administration of several doses of natalizumab (Figure 1Figure 1Retinal Images of Patient 2.). Further treatment with natalizumab was withheld by her neurologist. The patient had no history of melanoma but did have many atypical moles. In addition, both her father and a brother had had melanoma and were alive and well.

These findings suggest that therapy with antibodies against α₄ integrins may lead to the development and progression of melanoma. In both patients, there were close temporal relationships between the administration of natalizumab and dramatic changes in long-standing nevi. Moreover, another case of metastatic melanoma has been reported in a patient receiving natalizumab.1 In an experimental mouse model of melanoma, expression of the α₄β₁ integrin on melanoma cells promotes homotypic intercellular adhesion and a decreased ability to invade extracellular matrix gels, thus inhibiting the metastasis of melanoma at the earliest, invasive stage of the metastatic cascade.2 Bauer et al.3 demonstrated that melanoma inhibitory activity protein, a small protein that is secreted by melanoma cells and that is known to promote the cells' invasive and migratory potential, binds to α₄β₁ integrin and down-regulates its activity.

In addition, the immune system plays a critical role in the control of the growth and metastasis of melanoma tumors. Antibodies to α₄β₁ integrin inhibit the migration of lymphocytes to sites of cutaneous inflammation and cytokine injection,4 and anti–α₄-integrin antibodies induce apoptosis in activated, mature lymph-node T cells in an in vitro model.5 It is thus possible that anti–α₄-integrin antibodies down-regulate the immune system both at the primary tumor site and in the regional nodal basin, thereby promoting the locoregional spread of melanoma.

In conclusion, we recommend that natalizumab not be administered to patients with a personal or family history of melanoma or to those with atypical moles or ocular nevi. At the very least, we recommend that alternative therapies be strongly considered in such patients.

John T. Mullen, M.D.
Timothy K. Vartanian, M.D.
Michael B. Atkins, M.D.
Beth Israel Deaconess Medical Center, Boston, MA 02215
jtmullen@bidmc.harvard.edu

Dr. Vartanian reports receiving lecture fees from EMD Serono and consulting fees and grant support from Biogen Idec; and Dr. Atkins, consulting fees from Schering-Plough and grant support from SAIC-Frederick. No other potential conflict of interest relevant to this letter was reported.

5 References

1. 1

   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

2. 2

   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

3. 3

   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

4. 4

   Issekutz TB, Wykretowicz A. Effect of a new monoclonal antibody, TA-2, that inhibits lymphocyte adherence to cytokine stimulated endothelium in the rat. J Immunol 1991;147:109-116
   Web of Science | Medline

5. 5

   Tchilian EZ, Owen JJ, Jenkinson EJ. Anti-alpha 4 integrin antibody induces apoptosis in murine thymocytes and staphylococcal enterotoxin B-activated lymph node T cells. Immunology 1997;92:321-327
   CrossRef | Web of Science | Medline

Citing Articles (32)

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

   Igal Ifergan, Hania Kebir, Simone Terouz, Jorge I. Alvarez, Marc-André Lécuyer, Steve Gendron, Lyne Bourbonnière, Ildiko R. Dunay, Alain Bouthillier, Robert Moumdjian, Adriano Fontana, Arsalan Haqqani, Armelle Klopstein, Marco Prinz, Rubèn López-Vales, Thomas Birchler, Alexandre Prat. (2011) Role of ninjurin-1 in the migration of myeloid cells to central nervous system inflammatory lesions. Annals of Neurology 70:5, 751-763
   CrossRef

3. 3

   Eugenio Pucci, Giorgio Giuliani, Alessandra Solari, Silvana Simi, Silvia Minozzi, Carlo Di Pietrantonj, Ian Galea, Eugenio Pucci. 2011. Natalizumab for relapsing remitting multiple sclerosis. .
   CrossRef

4. 4

   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

5. 5

   Esther V Hobson, Basil Sharrack. (2011) Emerging oral disease-modifying therapies in multiple sclerosis: a review of the latest clinical evidence. Clinical Investigation 1:7, 1049-1058
   CrossRef

6. 6

   A. Horga, M. Tintoré. (2011) Natalizumab para la esclerosis múltiple remitente-recurrente. Neurología 26:6, 357-368
   CrossRef

7. 7

   Kavita V Nair, John Corboy, Kristijan Kahler, Richard Read Allen, Vahram Ghushcyan, Robert Brett McQueen, Jacci Bainbridge, Homa Dastani, Nikita Mody-Patel. (2011) Use of diagnostic tests and procedures for disease-modifying therapy users and non-disease-modifying therapy users with multiple sclerosis. Expert Review of Neurotherapeutics 11:6, 787-798
   CrossRef

8. 8

   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

9. 9

   A. Horga, M. Tintoré. (2011) Natalizumab for relapsing-remitting multiple sclerosis. Neurología (English Edition) 26:6, 357-368
   CrossRef

10. 10

    Peter O. Behan, Abhijit Chaudhuri. (2010) The sad plight of multiple sclerosis research (low on fact, high on fiction): critical data to support it being a neurocristopathy. Inflammopharmacology 18:6, 265-290
    CrossRef

11. 11

    Chiara Zecca, Claudio Städler, Claudio Gobbi. (2010) Hydrocephalus during natalizumab treatment. Neurological Sciences 31:5, 635-637
    CrossRef

12. 12

    D. T. Selewski, G. V. Shah, B. M. Segal, P. A. Rajdev, S. K. Mukherji. (2010) Natalizumab (Tysabri). American Journal of Neuroradiology 31:9, 1588-1590
    CrossRef

13. 13

    M. Buttmann, H. Wiendl. (2010) Therapeutische monoklonale Antikörper in der Neurologie. Der Nervenarzt 81:6, 753-766
    CrossRef

14. 14

    Mathias Buttmann. (2010) Treating multiple sclerosis with monoclonal antibodies: a 2010 update. Expert Review of Neurotherapeutics 10:5, 791-809
    CrossRef

15. 15

    Giancarlo Comi. (2009) Treatment of multiple sclerosis: role of natalizumab. Neurological Sciences 30:S2, 155-158
    CrossRef

16. 16

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

17. 17

    Richard M. Ransohoff. (2009) Natalizumab, multiple sclerosis, and primary central nervous system lymphoma: Enigma, wrapped in mystery, enclosed in conundrum. Annals of Neurology 66:3, 259-261
    CrossRef

18. 18

    Lisa M. DeAngelis. (2009) Natalizumab: A double-edged sword?. Annals of Neurology 66:3, 262-263
    CrossRef

19. 19

    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

20. 20

    John W. Rose, John F. Foley, Noel G. Carlson. (2009) Monoclonal antibody treatments for multiple sclerosis. Current Treatment Options in Neurology 11:3, 211-220
    CrossRef

21. 21

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

22. 22

    Joseph R. Berger, Sidney Houff. (2009) Opportunistic infections and other risks with newer multiple sclerosis therapies. Annals of Neurology 65:4, 367-377
    CrossRef

23. 23

    P. S. Rommer, O. Stüve, R. Goertsches, E. Mix, U. K. Zettl. (2008) Monoclonal antibodies in the therapy of multiple sclerosis. Journal of Neurology 255:S6, 28-35
    CrossRef

24. 24

    Ralf A. Linker, Bernd C. Kieseier, Ralf Gold. (2008) Identification and development of new therapeutics for multiple sclerosis. Trends in Pharmacological Sciences 29:11, 558-565
    CrossRef

25. 25

    B.K. Kleinschmidt-DeMasters, Denise M. Damek, Kevin O. Lillehei, Ahmed Dogan, Caterina Giannini. (2008) Epstein Barr Virus-Associated Primary CNS Lymphomas in Elderly Patients on Immunosuppressive Medications. Journal of Neuropathology and Experimental Neurology 67:11, 1103-1111
    CrossRef

26. 26

    R.A. Linker, B.C. Kieseier. (2008) Therapieentscheidungen bei Multipler Sklerose. Der Nervenarzt 79:10, 1123-1134
    CrossRef

27. 27

    J.-L. Schmutz, A. Barbaud, P. Tréchot. (2008) Mélanome et traitement de la sclérose en plaques par natalizumab (Tysabri®). Annales de Dermatologie et de Vénéréologie 135:10, 725-726
    CrossRef

28. 28

    , H. Wiendl, K. V. Toyka, P. Rieckmann, R. Gold, H.-P. Hartung, R. Hohlfeld. (2008) Basic and escalating immunomodulatory treatments in multiple sclerosis: Current therapeutic recommendations. Journal of Neurology 255:10, 1449-1463
    CrossRef

29. 29

    John W. Rose, John Foley, Noel Carlson. (2008) Monoclonal antibody treatments for multiple sclerosis. Current Neurology and Neuroscience Reports 8:5, 419-426
    CrossRef

30. 30

    Jefferson W Tilley. (2008) Very late antigen-4 integrin antagonists. Expert Opinion on Therapeutic Patents 18:8, 841-859
    CrossRef

31. 31

    (2008) More on Melanoma with Transdifferentiation. New England Journal of Medicine 359:1, 99-100
    Full Text

32. 32

    Pietro Bulian, Gianluca Gaidano, Giovanni Del Poeta, Valter Gattei. (2008) CD49d expression in chronic lymphocytic leukemia: a prognostic parameter and a therapeutic target. Future Oncology 4:3, 355-358
    CrossRef

Letters