Background/Objectives: Bendamustine (BEN) combined with rituximab (RTX) remains a standard first-line therapy for transplant-ineligible patients with newly diagnosed mantle cell lymphoma (MCL). Meanwhile, novel targeted therapies such as Bruton tyrosine kinase inhibitors (BTKis) are increasingly used in the treatment of relapsed/refractory (R/R) MCL. We recently reported that a novel oral formulation of BEN exhibits comparable efficacy to the intravenous counterpart. In this study, we investigated the efficacy of oral BEN administered alone or in combination with the oral BCL-2 inhibitor Venetoclax (VEN) and/or the oral BTKi Acalabrutinib (ACAL), against two human MCL cell lines (Jeko-1 and Z-138) representative of the R/R disease subtype.Methods: We performed in vitro analyses using MTS viability and Annexin V/PI apoptosis assays. For the in vivo studies, all treatments were administered via oral gavage in xenograft mouse models. Therapeutic efficacy was evaluated by monitoring tumor growth and survival.Results: BEN induced significant cytotoxicity in both cell lines at low, clinically relevant concentrations. In contrast, VEN demonstrated limited efficacy as monotherapy, with Z-138 showing sensitivity only at high doses. However, combining BEN with VEN with or without ACAL, enhanced apoptosis and cytotoxicity, with more pronounced effects in Z-138. In vivo, oral BEN significantly reduced tumor growth and prolonged survival in both xenograft models. In the Z-138 model, the addition of VEN ± ACAL further improved survival outcomes.Conclusions: Our findings support the efficacy of oral BEN as both a monotherapy and as part of an all-oral treatment regimen for MCL. These results warrant further investigation into the clinical potential of oral BEN, particularly in combination with targeted agents.
背景/目的：苯达莫司汀（BEN）联合利妥昔单抗（RTX）仍是新诊断套细胞淋巴瘤（MCL）且不适合移植患者的标准一线治疗方案。与此同时，布鲁顿酪氨酸激酶抑制剂（BTKis）等新型靶向疗法越来越多地用于复发/难治性（R/R）MCL的治疗。我们近期报道了一种新型口服BEN制剂，其疗效与静脉制剂相当。本研究探讨了口服BEN单药或联合口服BCL-2抑制剂维奈克拉（VEN）和/或口服BTKi阿卡替尼（ACAL）对两种代表性R/R亚型人MCL细胞系（Jeko-1和Z-138）的疗效。方法：通过MTS细胞活力检测和膜联蛋白V/PI凋亡实验进行体外分析。在体内研究中，所有治疗均通过口服灌胃方式在异种移植小鼠模型中实施，通过监测肿瘤生长和生存期评估疗效。结果：BEN在低临床相关浓度下即可对两种细胞系产生显著细胞毒性。相比之下，VEN单药疗效有限，仅在高剂量时对Z-138细胞显示敏感性。然而，BEN联合VEN（无论是否联用ACAL）能增强细胞凋亡和细胞毒性，在Z-138细胞中效果更为显著。在体内实验中，口服BEN在两种异种移植模型中均显著抑制肿瘤生长并延长生存期。在Z-138模型中，联用VEN±ACAL可进一步改善生存结局。结论：本研究证实口服BEN作为单药或全口服方案组成部分对MCL具有治疗潜力，这些结果为深入探索口服BEN（特别是与靶向药物联用）的临床价值提供了依据。
肿瘤(癌症)患者之家