Tomkins Oliver, D'Sa Shirley
UCLH Centre for Waldenström's Macroglobulinaemia and Related Conditions, Department of Haematology, University College London Hospitals NHS Foundation Trust, London, United Kingdom.
Front Oncol. 2024 Nov 4;14:1490202. doi: 10.3389/fonc.2024.1490202. eCollection 2024.
Lymphoplasmacytic lymphoma (LPL) is a relatively rare form of indolent B-cell non-Hodgkin's lymphoma, termed Waldenström's macroglobulinaemia (WM) in the presence of an IgM paraprotein. Although traditionally treated with combination chemoimmunotherapy, the management is evolving in the era of targeted molecular therapies including Bruton's tyrosine kinase inhibitors (BTKi). However, intolerance and refractoriness to BTKi mean newer agents are required, and the prognosis of so-called quadruple-refractory patients is poor. BCL2 is an anti-apoptotic, pro-survival protein that promotes lymphoma cell survival. Inhibition of BCL2 using first-in-class agent venetoclax has already altered the treatment paradigm in other conditions, including chronic lymphocytic leukaemia (CLL). inhibition of BCL2 has been shown to lead to apoptosis of LPL/WM cells. Five studies have published results on the use of BCL2 inhibitors in WM to date, including oblimersen sodium, venetoclax, and sonrotoclax. Fixed-duration venetoclax resulted in high response rates, but many patients relapsed following the completion of therapy. The combination of venetoclax with ibrutinib resulted in higher and relatively deep response rates, but unexpected deaths due to ventricular events mean this combination cannot be explored. Two pivotal trials are currently evaluating the use of fixed-duration venetoclax, either in combination with rituximab or pirtobrutinib, whereas another multi-arm study is studying the use of continuous sonrotoclax monotherapy for R/R WM or in fixed-duration combination with Zanubrutinib for treatment-naïve patients. The potential role of BCL2 inhibitors in WM/LPL remains under study, with many hopeful that they may provide an additional chemotherapy-free oral alternative for patients requiring treatment. In an indolent condition with existing effective treatment regimens, including CIT and cBTKi, cost-effectiveness and toxicity profile will be key, although an additional treatment modality for quadruple-refractory patients with limited treatment options is urgently required.
淋巴浆细胞淋巴瘤（LPL）是一种相对罕见的惰性B细胞非霍奇金淋巴瘤，在存在IgM副蛋白的情况下被称为华氏巨球蛋白血症（WM）。尽管传统上采用联合化学免疫疗法进行治疗，但在包括布鲁顿酪氨酸激酶抑制剂（BTKi）在内的靶向分子疗法时代，治疗方法正在不断发展。然而，对BTKi的不耐受和难治性意味着需要更新的药物，而所谓的四重难治性患者的预后很差。BCL2是一种抗凋亡、促生存蛋白，可促进淋巴瘤细胞存活。使用一流药物维奈克拉抑制BCL2已经改变了包括慢性淋巴细胞白血病（CLL）在内的其他疾病的治疗模式。已证明抑制BCL2可导致LPL/WM细胞凋亡。迄今为止，已有五项研究发表了关于在WM中使用BCL2抑制剂的结果，包括奥布利森钠、维奈克拉和索罗托克拉。固定疗程的维奈克拉导致了较高的缓解率，但许多患者在治疗结束后复发。维奈克拉与伊布替尼联合使用导致了更高且相对较深的缓解率，但由于心室事件导致的意外死亡意味着这种联合方案无法进行探索。目前有两项关键试验正在评估固定疗程的维奈克拉的使用情况，要么与利妥昔单抗联合使用，要么与pirtobrutinib联合使用，而另一项多组研究正在研究连续使用索罗托克拉单药治疗复发/难治性WM，或与泽布替尼固定疗程联合使用治疗初治患者。BCL2抑制剂在WM/LPL中的潜在作用仍在研究中，许多人希望它们可能为需要治疗的患者提供另一种无需化疗的口服选择。在一种已有包括CIT和cBTKi在内的有效治疗方案的惰性疾病中，成本效益和毒性特征将是关键，尽管迫切需要为治疗选择有限的四重难治性患者提供额外的治疗方式。
