Brown Rebecca J, Araujo-Vilar David, Walkovich Kelly J, Barbarosie Alexandru, Magee David A, Akinci Baris, Oral Elif A
Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States.
UETeM-Molecular Pathology of Rare Diseases Group, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), School of Medicine and Dentistry, University of Santiago de Compostela, Santiago de Compostela, Spain.
Front Endocrinol (Lausanne). 2025 May 21;16:1582715. doi: 10.3389/fendo.2025.1582715. eCollection 2025.
Metreleptin is a form of leptin replacement therapy used with diet and lifestyle modifications to treat the metabolic complications of leptin deficiency in lipodystrophy, a rare disease characterized by adipose tissue deficiency. Previously, identification of T-cell lymphomas in three metreleptin-treated patients with acquired generalized lipodystrophy (AGL) suggested a possible relationship between metreleptin and lymphoma development. To further investigate this, we performed a real-world pharmacovigilance assessment and literature review to identify lymphomas in patients with lipodystrophy and congenital leptin deficiency (CLD) who were either metreleptin-naïve, or who had previously received/were receiving metreleptin at the time of lymphoma diagnosis.
Cases were identified from PubMed, Embase and the Cochrane Library (from database inception through to November 22, 2024), and through review of 11 years post-marketing data from the global safety database (GSD) of the marketing authorization holder for metreleptin.
The final analysis set comprised 17 lymphomas in 16 patients reported in 11 published articles and one GSD case report. Twelve lymphomas were recorded in 12 metreleptin-naïve patients - these comprised six T-cell lymphomas (one each in six patients with AGL), three B-cell lymphomas (in two patients with familial partial lipodystrophy and one patient with AGL), and three Hodgkin lymphomas (separately reported in one patient each with generalized lipodystrophy, juvenile-onset dermatomyositis-associated lipodystrophy, and CLD). Five lymphomas were identified in four metreleptin-treated patients, three of whom (all with AGL and T-cell lymphomas) were reported in previously published studies. The remaining metreleptin-treated patient (from the GSD) had generalized lipodystrophy-associated atypical progeroid syndrome and developed a B-cell lymphoma and brain lymphoma following solid organ transplantation and immunosuppressant therapy. All nine T-cell lymphomas occurred in patients with AGL, and additional autoimmune and/or inflammatory disorders were commonly reported in these patients.
While a contributory role for metreleptin in lymphoma development in patients with lipodystrophy cannot be excluded, our analysis suggests that lymphoma development may be associated with underlying pathophysiology that also leads to lipodystrophy rather than the pharmacological actions of metreleptin. Our findings support the view that, in some instances, immunoproliferative disorders of T-cells may contribute to syndromes involving autoimmune processes, including AGL.
美曲普明是一种瘦素替代疗法，与饮食和生活方式改变相结合，用于治疗脂肪营养不良（一种以脂肪组织缺乏为特征的罕见疾病）中瘦素缺乏的代谢并发症。此前，在三名接受美曲普明治疗的获得性全身性脂肪营养不良（AGL）患者中发现了T细胞淋巴瘤，这表明美曲普明与淋巴瘤发展之间可能存在关联。为进一步研究这一问题，我们进行了一项真实世界的药物警戒评估和文献综述，以确定脂肪营养不良和先天性瘦素缺乏（CLD）患者中的淋巴瘤，这些患者要么未使用过美曲普明，要么在淋巴瘤诊断时之前接受过/正在接受美曲普明治疗。
从PubMed、Embase和Cochrane图书馆（从数据库创建到2024年11月22日）以及通过审查美曲普明上市许可持有人全球安全数据库（GSD）11年的上市后数据来确定病例。
最终分析集包括11篇已发表文章和1篇GSD病例报告中报道的16例患者的17例淋巴瘤。12例未使用过美曲普明的患者记录了12例淋巴瘤——其中包括6例T细胞淋巴瘤（6例AGL患者各1例）、3例B细胞淋巴瘤（2例家族性部分脂肪营养不良患者和1例AGL患者各1例）以及3例霍奇金淋巴瘤（分别在1例全身性脂肪营养不良、青少年型皮肌炎相关脂肪营养不良和CLD患者中报道）。在4例接受美曲普明治疗的患者中发现了5例淋巴瘤，其中3例（均为AGL和T细胞淋巴瘤）在先前发表的研究中已有报道。其余接受美曲普明治疗的患者（来自GSD）患有全身性脂肪营养不良相关的非典型早衰综合征，在实体器官移植和免疫抑制治疗后发生了B细胞淋巴瘤和脑淋巴瘤。所有9例T细胞淋巴瘤均发生在AGL患者中，这些患者通常还伴有其他自身免疫和/或炎症性疾病。
虽然不能排除美曲普明在脂肪营养不良患者淋巴瘤发展中起作用，但我们的分析表明，淋巴瘤的发展可能与导致脂肪营养不良的潜在病理生理学有关，而非美曲普明的药理作用。我们的研究结果支持这样一种观点，即在某些情况下，T细胞的免疫增殖性疾病可能导致包括AGL在内的涉及自身免疫过程的综合征。
