摘要：2024年12月7日至10日，第66届美国血液学会（ASH）年会在美国圣迭戈隆重召开，全球血液学专家学者齐聚一堂，共同对血液领域最新研究进展进行深入探讨与交流。《肿瘤瞭望-血液时讯》特邀纪念斯隆凯特琳癌症中心（MSK）Gilles Salles教授分享淋巴瘤领
编者按：2024年12月7日至10日，第66届美国血液学会（ASH）年会在美国圣迭戈隆重召开，全球血液学专家学者齐聚一堂，共同对血液领域最新研究进展进行深入探讨与交流。《肿瘤瞭望-血液时讯》特邀纪念斯隆凯特琳癌症中心（MSK）Gilles Salles教授分享淋巴瘤领域的关键发现以及参会感受。
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《肿瘤瞭望-血液时讯》：首先请您简要介绍一下您的专业领域和研究方向？
Gilles Salles教授：大家好，我是纪念斯隆凯特琳癌症中心（MSK）的Gilles Salles博士。我始终专注于淋巴瘤治疗领域的研究，尤其深耕于B细胞淋巴瘤，涵盖了大B细胞淋巴瘤以及惰性淋巴瘤，如滤泡性淋巴瘤。当下，我们正处于淋巴瘤治疗极具突破性的时代。回顾过往，传统化疗或高剂量化疗模式逐渐被革新。25年前，利妥昔单抗的出现成为首个重大突破，开启了淋巴瘤治疗新篇章；随后，细胞疗法蓬勃兴起，CAR-T细胞疗法备受瞩目；时至今日，双特异性抗体又为治疗带来了新契机，这些创新药物都促使淋巴瘤治疗不断迈向新台阶，取得诸多实质性成果。与此同时，随着科研深入，我们对B细胞淋巴瘤的分子层面认知愈发深入，不同分子亚型得以精准区分，这为后续的个性化治疗奠定了基础，进而为B细胞淋巴瘤的亚型制定特定治疗方案。
我和我的团队正在这些领域攻坚克难。以双特异性抗体为例，我们着力探索如何优化其临床应用，特别是针对滤泡性淋巴瘤患者。为进一步探索双特异性抗体的作用机制，我们开展了体外与体内试验。另外，大样本量患者的分子数据研究也在推进，旨在为患者提供更合适的治疗方案。
尽管我们不能治愈所有患者，但不可否认，过往积累的诸多实质性的成果已让我们向前迈进一大步。这一伟大进程凝聚着全球淋巴瘤领域同仁的心血，无论他们身处美国、中国，还是世界其他角落，大家携手奋进，共同为攻克淋巴瘤难题不懈努力。
Oncology Frontier-Hematology Frontier：Could you please briefly introduce yourself, as well as your field and research directions?
Dr. Gilles Salles：Hello everyone, I am Dr. Gilles Salles from Memorial Sloan Kettering Cancer Center (MSK). I have always been dedicated to research in the field of lymphoma treatment, with a particular focus on B-cell lymphomas, including diffuse large B-cell lymphoma and indolent lymphomas such as follicular lymphoma. Today, we are in an era of groundbreaking advancements in lymphoma treatment. Looking back, traditional chemotherapy or high-dose chemotherapy regimens have gradually been revolutionized. 25 years ago, the emergence of rituximab marked the first significant breakthrough, opening a new chapter in lymphoma treatment; subsequently, cellular therapies have flourished, with CAR-T cell therapy garnering considerable attention; now, bispecific antibodies have brought new opportunities for treatment, and these innovative drugs have continuously pushed lymphoma treatment to new levels, achieving many substantial outcomes. At the same time, with in-depth research, our understanding of the molecular aspects of B-cell lymphomas has become more profound, allowing for the precise differentiation of various molecular subtypes, which lays the foundation for subsequent personalized treatment and paves the way for specific treatment plans for subtypes of B-cell lymphoma.
My team and I are tackling challenges in these areas. Taking bispecific antibodies as an example, we are focusing on exploring how to optimize their clinical application, especially for patients with follicular lymphoma. To further investigate the mechanisms of action of bispecific antibodies, we have conducted in vitro and in vivo experiments. Additionally, large-sample molecular data research on patients is also underway, aiming to provide more appropriate treatment plans.
Although we cannot cure all patients, it is undeniable that the many substantial outcomes accumulated over the past have allowed us to take a significant step forward. This great process is the result of the efforts of colleagues in the global lymphoma field, whether they are in the United States, China, or other parts of the world, everyone is working together to make unremitting efforts to conquer the challenges of lymphoma.
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《肿瘤瞭望-血液时讯》：您能简要介绍一下在这次会议期间汇报的研究吗？
Gilles Salles教授：我们报告的这项POLARIX研究（NCT03274492），其方法曾于2022年发表在NEJM上。18-80岁患者以1:1的比例随机接受6个周期Pola-R-CHP或R-CHOP治疗，以及2个周期利妥昔单抗治疗。主要终点为PFS。我们此次报告了POLARIX研究的5年长期随访研究数据，探讨了与R-CHOP方案相比，维泊妥昔单抗+利妥昔单抗、环磷酰胺、多柔比星和泼尼松（Pola-R-CHP）治疗中高危弥漫性大B细胞淋巴瘤（DLBCL）患者的长期疗效。
综上，POLARIX研究的5年随访结果显示，与接受R-CHOP治疗的患者相比，接受Pola-R-CHP治疗的患者PFS和DFS持续且显著获益。Pola-R-CHP组与R-CHOP组的OS均尚可，然而，R-CHOP组的（包括淋巴瘤相关死亡）死亡人数更多，且治疗的2年以上的死亡率更高。此外，两组之间的安全性特征持续相似，未观察到新的安全性信号，证实Pola-R-CHP作为中高危DLBCL患者标准一线治疗的疗效及安全性。
中文标题：POLARIX研究的5年分析：延长随访证实维泊妥珠单抗联合利妥昔单抗、环磷酰胺、多柔比星和泼尼松（Pola-R-CHP）对临床疗效有积极影响
英文标题：Five-Year Analysis of the POLARIX Study: Prolonged Follow-up Confirms Positive Impact of Polatuzumab Vedotin Plus Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (Pola-R-CHP) on Outcomes
摘要号：469
入组患者情况如下：在意向分析治疗（ITT）人群中，分别有879例患者（Pola-R-CHP组为440例，R-CHOP组为439例）和873例患者（Pola-R-CHP组为435例，R-CHOP组为438例）的数据可评估疗效和安全性。在扩展人群中，分别有1000例患者（Pola-R-CHP组为500例，R-CHOP组为500例）和993例患者（Pola-R-CHP组为495例，R-CHOP组为498例）的数据可评估疗效和安全性。
在ITT人群中（中位随访时间60.9个月），Pola-R-CHP组和R-CHOP组的5年PFS率分别为64.2% vs. 59.1%，前者显示出显著获益（HR：0.78；95%CI：0.623-0.980）。Pola-R-CHP组和R-CHOP组的5年OS率估计值分别为82.2%（95%CI：78.53%-85.82%）vs. 79.6%（95%CI：75.70%-83.47%），与2年随访时的风险比（HR 0.94；95%CI：0.650-1.370）相比，5年随访时的风险比有所改善（HR：0.87；95%CI：0.641-1.175）。Pola-R-CHP组和R-CHOP组的5年无病生存（DFS）率分别为 71.3%（95%CI：65.46%-77.05%）vs. 65.5%（95%CI：59.45%-71.45%），（HR：0.75；95%CI：0.570-0.992）。
在扩展人群中（中位随访时间60.5个月），观察到相似的5年PFS数据显著获益，Pola-R-CHP组和R-CHOP组的5年PFS率估计值分别为 63.1%（95%CI：57.90%-68.26%）vs. 59.1%（95%CI：54.07%-64.15%），（HR：0.81；95%CI：0.652-0.996）。Pola-R-CHP组和R-CHOP组接受后续淋巴瘤全身治疗的患者分别为106例（21%）vs. 145例（29%）。Pola-R-CHP组和R-CHOP组的5年OS率分别为82.2%（95%CI：78.78%-85.68%）vs. 79.0%（95%CI：75.24%-82.70%），（HR：0.84；95%CI：0.632-1.119），两者差异无统计学意义。Pola-R-CHP组和R-CHOP组的5年DFS率分别为69.4%（95%CI：63.78%-75.05%）vs. 65.1%（95%CI：59.30%-70.92%），（HR：0.81；95%CI：0.625-1.042）。
在扩展人群可评估安全性的993例患者中，Pola-R-CHP组和R-CHOP组的3-5级不良事件（AE）发生率分别为62.6% vs. 60.8%。Pola-R-CHP组（n=5）比R-CHOP组（n=12）的继发性恶性肿瘤发生率更低。在长期随访期间，未观察到新的安全性信号。Pola-R-CHP组和R-CHOP组的新发严重AE发生率相似，分别为1.8%和2.2%。无新发周围神经病变患者。Pola-R-CHP组和R-CHOP组分别有4例（0.8%）和1例（0.2%）患者发生严重感染。
在扩展人群中，Pola-R-CHP组与R-CHOP组相比，患者死亡人数更少（90 例 vs. 107 例）。Pola-R-CHP组和R-CHOP组的淋巴瘤相关死亡分别为46例 vs. 62例（前2年，32例 vs. 39例；2年以上，14例 vs. 23例）。Pola-R-CHP组和R-CHOP组的感染（7 例 vs. 11 例）、心血管疾病（4 例 vs. 5 例）、继发性恶性肿瘤导致死亡（7例 vs. 5例）的发生情况相似。在一项竞争风险分析中，以非淋巴瘤相关死亡（包括研究治疗导致的死亡）作为竞争事件，Pola-R-CHP组和R-CHOP 组的 5 年淋巴瘤相关死亡累积发生率分别为 9.1% vs. 12.2%。
Oncology Frontier-Hematology Frontier：And could you please briefly introduce the research presented during this kind of meeting?
Dr. Gilles Salles：POLARIX (NCT03274492) methods were published in Tilly et al. NEJM 2022. Pts 18–80 years were randomized 1:1 to receive 6 cycles of Pola-R-CHP or R-CHOP, plus 2 cycles of rituximab. The primary endpoint was PFS. In this analysis, 1000 pts (expanded population) were evaluated; 879 pts (global ITT population) from the main study (enrolled Nov 2017–Jun 2019) and 121 pts from a Chinese extension cohort (enrolled Jul 2019–Dec 2020; Song et al. Blood 2023). Extended follow-up of efficacy and safety are described. A competing risk analysis assessed the risk of death from lymphoma vs other causes.we report outcomes after 5 years of follow-up (cut-off, 5 July 2024)
In the global ITT population, 879 (Pola-R-CHP, n=440; R-CHOP, n=439) and 873 pts (Pola-R-CHP, n=435; R-CHOP, n=438) were evaluable for efficacy and safety, respectively. In the expanded population, 1000 (Pola-R-CHP, n=500; R-CHOP, n=500) and 993 pts (Pola-R-CHP, n=495; R-CHOP, n=498) were evaluable for efficacy and safety, respectively.
In the global ITT population (median follow-up 60.9 months), the 5-year PFS estimates were 64.2% (95% CI: 58.78–69.53) vs 59.1% (95% CI: 53.87–64.40) with Pola-R-CHP vs R-CHOP, showing a significant benefit (HR 0.78; 95% CI: 0.623–0.980). The 5-year OS estimates were 82.2% (95% CI: 78.53–85.82) vs 79.6% (95% CI: 75.70–83.47) with Pola-R-CHP vs R-CHOP, with an improved HR (0.87; 95% CI: 0.641–1.175) compared with the 2-year follow-up HR (0.94; 95% CI: 0.650–1.370). The 5-year disease-free survival (DFS) estimates were 71.3% (95% CI: 65.46–77.05) vs 65.5% (95% CI: 59.45–71.45) with Pola-R-CHP vs R-CHOP (HR 0.75; 95% CI: 0.570–0.992).
In the expanded population (median follow-up 60.5 months), a similar significant 5-year PFS benefit was observed, with estimates of 63.1% (95% CI: 57.90–68.26) vs 59.1% (95% CI: 54.07–64.15) with Pola-R-CHP vs R-CHOP (HR 0.81; 95% CI: 0.652–0.996). The number of pts requiring subsequent systemic lymphoma therapy was 106 (21%) vs 145 (29%) with Pola-R-CHP vs R-CHOP. The 5-year OS estimates were 82.2% (95% CI: 78.78–85.68) vs 79.0% (95% CI: 75.24–82.70) with Pola-R-CHP vs R-CHOP, with no statistically significant difference (HR 0.84; 95% CI: 0.632–1.119). The 5-year DFS estimates were 69.4% (95% CI: 63.78–75.05) vs 65.1% (95% CI: 59.30–70.92) with Pola-R-CHP vs R-CHOP (HR 0.81; 95% CI: 0.625–1.042).
Safety profiles were comparable with Pola-R-CHP vs R-CHOP across all safety-evaluable pts in the expanded population (n=993), including Grade 3–5 AE rates (62.6% vs 60.8%). Fewer secondary malignancies were observed with Pola-R-CHP (n=5) vs R-CHOP (n=12). No new safety signals were observed during long-term follow-up; similar rates of new serious AEs were reported with Pola-R-CHP and R-CHOP (1.8% and 2.2%, respectively). No new cases of peripheral neuropathy were reported. Serious infections occurred in 4 pts (0.8%) vs 1 (0.2%) pt with Pola-R-CHP vs R-CHOP.
In the expanded population, fewer total deaths were observed in pts treated with Pola-R-CHP vs R-CHOP (90 vs 107). Lymphoma-related deaths occurred in 46 vs 62 pts with Pola-R-CHP vs R-CHOP (during the first 2 years, 32 vs 39 pts; beyond 2 years, 14 vs 23 pts for Pola-R-CHP vs R-CHOP). Similar numbers of deaths from infection (7 vs 11), cardiovascular disease (4 vs 5), and secondary malignancy (7 vs 5) were observed with Pola-R-CHP vs R-CHOP. In a competing risk analysis, with non-lymphoma-related deaths (including death due to study treatment) as competing events, the cumulative incidence of lymphoma-related death at 5 years was 9.1% vs 12.2% for Pola-R-CHP vs R-CHOP.
In summary，extended 5-year follow-up of POLARIX demonstrated sustained and significant PFS and DFS benefits for pts receiving Pola-R-CHP vs R-CHOP. OS was reassuring between pts with Pola-R-CHP and R-CHOP, with more deaths, including lymphoma-related deaths, observed with R-CHOP. With the observation that a higher proportion of pts receiving R-CHOP died beyond 2 years, prolonged follow-up will be of interest. Safety profiles remained similar between arms, and no new safety signals were identified. These outcomes confirm Pola-R-CHP as a standard of care for pts with previously untreated intermediate- or high-risk DLBCL
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《肿瘤瞭望-血液时讯》：您认为此次会议哪些重要进展或突破性研究值得关注？这些发展可能会如何影响临床诊断和治疗？
Gilles Salles教授：在淋巴瘤相关研究领域，诸多杰出成果不断涌现。中国学者运用前沿的成像质谱流式技术取得了重大突破，一方面，针对 EBV+DLBCL展开深入探究，全方位阐释了其具有免疫抑制特性的微环境，并且精准剖析出引发该免疫抑制性微环境的内在调控机理（摘要号：452）；另一方面，还发现了肿瘤免疫微环境（TIME）在滤泡性淋巴瘤（FL）的早期进展历程中扮演着举足轻重的角色（摘要号：1621）。
与此同时，在免疫疗法的优化探索上也有新进展。生酮饮食这一干预手段被证实可通过 β- 羟基丁酸来强化 CAR-T 细胞的抗肿瘤功能（摘要号：4）。综合这些前沿发现来看，无论是当下的淋巴瘤治疗实践，还是面向未来的免疫疗法研发，均存在着诸多可拓展的领域与创新方法，有望助力免疫疗法实现质的飞跃。
这些研究成果必然会对淋巴瘤治疗产生深远影响。在诊断层面，随着技术发展，分子分类得以持续优化，如今已能够依据患者的分子特征，更为精准、有针对性地筛选合适药物，进而提升治疗的精准度与有效性，为淋巴瘤患者带来更多治愈希望。
Oncology Frontier-Hematology Frontier：And during this meeting, what are the significant advancements or groundbreaking research presented at this conference that you think deserve attention?And how might those developments impact clinical diagnosis and treatment?
Dr. Gilles Salles：In the field of lymphoma-related research, numerous outstanding achievements continue to emerge. Chinese scholars have made significant breakthroughs using cutting-edge imaging mass cytometry technology. On one hand, they have conducted in-depth studies on EBV+DLBCL, comprehensively elucidating its microenvironment with immune-suppressive characteristics and precisely dissecting the internal regulatory mechanisms that lead to this immune-suppressive microenvironment (Abstract No.: 452). On the other hand, they have also discovered that the tumor immune microenvironment (TIME) plays a pivotal role in the early progression of follicular lymphoma (FL) (Abstract No.: 1621).
At the same time, there have been new developments in the optimization of immunotherapy. The ketogenic diet, as an intervention measure, has been proven to enhance the anti-tumor function of CAR-T cells through β-hydroxybutyrate (Abstract No.: 4). Integrating these cutting-edge findings, there are many expandable fields and innovative methods in both current lymphoma immunotherapy practices and future immunotherapy research and development, which are expected to help immunotherapy achieve a qualitative leap.
These research outcomes will undoubtedly have a profound impact on lymphoma treatment. In terms of diagnosis, with technological advancements, molecular classification continues to be optimized. Now, it is possible to select appropriate drugs more accurately and specifically based on the molecular characteristics of patients, thereby enhancing the precision and effectiveness of treatment and bringing more hope for cure to lymphoma patients.
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《肿瘤瞭望-血液时讯》：通过这次会议，您获得了哪些见解，这些见解将如何影响您的临床实践和未来的研究方向？
Gilles Salles教授：ASH会议为我们提供了与世界专家学者交流最新研究成果、探讨行业发展趋势的机会。我们在CAR-T细胞治疗领域收获颇多，并学习到了如何把临床试验结果转化为实践应用。新型药物如同雨后春笋不断涌现，极大地促进了我们对疾病的深入理解。这些进步不仅为患者群体带来了直接的益处，而且对整个医疗行业产生了深远的影响。
Oncology Frontier-Hematology Frontier：And through this meeting, what might be some insights you've gained, and how will those insights influence your clinical practice and future research directions?
Dr. Gilles Salles：The ASH conference provides us with the opportunity to exchange the latest research findings with experts and scholars from around the world and to discuss industry trends. We have gained a lot in the field of CAR-T cell therapy and learned how to translate clinical trial results into practical applications. New drugs are emerging like mushrooms after rain, greatly promoting our in-depth understanding of diseases. These advancements have not only brought direct benefits to patient groups but also had a profound impact on the entire medical industry.
来源：肿瘤瞭望