Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
UO Ematologia, Università degli Studi di Pisa, Pisa, Italy.
Curr Treat Options Oncol. 2020 Mar 13;21(4):24. doi: 10.1007/s11864-020-0715-5.
Treatment landscape of chronic lymphocytic leukemia (CLL) has changed since 2014 after the introduction of inhibitors of B-cell receptor signaling pathway (ibrutinib, acalabrutinib, idelalisib and duvelisib) and the inhibitor of the anti-apoptotic protein BCL-2 (venetoclax). In 2019, novel agents were upgraded from being a "great treatment option" to the "preferred choice" for all lines of treatment after number of randomized clinical trials proved their superiority compared to conventional chemoimmunotherapy (CIT) regimens. A growing number of next-generation molecules are in clinical trials with a promise of improved efficacy and less toxicity. This includes agents with expected better safety profile (zanubrutinib, umbralisib, etc.) or more importantly with a potential to overcome the resistance mechanism to early generation agents (ARQ-531, LOXO-305, or vecabrutinib). Early intervention has once again become an active topic of research and, if proven to provide an overall survival benefit, will eliminate the "watch and wait" strategy for asymptomatic CLL patients. Until then, treatment should only be offered to patients who meet the standard treatment indication in standard practice. With our upgraded therapeutic toolbox, there are and will be many unanswered questions. CLL field will need to define the optimal treatment sequence and most effective combinations with a goal of having a time-limited and chemotherapy-free regimen that provides longest remissions and potentially cure. Cellular immunotherapy with chimeric antigen receptor T-cell (CAR-T) may become available for high-risk CLL along with allogeneic stem cell transplant (allo-SCT). Financial toxicity of novel agents especially when used in combination will need to be an important aspect of research in coming years to avoid unnecessary overtreatment of patients. As current prognostic models (CLL-IPI, etc.) were developed and validated in the CIT era, there is ongoing effort to develop new models using clinical and molecular characteristics to accurately define high-risk CLL in the era of novel agents. We all need to keep in mind that access to the novel agents is currently limited to certain developed countries and every effort should be made to make sure patients around the world also benefit from these outstanding drugs.
自 2014 年以来，随着 B 细胞受体信号通路抑制剂（依鲁替尼、阿卡替尼、idelalisib 和 duvelisib）和抗凋亡蛋白 BCL-2 抑制剂（venetoclax）的引入，慢性淋巴细胞白血病（CLL）的治疗格局发生了变化。2019 年，多项随机临床试验证明，新型药物在治疗所有阶段均优于传统化疗免疫疗法（CIT）方案，从而从“最佳治疗选择”升级为“首选”。越来越多的下一代分子正在临床试验中，有望提高疗效和降低毒性。这包括具有预期更好安全性的药物（zanubrutinib、umbralisib 等），或者更重要的是，具有克服早期药物耐药机制的潜力（ARQ-531、LOXO-305 或 vecabrutinib）。早期干预再次成为研究的热门话题，如果证明能提供总体生存获益，将消除无症状 CLL 患者的“观察等待”策略。在此之前，只有符合标准治疗适应证的患者才应接受治疗。随着我们升级的治疗工具包，仍有许多未解决的问题。CLL 领域需要确定最佳治疗顺序和最有效的组合，以实现有限时间和无化疗的方案，提供最长的缓解和潜在治愈。嵌合抗原受体 T 细胞（CAR-T）的细胞免疫疗法可能可用于高危 CLL 以及同种异体干细胞移植（allo-SCT）。新型药物的财务毒性，尤其是在联合使用时，需要成为未来几年研究的一个重要方面，以避免对患者进行不必要的过度治疗。由于当前的预后模型（CLL-IPI 等）是在 CIT 时代开发和验证的，因此正在努力使用临床和分子特征开发新的模型，以在新型药物时代准确定义高危 CLL。我们都需要记住，新型药物目前仅限于某些发达国家，应尽一切努力确保全球的患者也能从这些优秀药物中受益。
