ESPE Abstracts

Introduction: Metreleptin is a leptin replacement therapy used as an adjunct to diet to treat the metabolic complications of leptin deficiency in lipodystrophy, a rare disease characterised by loss of adipose tissue. Previously, identification of T-cell lymphomas in three metreleptin-treated patients with acquired generalised lipodystrophy (AGL) led to concerns of a potential link between metreleptin and lymphoma development.

Methods: To further investigate a relationship between metreleptin and lymphoma development, we performed a real-world pharmacovigilance assessment and literature review to identify lymphoma events in patients with lipodystrophy and congenital leptin deficiency (CLD) who had previously received or were receiving metreleptin (metreleptin-treated), or who had never received metreleptin (metreleptin-naïve) at the time of lymphoma diagnosis. Cases were identified by searching PubMed, Embase, and the Cochrane Library (from database inception up to 31 May 2024) and through analysis of 11 years post-marketing data (up to 31 May 2024) from the global safety database (GSD) of the marketing authorisation holder for metreleptin.

Results: The final analysis set consisted of 16 lymphoma events identified in 15 patients (retrieved from 10 published articles and one case report from the GSD). Eleven lymphoma events occurred in 11 metreleptin-naïve patients; these comprised five T-cell lymphomas (five AGL cases), three B-cell lymphomas (two familial partial lipodystrophy cases and one AGL case), and three Hodgkin’s lymphomas (each reported in single cases of congenital generalised lipodystrophy, juvenile-onset dermatomyositis-associated lipodystrophy, and CLD). Five lymphoma events occurred in four metreleptin-treated patients, three of whom (all with AGL and T-cell lymphomas) were identified in clinical studies and previously published. The remaining metreleptin-treated patient (identified from the GSD) had progeroid-associated lipodystrophy and developed two lymphomas (one B-cell and one central nervous system lymphoma) following solid organ transplant while on systemic immunosuppressant medications. Notably, all eight T-cell lymphoma events occurred in patients with AGL (n = 8). Underlying autoimmune and/or inflammatory disorders were commonly reported in the cases identified.

Discussion: While a contributory role for metreleptin in lymphoma development in patients with lipodystrophy cannot be fully excluded, our analysis suggests that lymphoma development may be associated with the underlying pathophysiology of lipodystrophy rather than the pharmacological actions of metreleptin. The observed association between AGL and T-cell lymphomas may suggest that, in some cases, the presence of an immunoproliferative disorder of T-cells could contribute to syndromes involving autoimmune processes, including AGL. The potential role of autoimmune processes in the aetiology of acquired forms of lipodystrophy requires further investigation.