A Randomized, Placebo-Controlled Trial of Natalizumab for Relapsing Multiple Sclerosis

Polman, Chris H.; O’Connor, Paul; Havrdová, Eva; Hutchinson, Michael; Kappos, Ludwig; Miller, David H.; Phillips, J. Theodore; Lublin, Fred; Giovannoni, Gavin; Wajgt, A; Toal, Martin; Lynn, F; Panzara, Michael A.; Sandrock, Alfred

doi:10.1056/nejmoa044397

Cited by 2,976 publications

(2,576 citation statements)

References 30 publications

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“…Case information for seven published cases was reviewed (Table 2) 2, 18, 19, 20, 21, 22, 23. Among the seven cases, six patients were female.…”

Section: Resultsmentioning

confidence: 99%

“…The median age of the patients was 41 years at the time of diagnosis of melanoma (range: 38–48 years). Three patients were enrolled in clinical trials evaluating natalizumab when melanoma was diagnosed, including two patients who were enrolled on a prospective phase III randomized trial at the time of diagnosis of melanoma 18, 21, 24. One 38‐year‐old male was enrolled on the randomized phase III study comparing natalizumab versus placebo.…”

Section: Resultsmentioning

confidence: 99%

“…One 38‐year‐old male was enrolled on the randomized phase III study comparing natalizumab versus placebo. This person received one dose of natalizumab prior to the diagnosis of recurrent melanoma 21, 24. One patient was a 48‐year‐old female, also on the same phase III clinical trial, who received 30 infusions of natalizumab on the clinical trial and was subsequently, in an open label phase of the trial, received five more infusions 21.…”

Section: Resultsmentioning

confidence: 99%

“…This person received one dose of natalizumab prior to the diagnosis of recurrent melanoma 21, 24. One patient was a 48‐year‐old female, also on the same phase III clinical trial, who received 30 infusions of natalizumab on the clinical trial and was subsequently, in an open label phase of the trial, received five more infusions 21. Treatment was discontinued when the clinical trial was put on hold following reporting of three cases of progressive multifocal leukoencephalopathy 24.…”

Section: Resultsmentioning

confidence: 99%

“…One patient was enrolled on a phase III trial. A skin lesion was noted when the first dose of natalizumab was administered, melanoma was diagnosed after five doses, and the patient died from melanoma (patient 1, Table 2) 21, 23. The number of doses of natalizumab before melanoma onset is of interest.…”

Section: Discussionmentioning

confidence: 99%

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Melanoma complicating treatment with natalizumab for multiple sclerosis: A report from the Southern Network on Adverse Reactions (SONAR)

et al. 2017

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A 43‐year‐old female with multiple sclerosis developed urethral melanoma. The only potential risk factor was treatment with natalizumab, a humanized monoclonal antibody against α4 integrins. To investigate the risk‐exposure relationship, we reviewed this case, all other published cases, and cases of natalizumab‐associated melanoma reported to regulatory agencies. Data sources included the Food and Drug Administration's (FDA) Adverse Event Reporting System (FAERS) (2004–2014), a FDA Advisory Committee Meeting Report, and peer‐reviewed publications. In the United States, the manufacturer maintains an FDA‐mandated Tysabri Safety Surveillance Program (part of the Tysabri Outcomes Unified Commitment to Health (TOUCH)) of natalizumab‐treated patients. We statistically compared reporting completeness for natalizumab‐associated melanoma cases in FAERs for which information was obtained entirely from the TOUCH program versus cases where FAERS information was supplemented by TOUCH program information. FAERS included 137 natalizumab‐associated melanoma reports in patients with multiple sclerosis. Median age at melanoma diagnosis was 45 years (range: 21–74 years). Changes in preexisting nevi occurred in 16%, history of cutaneous nevi occurred in 22%, diagnosis within 2 years of beginning natalizumab occurred in 34%, and 74% had primary surgical treatment. Among seven natalizumab‐treated MS patients who developed biopsy‐confirmed melanoma on treatment and reported in the literature, median age at diagnosis was 41 years (range: 38–48 years); and the melanoma diagnosis occurred following a median of 12 natalizumab doses (range: 1–77 doses). A history of mole or nevi was noted in four patients and a history of prior melanoma was noted in one patient. Completeness scores for reports were significantly lower for FAERS cases reported from the TOUCH program versus FAERS cases supplemented by TOUCH information (median score of 2 vs. 4 items out of 8‐possible items, P < 0.0007). Clinicians should monitor existing nevi and maintain suspicion for melanoma developing in natalizumab‐treated patients. The TOUCH Safety Surveillance Program, currently focused on progressive multifocal leukoencephalopathy, should be expanded to include information on other serious complications including malignancies, particularly if they are immunologic in nature.

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“…Case information for seven published cases was reviewed (Table 2) 2, 18, 19, 20, 21, 22, 23. Among the seven cases, six patients were female.…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Melanoma complicating treatment with natalizumab for multiple sclerosis: A report from the Southern Network on Adverse Reactions (SONAR)

et al. 2017

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Evolution of Nevi During Treatment With Natalizumab

Castela¹,

Lebrun-Frénay²,

Laffon³

et al. 2010

Arch Dermatol

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Altered CD4+/CD8+ T-Cell Ratios in Cerebrospinal Fluid of Natalizumab-Treated Patients With Multiple Sclerosis

Stüve¹,

Marra²,

Bar‐Or³

et al. 2006

Arch Neurol

260

182

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Background: Treatment with natalizumab, a monoclonal antibody against the adhesion molecule very late activation antigen 4, an ␣4␤ 1 integrin, was recently associated with the development of progressive multifocal leukoencephalopathy, a demyelinating disorder of the central nervous system caused by JC virus infection. Objective: To test the effect of natalizumab treatment on the CD4 ϩ /CD8 ϩ T-cell ratios in cerebrospinal fluid (CSF) and peripheral blood.

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A Randomized, Placebo-Controlled Trial of Natalizumab for Relapsing Multiple Sclerosis

Cited by 2,976 publications

References 30 publications

Melanoma complicating treatment with natalizumab for multiple sclerosis: A report from the Southern Network on Adverse Reactions (SONAR)

Melanoma complicating treatment with natalizumab for multiple sclerosis: A report from the Southern Network on Adverse Reactions (SONAR)

Evolution of Nevi During Treatment With Natalizumab

Altered CD4+/CD8+ T-Cell Ratios in Cerebrospinal Fluid of Natalizumab-Treated Patients With Multiple Sclerosis

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