Sabol Rachel A, Noxon Virginia, Sartor Oliver, Berger Joseph R, Qureshi Zaina, Raisch Dennis W, Norris LeAnn B, Yarnold Paul R, Georgantopoulos Peter, Hrushesky William J, Bobolts Laura, Ray Paul, Lebby Akida, Kane Robert C, Bennett Charles L
Tulane University School of Medicine, New Orleans, Louisiana.
The Southern Network on Adverse Reactions (SONAR) program, University of South Carolina College of Pharmacy, Columbia, South Carolina.
Cancer Med. 2017 Jul;6(7):1541-1551. doi: 10.1002/cam4.1098. Epub 2017 Jun 20.
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.
一名患有多发性硬化症的43岁女性患上了尿道黑色素瘤。唯一可能的风险因素是使用那他珠单抗治疗，那他珠单抗是一种针对α4整合素的人源化单克隆抗体。为了研究风险-暴露关系，我们回顾了该病例、所有其他已发表的病例以及向监管机构报告的与那他珠单抗相关的黑色素瘤病例。数据来源包括美国食品药品监督管理局（FDA）的不良事件报告系统（FAERS）（2004 - 2014年）、一份FDA咨询委员会会议报告以及同行评审的出版物。在美国，制造商维持着一项FDA规定的那他珠单抗治疗患者的泰萨比里安全性监测计划（泰萨比里健康统一成果承诺（TOUCH）的一部分）。我们对FAERS中那他珠单抗相关黑色素瘤病例的报告完整性进行了统计学比较，其中一部分病例的信息完全来自TOUCH计划，另一部分病例的FAERS信息由TOUCH计划信息补充。FAERS包括137例多发性硬化症患者中与那他珠单抗相关的黑色素瘤报告。黑色素瘤诊断时的中位年龄为45岁（范围：21 - 74岁）。16%的患者原有痣出现变化，22%有皮肤痣病史，34%在开始使用那他珠单抗后2年内确诊，74%接受了初次手术治疗。在文献中报道的7例接受那他珠单抗治疗且经活检确诊为黑色素瘤的多发性硬化症患者中，诊断时的中位年龄为41岁（范围：38 - 48岁）；黑色素瘤诊断发生在使用那他珠单抗的中位剂量为12剂之后（范围：1 - 77剂）。4例患者有痣或色素痣病史，1例患者有既往黑色素瘤病史。与由TOUCH信息补充的FAERS病例相比，TOUCH计划报告的FAERS病例的报告完整性得分显著更低（8项可能项目中的中位数得分分别为2项和4项，P < 0.0007）。临床医生应监测现有痣，并对接受那他珠单抗治疗的患者发生黑色素瘤保持怀疑。目前专注于进行性多灶性白质脑病的TOUCH安全性监测计划应扩大，以纳入关于其他严重并发症（包括恶性肿瘤，特别是如果它们本质上是免疫性的）的信息。
