Deshpande Anagha, Munoz Javier
Mayo Clinic Alix School of Medicine, Scottsdale, AZ, USA.
Division of Hematology and Oncology, Mayo Clinic, Phoenix, AZ, USA.
Ther Clin Risk Manag. 2022 Jun 23;18:657-668. doi: 10.2147/TCRM.S338655. eCollection 2022.
In Waldenström macroglobulinemia (WM), a lymphoplasmacytic lymphoma characterized by monoclonal immunoglobulin M (IgM) gammopathy, aberrant Bruton tyrosine kinase (BTK) signaling has been identified as one mechanism of pathogenesis. For this reason, selective BTK inhibiting therapies have emerged as an attractive option for treatment within the therapeutic landscape also comprising chemotherapy, monoclonal antibodies, proteasome inhibitors, and B-cell lymphoma 2 (BCL2) inhibitors. The first BTK inhibiting therapy, ibrutinib, showed great efficacy in treating WM. However, response rates were dependent on whether patients had the mutation, a molecular aberration that may confer resistance to BTK inhibitors. Furthermore, ibrutinib's toxicities, most notably hypertension and atrial arrhythmia, led to dose reductions or discontinuation. The toxicity profile of ibrutinib can be attributed to the inhibition of additional kinases that are structurally related to BTK. Therefore, the next-generation highly selective zanubrutinib was developed to address the concerns regarding toxicity and tolerance related to ibrutinib therapy. Based on the results of the randomized, open-label Phase 3 ASPEN (NCT03053440) trial, the Food and Drug Administration (FDA) approved zanubrutinib for treating WM. This trial directly compared zanubrutinib to ibrutinib in patients with treatment-naïve or relapsed/refractory WM, and the results showed stronger responses with zanubrutinib. More importantly, patients responded strongly to zanubrutinib therapy regardless of mutation status. Additionally, zanubrutinib was associated with fewer grade 3 or higher toxicities and was generally better tolerated. Another Phase 1/2 study has been conducted with just zanubrutinib in WM showcasing high efficacy with few toxicities as well. Even though zanubrutinib has been the third and last BTK inhibitor to currently penetrate the market for B-cell lymphoproliferative malignancies, we highlight the emergence of zanubrutinib as a key player in the forefront of the therapeutic landscape in WM.
在华氏巨球蛋白血症（WM）中，一种以单克隆免疫球蛋白M（IgM）丙种球蛋白病为特征的淋巴浆细胞淋巴瘤，异常的布鲁顿酪氨酸激酶（BTK）信号传导已被确定为发病机制之一。因此，选择性BTK抑制疗法已成为治疗领域中一种有吸引力的选择，该治疗领域还包括化疗、单克隆抗体、蛋白酶体抑制剂和B细胞淋巴瘤2（BCL2）抑制剂。首个BTK抑制疗法伊布替尼在治疗WM方面显示出巨大疗效。然而，缓解率取决于患者是否有 突变，这是一种可能导致对BTK抑制剂耐药的分子异常。此外，伊布替尼的毒性，最显著的是高血压和房性心律失常，导致剂量减少或停药。伊布替尼的毒性特征可归因于对与BTK结构相关的其他激酶的抑制。因此，开发了下一代高选择性泽布替尼，以解决与伊布替尼治疗相关的毒性和耐受性问题。基于随机、开放标签的3期ASPEN（NCT03053440）试验结果，美国食品药品监督管理局（FDA）批准泽布替尼用于治疗WM。该试验将泽布替尼与伊布替尼直接对比，纳入初治或复发/难治性WM患者，结果显示泽布替尼的反应更强。更重要的是，无论 突变状态如何，患者对泽布替尼治疗反应强烈。此外，泽布替尼与3级或更高等级毒性的发生率较低相关，总体耐受性更好。另一项1/2期研究仅使用泽布替尼治疗WM，也显示出高疗效且毒性较小。尽管泽布替尼是目前进入B细胞淋巴增殖性恶性肿瘤市场的第三种也是最后一种BTK抑制剂，但我们强调泽布替尼已成为WM治疗领域前沿的关键药物。
