Pharmacy Times：BCL-2 抑制剂联合 BTK 抑制剂治疗：利沙托克拉能否填补高危慢性淋巴细胞白血病的治疗空白？

作者：Alexandra Gerlach, Content Producer; 内容审核：Kirsty Mackay

Author(s) Alexandra Gerlach, Content Producer; Fact checked by: Kirsty Mackay

核心要点 | Key Takeaways

• BCL-2 抑制剂可通过非 B 细胞受体通路诱导肿瘤细胞凋亡，与 BTK 抑制剂形成机制互补，为在患者出现耐药前优化 BTK 抑制剂疗效不佳的现状提供了理论依据。
• 利沙托克拉在复发 / 难治性、BTK 抑制剂耐药的慢性淋巴细胞白血病（CLL）患者（含 17p 缺失 / TP53 突变人群）中展现出显著临床疗效；其与阿可替尼联用的早期数据显示总缓解率超 97%。
• GLORA 研究（试验编号：NCT06104566）纳入成人慢性淋巴细胞白血病 / 小淋巴细胞淋巴瘤（CLL/SLL）患者，既往最多接受 3 线治疗、使用 BTK 抑制剂单药治疗满 12 个月及以上，疾病未达完全缓解且无进展；受试者需携带高危基因特征，或存在微小残留病且淋巴结长径≥2.5 厘米。
• 研究计划入组约 440 例患者，随机分为两组：试验组使用利沙托克拉联合临床医生选择的 BTK 抑制剂（阿可替尼、泽布替尼或伊布替尼），对照组继续用 BTK 抑制剂单药；利沙托克拉采用 5 天剂量爬坡方案，最终日剂量增至 400 毫克。
• 本研究在全球 18 个国家的126 家研究中心开展。主要研究终点为独立评审委员会依据 2018 年国际慢性淋巴细胞白血病工作组标准评估的无进展生存期（PFS），总生存期（OS）为关键次要终点；其余终点包括微小残留病转阴率（MRD negativity）、客观缓解率（ORR）、缓解持续时间（DOR）及安全性。
• BCL-2 inhibition complements BTK blockade by inducing apoptosis via BCR-independent pathways, providing a mechanistic rationale to deepen suboptimal BTKi responses before resistance emerges.
• Lisaftoclax has shown clinically meaningful activity in relapsed/refractory and BTKi-refractory CLL, including del(17p)/TP53-mutated disease, and early combination data with acalabrutinib demonstrated >97% response rates.
• GLORA (NCT06104566) enrolls adults with CLL/SLL on BTKi for 12 months or more (up to 3 prior lines) with neither CR nor progression, requiring high-risk genetics and/or MRD with nodes of 2.5 cm or larger.
• Approximately 440 patients are randomly assigned to lisaftoclax plus physician’s-choice BTKi (acalabrutinib, zanubrutinib, or ibrutinib) vs continued BTKi monotherapy, with a 5-day ramp-up to 400 mg daily.
• The primary end point is IRC-assessed PFS per iwCLL 2018, with overall survival a key secondary end point; additional end points include MRD negativity, ORR, DOR, and safety across 126 sites in 18 countries.

在 2026 年美国临床肿瘤学会（ASCO）年会上，GLORA 研究团队公布相关研究数据：对于高危慢性淋巴细胞白血病 / 小淋巴细胞淋巴瘤患者，在 BTK 抑制剂治疗基础上联用利沙托克拉，可进一步提升缓解深度并延缓疾病进展。

对于接受布鲁顿酪氨酸激酶抑制剂（BTK 抑制剂）治疗一年及以上、仍未实现完全缓解的慢性淋巴细胞白血病 / 小淋巴细胞淋巴瘤患者，后续治疗该如何开展？这类患者体内仍有肿瘤残留，同时面临 BTK 抑制剂耐药风险，疾病早期进展风险较高。这也意味着，临床亟需全新治疗方案，在耐药发生前进一步提升治疗效果。

At ASCO 2026, GLORA investigators report on lisaftoclax as an addition to BTK inhibitors to deepen responses and delay progression in high-risk CLL/SLL.

For patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) who have been on Bruton tyrosine kinase inhibitor (BTKi) therapy for a year or more without achieving a complete response, what comes next? Residual disease and the potential risk of BTKi resistance leave this population at meaningful risk for early progression, underscoring the critical need for strategies that can deepen responses before resistance takes hold.

BCL-2 抑制剂介绍 | Introducing BCL-2 Inhibitors

BTK 抑制剂通过阻断 B 细胞受体（BCR）信号通路发挥作用，但无法全面切断维持慢性淋巴细胞白血病肿瘤细胞存活的所有通路。而 BCL-2 抑制剂作用机制不同，可通过非 B 细胞受体通路调控肿瘤细胞凋亡进程。两种药物联合使用，正是本次临床试验开展的核心理论基础。

利沙托克拉（APG-2575，亚盛医药）是一款高选择性口服 BCL-2 抑制剂，半衰期仅 4~6 小时，支持每日单次给药。目前该药已在中国获批用于慢性淋巴细胞白血病的二线治疗。

临床数据显示，利沙托克拉治疗复发 / 难治性慢性淋巴细胞白血病的总缓解率为 67%，针对 BTK 抑制剂耐药患者的总缓解率达 62.5%，其中涵盖 17p 缺失、TP53 突变等高危患者人群。利沙托克拉联合阿可替尼（商品名：Calquence，阿斯利康）的研究数据显示，联合方案总缓解率超过 97%，且整体耐受性良好，初步证实该联合疗法疗效确切、安全性可控。

BTK inhibitors work by blocking B-cell receptor (BCR) signaling but they don’t address all pathways that drive CLL survival. BCL-2 inhibitors take a different route, targeting the apoptotic machinery of cancer cells through a BCR-independent mechanism. The combination of these 2 approaches forms the scientific rationale behind this trial.

Lisaftoclax (APG-2575; Ascentage Pharma) is a selective, oral BCL-2 inhibitor with a short half-life of 4 to 6 hours, allowing for once-daily dosing. Already approved in China as a second-line CLL therapy, lisaftoclax has demonstrated overall response rates of 67% in relapsed/refractory CLL and 62.5% in BTKi-refractory disease—including patients with high-risk features such as del(17p) and TP53 mutations. When combined with acalabrutinib (Calquence; AstraZeneca Pharmaceuticals LP), response rates exceeded 97%, and the combination demonstrated a favorable tolerability profile, providing early evidence that the combination is both active and manageable.

GLORA 临床试验详情 | The GLORA Trial

GLORA 是一项全球多中心、开放标签、随机对照 III 期注册临床试验（试验编号：NCT06104566）。研究纳入慢性淋巴细胞白血病 / 小淋巴细胞淋巴瘤成人患者，受试者既往最多经历 3 线治疗，且使用 BTK 抑制剂单药治疗至少 12 个月，疾病既未达到完全缓解，也未出现进展。患者处于部分缓解的平台期，正是在耐药出现前优化治疗、提升疗效的最佳窗口期。

入组患者需至少具备一项高危特征，包括 17p 缺失 / TP53 突变、IGHV无突变、存在 5 处及以上异常的复杂核型，或是检出微小残留病且淋巴结长径≥2.5 厘米。既往使用过 BCL-2 抑制剂、发生里希特转化的患者不予入组。

The global, multicenter, open-label, randomized phase 3 registrational GLORA study (NCT06104566) is investigating lisaftoclax as a monotherapy for adults with CLL/SLL who, after at least 12 months of BTKi monotherapy across up to 3 lines of therapy, have neither a complete response nor progressive disease. This partial response plateau represents a window of opportunity to deepen responses before resistance takes hold.

Eligible patients must also have at least 1 high-risk feature, such as del(17p)/TP53 mutation, unmutated IGHV, or complex karyotype with 5 or more abnormalities, or have measurable residual disease with lymph nodes of 2.5 cm or larger. Patients with prior BCL-2 inhibitor exposure or Richter transformation are excluded.

试验设计 | Study Design

研究计划入组约 440 例患者，进行随机分组：

1. 试验组：利沙托克拉联合临床医生选择的 BTK 抑制剂（阿可替尼、泽布替尼（或伊布替尼）；
2. 对照组：继续用 BTK 抑制剂单药。

试验组患者服用利沙托克拉时，先进行 5天剂量爬坡，最终维持每日 400 毫克的标准剂量；以 28 天为一个治疗周期持续用药，直至疾病进展或出现不可耐受的毒性。研究随机分层依据为患者是否存在 17p 缺失 / TP53 突变。

研究终点：主要终点为独立评审委员会按照 2018 年国际慢性淋巴细胞白血病工作组评估标准判定的无进展生存期（PFS）；总生存期（OS）为关键次要终点。其他评估指标包括研究者评估的无进展生存期（PFS）、客观缓解率（ORR）、缓解持续时间（DOR）、微小残留病转阴率（MRD negativity）以及整体安全性。

Approximately 440 patients will be randomized to receive either lisaftoclax plus their physician’s choice of BTKi (acalabrutinib, zanubrutinib [Brukinsa; BeiGene], or ibrutinib [Imbruvica; Janssen Biotech]) or to continue BTKi monotherapy. Patients in the investigational arm undergo a 5-day oral lisaftoclax ramp-up to 400 mg once daily, then continue in 28-day cycles until progression or unacceptable toxicity. Randomization is stratified by del(17p)/TP53 mutation status.

The primary end point is progression-free survival (PFS) by independent review committee per 2018 International Workshop on Chronic Lymphocytic Leukemia criteria, with overall survival as the key secondary end point. Additional end points include investigator-assessed PFS, overall response rate, duration of response, minimal residual disease negativity, and safety.

研究展望 | Looking Ahead

目前该试验已在全球 18 个国家的 126 家研究中心积极开展患者入组工作。若利沙托克拉联合 BTK 抑制剂能够有效提升此类高危患者的治疗应答、延长无进展生存期，该方案有望成为这类患者全新的联合治疗选择。

Enrollment is actively ongoing across 126 sites in 18 countries. If lisaftoclax plus BTKi succeeds in deepening responses and prolonging PFS in this high-risk population, it could establish a new combination strategy for patients with minimal

参考文献 | REFERENCE

Davids MS, Ailawadhi S, Musuraca G, et al. A global multicenter, open-label, randomized, phase 3 registrational study of lisaftoclax (APG-2575) in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): GLORA trial in progress. Presented at: 2026 ASCO Annual Meeting; May 29-June 2, 2026; Chicago, IL. Abstract TPS7101.