慢性淋巴细胞白血病（CLL）/小淋巴细胞淋巴瘤（SLL）是一类主要发生于中老年人群的成熟B细胞克隆性增殖性肿瘤，具有独特免疫表型。在2025年ASH大会LBA专场中，玛丽亚·斯克沃多夫斯卡-居里国家肿瘤研究所Wojciech Jurczak教授报告了BRUIN CLL-313研究的首次结果，该随机Ⅲ期试验比较了非共价BTK抑制剂匹妥布替尼与苯达莫司汀联合利妥昔单抗（BR）在初治CLL/SLL患者中的疗效与安全性。《肿瘤瞭望-血液时讯》现场特邀Wojciech Jurczak教授对研究背景、设计及临床意义进行解读，为临床实践提供前沿参考。
《肿瘤瞭望-血液时讯》：在本次ASH大会上，您报告了匹妥布替尼与苯达莫司汀联合利妥昔单抗（BR）治疗未治疗CLL/SLL患者的比较研究。可以请您详细介绍一下这项研究的背景和研究设计，以及为何选择将匹妥布替尼与BR进行对比？
Wojciech Jurczak教授：欢迎来到奥兰多2025 ASH年会。我很荣幸向各位介绍BRUIN CLL-313研究。这是一项针对初治CLL患者的随机对照试验，旨在比较口服BTK抑制剂匹妥布替尼与苯达莫司汀联合利妥昔单抗（BR方案）的疗效。入组患者均需符合iwCLL 2018标准的治疗指征。
在研究设计阶段，化学免疫治疗对包括高危患者在内的所有病例仍被视为合理选择。当时，靶向治疗主要以BTK抑制剂为基础，大多数接受治疗的患者采用无限期BTK抑制剂方案。虽然化学免疫治疗仍可作为备选方案，但如今临床实践已发生显著变化。
值得注意的是，尽管17p缺失患者未被纳入研究，但中心实验室分析显示约10%的患者存在TP53突变。这些患者被纳入研究方案，并在两治疗组间分布均衡。
Oncology Frontier-Hematology Frontier：At this ASH meeting, you reported on the study comparing pirtobrutinib with bendamustine plus rituximab (BR) in treatment-naïve CLL/SLL patients. Could you please elaborate on the background and design of this study, and why you chose to compare pirtobrutinib with BR?
Professor Wojciech Jurczak：Welcome to the 2025 ASH Annual Meeting in Orlando. It is my honor to present the BRUIN CLL-313 study. This is a randomized controlled trial evaluating the oral BTK inhibitor pirtobrutinib versus bendamustine plus rituximab (BR regimen) in treatment-naïve patients with chronic lymphocytic leukemia (CLL) who meet treatment criteria according to the iwCLL 2018 guidelines.
At the time of study design, chemoimmunotherapy was still considered a reasonable option for all patients, including those with high-risk features. Targeted therapy was then primarily based on BTK inhibitors, with the majority of treated patients receiving indefinite BTK inhibitor therapy. Although chemoimmunotherapy remained an alternative at that time, clinical practice has since evolved substantially.
Notably, while patients with 17p deletion were excluded from the study, central laboratory analysis revealed that approximately 10% of enrolled patients harbored TP53 mutations. These patients were included in the trial and were evenly distributed between the two treatment arms.
《肿瘤瞭望-血液时讯》：研究结果表明，匹妥布替尼显著改善了IRC评估的无进展生存期（PFS）和总体缓解率（ORR）。并且，匹妥布替尼在IGHV突变型和非突变型患者中均表现出一致的PFS获益，您认为这一发现对临床治疗有何重要意义？
Wojciech Jurczak教授：本研究的主要终点为独立评审委员会评估的无进展生存期（PFS）。苯达莫司汀联合利妥昔单抗（BR）组中位PFS为34个月，而匹妥布替尼组尚未达到。在两年随访分析中，匹妥布替尼组的PFS率为94%，BR组为70%，差异具有统计学意义和临床意义。两组的风险比为0.20，为同类比较中的最佳水平；相比之下，其他BTK抑制剂的风险比接近0.3至0.4。这表明，匹妥布替尼可将患者疾病进展或任何原因导致死亡的风险降低80%，具有显著的临床意义。
总体生存期（OS）中期分析尚未成熟，但已显示有利趋势。2年OS率在匹妥布替尼组为98%，BR组为94%。在此过程中，匹妥布替尼组报告3例死亡，BR组报告12例死亡。
Oncology Frontier-Hematology Frontier：The results show that pirtobrutinib significantly improved IRC-assessed progression-free survival (PFS) and overall response rate (ORR). Additionally, pirtobrutinib showed consistent PFS benefit in both IGHV-mutated and unmutated patients. What do you think is the clinical significance of this finding?
Professor Wojciech Jurczak：The primary endpoint of this study was progression-free survival (PFS) assessed by an independent review committee. The median PFS was 34 months in the bendamustine plus rituximab (BR) arm, while it was not reached in the pirtobrutinib arm. At the two-year follow-up analysis, the PFS rate was 94% in the pirtobrutinib arm compared with 70% in the BR arm, with the difference being statistically and clinically significant. The hazard ratio between the two arms was 0.20, representing the best level among similar comparisons; in contrast, other BTK inhibitors had hazard ratios close to 0.3–0.4. This indicates that pirtobrutinib reduced the risk of disease progression or death from any cause by 80%, demonstrating substantial clinical benefit.
The interim analysis of overall survival (OS) is still immature but shows a favorable trend. The two-year OS rate was 98% in the pirtobrutinib arm and 94% in the BR arm. During this period, there were 3 deaths reported in the pirtobrutinib arm and 12 deaths in the BR arm.
《肿瘤瞭望-血液时讯》：尽管目前OS数据尚不成熟，但您在研究中观察到有利匹妥布替尼的生存趋势。您如何看待匹妥布替尼在未治疗CLL/SLL患者中的潜力，特别是在可能仅接受一线治疗的老年患者中？
Wojciech Jurczak教授：本研究显示匹妥布替尼在PFS方面具有显著优势，并显示出潜在的OS获益，结合BRUIN CLL-314研究结果，有望推动匹妥布替尼获批用于初治慢性淋巴细胞白血病（CLL）患者。匹妥布替尼于2023年12月首次获FDA加速批准，用于既往接受过BTK抑制剂和BCL2抑制剂治疗的双重耐药患者；2025年12月3日，其适应症进一步扩展至所有经共价BTK抑制剂治疗后疾病进展的患者。若上述两项随机对照研究数据获得监管机构认可，匹妥布替尼有望成为初治CLL患者的治疗选择。
从临床实践角度，BTK抑制剂已不再是靶向治疗的唯一核心选项。当前治疗策略已扩展至固定疗程联合方案，包括维奈克拉联合抗CD20单抗，或BTK抑制剂联合BCL2抑制剂。对于年轻且身体状态良好的患者，尤其是希望在治疗结束后恢复正常生活质量的患者，优先推荐固定疗程方案。而对于老年或伴有共病的体弱患者，治疗决策需综合考虑其功能状态。此类患者日常活动受限，每次就医可能增加感染风险甚至危及生命，因此每日单药口服、便于基层管理的方案可能更具实用性和安全性。
Oncology Frontier-Hematology Frontier：Although the overall survival (OS) data is not yet fully mature, you observed a trend favoring pirtobrutinib in survival. How do you assess the potential of pirtobrutinib in treatment-naïve CLL/SLL patients, particularly in elderly patients who may only receive first-line treatment?
Professor Wojciech Jurczak：The present study demonstrates that pirtobrutinib confers a significant advantage in progression-free survival (PFS) and suggests potential overall survival (OS) benefit. Combined with results from the BRUIN CLL-314 study, these findings are expected to support regulatory submission for approval of pirtobrutinib in treatment-naïve patients with chronic lymphocytic leukemia (CLL).
Pirtobrutinib initially received accelerated FDA approval in December 2023 for patients previously treated with both a BTK inhibitor and a BCL2 inhibitor (double-exposed population). On December 3, 2025, the indication was expanded to include all patients whose disease progressed after treatment with a covalent BTK inhibitor. If the data from the aforementioned randomized controlled trials are accepted by regulatory authorities, pirtobrutinib may become an additional treatment option for treatment-naïve CLL patients.
From a clinical practice perspective, BTK inhibitors are no longer the sole cornerstone of targeted therapy. Current strategies have broadened to include fixed-duration combination regimens, such as venetoclax plus an anti-CD20 antibody, or a BTK inhibitor combined with a BCL2 inhibitor. For younger patients with good performance status—particularly those seeking to regain near-normal quality of life post-treatment—fixed-duration regimens are preferentially recommended to enable a treatment-free interval.
In contrast, for elderly or frail patients with comorbidities, treatment decisions must account for functional status. These patients often have limited daily activity, and frequent medical visits may heighten infection risk or pose life-threatening challenges. Consequently, a once-daily oral monotherapy that facilitates community-based management may offer greater practicality and safety.
《肿瘤瞭望-血液时讯》：研究还显示，匹妥布替尼具有较低的治疗相关不良事件（TEAE）发生率，尤其是与BR相比。您能否进一步探讨匹妥布替尼的安全性和耐受性，特别是对于年长患者或有合并症的患者？
Wojciech Jurczak教授：匹妥布替尼表现出良好的耐受性。在安全性分析中，患者平均接受匹妥布替尼治疗33个月，而固定苯达莫司汀联合利妥昔单抗（BR）方案仅为6个月。即使在原始数据中，匹妥布替尼的不良事件发生率亦较低，尤其是CTCAE 3级及以上的不良事件。时间校正分析显示，匹妥布替尼所有不良事件的发生率均低于BR方案，出血倾向虽略高，但大多数为轻度，仅观察到一例3级出血。在BTK抑制剂特别关注的不良事件中，房颤及房扑的发生率维持在低水平，研究中20名75岁以上患者仅有一例发生房颤。因此，匹妥布替尼可被视为安全性良好的治疗药物。
需要指出的是，接受长期治疗的患者可能存在免疫功能受损的情况。基于经验，一旦患者出现感染，应考虑暂停匹妥布替尼及所有BTK抑制剂，以避免药物相互作用，同时使全科医生能够根据当地标准对感染进行规范治疗。若在使用BTK抑制剂期间同时给予某些抗生素（不包括抗真菌药物），可能导致BTK抑制剂血药浓度升高，从而影响免疫功能并潜在干扰治疗效果。上述内容为在随机化研究方案基础上的补充说明，其中最后部分为个人经验性建议，不应作为普遍引用的指导。
Oncology Frontier-Hematology Frontier：The study also shows that pirtobrutinib has a lower incidence of treatment-emergent adverse events (TEAEs), especially compared to BR. Could you further discuss the safety and tolerability of pirtobrutinib, particularly for elderly patients or those with comorbidities?
Professor Wojciech Jurczak：Pirtobrutinib demonstrates a favorable tolerability profile. In the safety analysis, patients received pirtobrutinib for an average of 33 months, compared with only 6 months for the fixed-duration bendamustine plus rituximab (BR) regimen. Even in the raw data, the incidence of adverse events with pirtobrutinib was lower, particularly for CTCAE grade 3 or higher events. Time-adjusted analyses indicated that the incidence of all adverse events was lower with pirtobrutinib than with BR, although bleeding tendency was slightly higher; most events were mild, with only a single grade 3 hemorrhage observed. Among adverse events of special interest for BTK inhibitors, the incidence of atrial fibrillation and flutter remained low, with only one case occurring among 20 patients over 75 years of age. Therefore, pirtobrutinib can be considered a treatment with a favorable safety profile.
It should be noted that patients receiving long-term therapy may experience impaired immune function. Based on clinical experience, if a patient develops an infection, it is advisable to temporarily suspend pirtobrutinib and all BTK inhibitors to avoid drug interactions and allow general practitioners to manage the infection according to local standards. Concomitant use of certain antibiotics (excluding antifungals) with BTK inhibitors may increase BTK inhibitor blood concentrations, potentially impairing immune function and affecting treatment outcomes. The above statements are supplementary to data obtained from randomized trial protocols; the final section reflects personal clinical experience and should not be considered as broadly generalizable guidance.
专家简介
Wojciech Jurczak 教授
玛丽亚·斯克沃多夫斯卡-居里国家肿瘤研究所
医学博士，血液学顾问及教授
玛丽亚·斯克沃多夫斯卡-居里国家肿瘤研究所（Maria Skłodowska-Curie National Research Institute of Oncology）科室主任