靶向治疗的广泛应用显著改善了慢性淋巴细胞白血病（CLL）患者的长期预后，但“固定疗程”与“持续治疗”何者更优，始终缺乏直接比较的循证证据。在2025年ASH年会的全体科学大会上，德国科隆大学附属医院Othman Al-Sawaf教授报告了国际随机Ⅲ期CLL17研究的中期分析结果，首次以前瞻性方式比较了固定疗程治疗与持续BTK抑制治疗在初治CLL患者中的疗效，为CLL治疗策略优化提供了重要依据。《肿瘤瞭望-血液时讯》现场特邀Othman Al-Sawaf教授对该研究进行深入解读。
《肿瘤瞭望-血液时讯》：您在ASH上报告了关于CLL17试验的结果，比较了固定疗程治疗与持续靶向治疗在未经治疗的慢性淋巴细胞白血病（CLL）患者中的疗效。您能否简要介绍一下这项研究的背景和主要发现？这一发现如何改变我们对于CLL治疗的理解？
Othman Al-Sawaf教授：在CLL的治疗中，主要存在两种策略：固定疗程治疗和持续治疗。这两种策略均是在与化疗对照的基础上发展而来。目前尚缺乏二者直接比较的循证证据。为此，我们设计了一项临床研究，将未经治疗的CLL患者随机分配至固定疗程方案[维奈克拉联合奥妥珠单抗（VO）或维奈克拉联合伊布替尼(VI)]或持续治疗方案（伊布替尼，即持续BTK抑制治疗）组。本研究旨在前瞻性评估固定疗程方案的疗效表现，以验证其相对于持续治疗的非劣效性，主要终点为无进展生存期（PFS）。
Oncology Frontier-Hematology Frontier：You presented the results of the CLL17 trial at the ASH meeting, comparing fixed-duration treatment and continuous targeted treatment in previously untreated chronic lymphocytic leukemia (CLL) patients. Could you briefly introduce the background and key findings of this study? How do these findings change our understanding of CLL treatment?
Professor Othman Al-Sawaf：In the treatment of chronic lymphocytic leukemia (CLL), there are two primary strategies: fixed-duration therapy and continuous therapy. Both strategies were developed based on comparisons with chemotherapy. Currently, there is a lack of direct head-to-head evidence comparing the two approaches. To address this, we designed a clinical study in which treatment-naïve CLL patients are randomly assigned to either a fixed-duration regimen [venetoclax plus obinutuzumab (VO) or venetoclax plus ibrutinib (VI)] or a continuous therapy regimen (ibrutinib, i.e., indefinite BTK inhibitor therapy). This study aims to prospectively evaluate the efficacy of fixed-duration regimens and to demonstrate their non-inferiority relative to continuous therapy, with the primary endpoint being progression-free survival (PFS).
《肿瘤瞭望-血液时讯》：在您的研究中，固定疗程治疗的VO组合与伊布替尼（I）治疗在无进展生存期（PFS）上表现出非劣性。您认为这一发现对未来CLL患者治疗策略的影响如何？在临床实践中，VO与I治疗相比有哪些独特的优势和挑战？
Othman Al-Sawaf教授：本次中期分析结果证实，固定疗程治疗相对于持续治疗达到了非劣效性标准。在初治的CLL患者中，VO及VI方案均非劣效于持续伊布替尼单药治疗，显示出相当的临床疗效。该结果支持为患者提供限时治疗方案。大多数初治CLL患者可从固定疗程方案中获益，而无需长期持续用药。
Oncology Frontier-Hematology Frontier：In your study, the fixed-duration treatment of Venetoclax plus Obinutuzumab (VO) showed non-inferiority in progression-free survival (PFS) compared to ibrutinib (I). What do you think is the impact of this finding on future treatment strategies for CLL patients? What unique advantages and challenges does VO have compared to I in clinical practice?
Professor Othman Al-Sawaf：The interim analysis results confirm that fixed-duration therapy met the non-inferiority criterion relative to continuous therapy. In treatment-naïve CLL patients, both the VO and VI regimens demonstrated non-inferiority compared to continuous ibrutinib monotherapy, exhibiting comparable clinical efficacy. These findings support the use of time-limited treatment regimens in clinical practice. The majority of treatment-naïve CLL patients can benefit from fixed-duration therapy without the need for indefinite continuous treatment.
《肿瘤瞭望-血液时讯》：在研究的次要终点中，您提到固定疗程治疗方案在可检测微小残留病（uMRD）率上表现出显著优势。请您进一步阐述这一结果的临床意义，特别是在如何帮助患者实现长期无病生存方面。
Othman Al-Sawaf教授：微小残留病（MRD）作为次要终点具有重要价值，可反映患者缓解的深度。研究显示，只有固定疗程方案能够在至少半数患者中实现深度MRD阴性缓解，而持续单药治疗无法达到此效果。MRD阴性是实施固定疗程或限时治疗的前提条件，只有在达到深度缓解的情况下，患者才能实现无治疗缓解并维持疾病控制而无需额外干预。因此，这些次要终点具有重要意义。然而，仍需通过长期随访进一步评估MRD及缓解率等替代终点与患者长期生存之间的相关性。
Oncology Frontier-Hematology Frontier：In the secondary endpoints of the study, you mentioned that the fixed-duration treatment regimen showed a significant advantage in undetectable minimal residual disease (uMRD) rates. Could you further elaborate on the clinical significance of this result, especially in terms of how it might help patients achieve long-term disease-free survival?
Professor Othman Al-Sawaf：Minimal residual disease (MRD), as a secondary endpoint, holds significant prognostic value by reflecting the depth of patient response. The study demonstrates that only fixed-duration regimens achieved undetectable MRD at a deep level in at least half of patients, whereas continuous monotherapy did not attain this outcome. Undetectable MRD represents a prerequisite for implementing fixed-duration or time-limited therapy, as only deep MRD negativity enables patients to achieve treatment-free remission while maintaining disease control without additional intervention. Consequently, these secondary endpoints are of substantial clinical importance. However, their correlation with long-term patient survival requires further evaluation through extended follow-up.
《肿瘤瞭望-血液时讯》：您提到该研究对IGHV突变和del(17p)/TP53突变的不同亚群有不同的疗效。您如何看待这些亚群对治疗选择的影响？是否有可能基于分子特征来个性化治疗策略，从而提高CLL患者的治疗效果？
Othman Al-Sawaf教授：当前亚组分析虽仍属探索性，但具有重要临床意义。例如，在IGHV未突变患者（本研究中占比约55%）中，固定疗程方案同样相对于持续治疗达到了非劣效性。该发现意义重大，因为IGHV未突变是大多数活动性CLL患者的特征，与中高风险相关，且通常复发较早。长期以来，临床实践倾向于优先为这类患者选择持续治疗。然而，本研究结果表明，即使存在该风险因素，固定疗程方案仍可提供与持续治疗相当的疗效，因此固定疗程亦可作为此类患者的优选治疗策略。
至于TP53异常亚组，当前数据尚不成熟，本试验中仅8%的患者存在TP53改变。VO与VI方案间存在一定差异，其中VI方案在固定疗程模式下显示出较优疗效趋势，但证据强度有限，置信区间较宽，需更长随访期进一步验证。尽管如此，该结果进一步强调，治疗前应常规进行IGHV和TP53检测，以优化个体化治疗决策。
Oncology Frontier-Hematology Frontier：You mentioned that the study showed varying efficacy across different subgroups with IGHV mutations and del(17p)/TP53 mutations. How do you see these subgroups impacting treatment choices? Is there a possibility of personalizing treatment strategies based on molecular characteristics to enhance treatment outcomes for CLL patients?
Professor Othman Al-Sawaf：The current subgroup analyses, although exploratory in nature, carry substantial clinical significance. For instance, in patients with unmutated IGHV (accounting for approximately 55% of the study population), fixed-duration regimens similarly demonstrated non-inferiority relative to continuous therapy. This finding is of particular importance, as unmutated IGHV is characteristic of the majority of patients with active CLL, is associated with intermediate-to-high risk, and typically correlates with earlier relapse. Historically, clinical practice has favored continuous therapy as the preferred approach for this subgroup. However, the present study results indicate that, even in the presence of this risk factor, fixed-duration regimens can deliver efficacy comparable to continuous therapy, thereby positioning fixed-duration treatment as a viable preferred option for these patients.
Regarding the TP53-aberrant subgroup, the data remain immature, with only 8% of trial patients harboring TP53 alterations. Differences were observed between the VO and VI regimens, with the VI regimen showing a trend toward superior efficacy in the fixed-duration setting; however, the evidence is limited, with wide confidence intervals necessitating longer follow-up for confirmation. Nonetheless, these findings underscore the importance of routinely performing IGHV and TP53 testing prior to treatment initiation to guide individualized therapeutic decisions.
专家简介
Othman Al-Sawaf 教授
德国科隆大学附属医院
Othman Al-Sawaf是德国科隆大学附属医院的血液学及肿瘤内科医师，同时也是德国CLL研究组（GCLLSG）的研究者。
他在德国亚琛RWTH亚琛大学医学院学习医学，并于2016年加入科隆大学附属医院Michael Hallek教授领导的第一内科（Department I of Internal Medicine I）。2020年，他还以访问科学家的身份加入伦敦弗朗西斯·克里克研究所（Francis Crick Institute）Charles Swanton教授的实验室。
他担任多项国内和国际I至III期临床试验的协调医师和主要研究者。除临床试验工作外，他还关注癌症进化与代谢的原理，其研究重点是利用计算方法发现并开发临床肿瘤学的新治疗策略。