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

Abstract

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.

Melanoma subsequent to natalizumab exposure: A report from the RADAR (Research on Adverse Drug events And Reports) program

“…To the Editor: Although natalizumab is approved for treating multiple sclerosis, 1 reports have raised concern about malignant melanoma (MM) after natalizumab exposure. 2,3 The aim of this study was to determine if an association was detectable for MM after natalizumab exposure in patients with multiple sclerosis.…”

“…2 Natalizumab-exposed patients had a younger median age at MM diagnosis compared with the general (nonenatalizumab-exposed) US population. 2 Mechanisms underlying the association for MM with natalizumab are incompletely understood; however, it seems that the drug's inhibitory effects on 4 -integrins might relate to MM evolution because melanoma cells expressing 4 1 have increased homotypic intercellular adhesion and decreased ability to invade the extracellular matrix. 3 Inhibition of integrins with natalizumab might increase invasive potential.…”

“…Of note, the full prescribing information for natalizumab does not refer to melanoma, 1 To the Editor: Hidradenitis suppurativa (HS) is a chronic relapsing inflammatory skin condition that results in painful nodules, abscesses, and sinus tracts typically in intertriginous body sites. 1 Topical and oral antibiotics are the first-line treatment for HS 2,3 ; however, there is concern regarding antibiotic resistance in target and nontarget bacteria, as well as regarding the growth of opportunistic pathogens. 4 Some clinical practice guidelines for HS recommend concomitant antimicrobial washes, including chlorhexidine, bleach baths, and benzoyl peroxide for reducing inflammation and antibacterial resistance rates.…”

“…4 Some clinical practice guidelines for HS recommend concomitant antimicrobial washes, including chlorhexidine, bleach baths, and benzoyl peroxide for reducing inflammation and antibacterial resistance rates. 2,3 Importantly, for acne, studies have found that combining benzoyl peroxide with standard antibiotics can significantly reduce the antibacterial resistance in those lesions. 5 In this study, we sought to examine the association between antibiotic resistance in HS lesions and antimicrobial washes.…”

Multiple Sclerosis Treatment and Melanoma Development

“…There are reports in the literature about the development of cutaneous melanoma following MS therapy with either natalizumab [6][7][8][9][10][11][12][13] or fingolimod [14][15][16][17][18][19] but the number of cases was low and did not reach any statistical significance. Therefore, melanoma occurrence in these patients could be merely a coincidence [20].…”