Melanoma complicating treatment with Natalizumab (Tysabri) for multiple sclerosis

Abstract

Sirs, Natalizumab (Tysabri, Biogen Idec and Elan Pharmaceuticals) is a humanized monoclonal antibody which targets the a4 subunits of the cellular adhesion molecules a4b1 and a4b7 integrins, blocking their interaction with their co-receptors VCAM-1, CS-1 and MadCAM-1 [3, 15]. This action reduces leukocyte trafficking into the brain and gut and mediates the beneficial effect of natalizumab in multiple sclerosis (MS) and Crohn’s disease [3]. The efficacy of natalizumab in patients with relapsing remitting MS was demonstrated in two phase III studies, AFFIRM and SENTINAL [10, 12]. These studies showed that when natalizumab was used as mono therapy or in combination with interferon beta-1a (Avonex) it significantly reduced relapse rate and slowed the progression of disability. Natalizumab was well tolerated with the most common adverse effects being headache, infusion reactions and a modest increase in urinary and respiratory tract infections [10, 12]. Neither trial identified any apparent increase in cancer incidence. We report on a patient with MS who developed malignant melanoma following treatment with natalizumab. This was a 48-year-old female who was randomised into the active arm of the AFFIRM Study [10]. She received 30 infusions of natalizumab (300 mg every 4 weeks) and was subsequently enrolled in the open label phase of the trial and received an additional five infusions. The treatment was stopped thereafter when the trial was put on hold following the reporting of the three cases of progressive multifocal leukoencephalopathy (PML) [1]. Five months later, she noticed an increase in the size of a mole which was present on the lateral aspect of her right shin for many years. The patient had no previous history of melanoma or atypical naevi. She did not receive prior immunosuppressant therapy and had no history of melanoma. On examination, the lesion appeared flat, with a darker centre and regular borders. It was not ulcerated and there were no satellite lesions. She underwent local excision and histopathological examination revealed an in situ malignant melanoma with a potential invasive component. There was no evidence of metastasis. Margin re-excision of the biopsy site was undertaken. No recurrence has since been detected. Natalizumab was approved by the US Food and Drug Administration in 2004. Since then, three cases of melanoma associated with its use have been reported. Polman et al. [10] reported a patient in the AFFIRM study who died of malignant melanoma. This was a 38-year-old male with MS who had a past history of malignant melanoma excised from the left shoulder. Following the first dose of natalizumab, a new skin lesion was noticed. He received four additional doses before the diagnosis of malignant melanoma was confirmed. Mullen et al. [7] reported two further cases. The first was a 46-year-old woman with MS who had a mole on her shoulder. Shortly after the first infusion of natalizumab, she noticed a rapid change in its appearance. Further assessment confirmed this to be malignant melanoma with metastatic spread to her regional lymph nodes. The second patient was a 45-year-old woman with MS and a family history of melanoma who had a choroidal nevus in her right eye which had been stable for several years. After A. Ismail J. Kemp B. Sharrack (&) Department of Neurology, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF, UK e-mail: b.sharrack@sth.nhs.uk