酪氨酸激酶抑制剂（TKI）的问世为慢性髓性白血病（CML）治疗带来了革命性的变化，将CML的治疗转变为慢性病管理模式，使患者预期寿命与普通人群相近。然而，部分患者因对至少两种现有治疗不耐受或应答不足、发生耐药而治疗失败，且连续更换TKI与治疗失败风险增加相关。既往治疗不耐受、2年内未达到主要分子学反应（MMR）、BCR-ABL基因突变的患者，可能对现有TKI产生耐药，疾病进展风险随之增加。此外，随着治疗时间的延长，患者对治疗耐受性的要求提高。对长期生存而言，平衡疾病治疗与生活质量尤为重要。在近期召开的第12届美国血液肿瘤学会年会（SOHO 2024）期间，《肿瘤瞭望-血液时讯》有幸采访了美国佐治亚医学院佐治亚癌症中心主任Jorge E. Cortes教授，结合ASC4FIRST研究的关键发现，讨论Asciminib对当前CML治疗模式及未来治疗格局的深远影响。
《肿瘤瞭望-血液时讯》能否请您分享ASC4FIRST研究的主要结果，以及这些结果对CML治疗领域可能产生的影响？
Jorge E. Cortes教授：ASC4FIRST研究是一项比较口服Asciminib（ASC）与研究者选择的标准治疗TKI（IS TKI：伊马替尼、尼洛替尼、达沙替尼或博舒替尼）的III期、头对头、多中心、随机开放研究。主要终点是第48周达到MMR的患者比例，并分别比较：①Asciminib与IS TKI的疗效；②Asciminib与伊马替尼（随机分组前IS TKI为伊马替尼组）的疗效。
研究结果表明主要终点均已达到，提示Asciminib优于IS TKI，MMR比例差异约为20%，与伊马替尼对比差异约30%。次要终点如早期分子学反应、深度分子反应（MR4、MR4.5等）均获得显著差异。同时，安全性和耐受性等于或优于其他TKIs，Asciminib相关不良事件（AE）更少，导致治疗中断或停止的患者比例更低。总而言之，Asciminib在已有的基础上为新诊断的CML患者带来进一步的治疗获益和潜在生存改善。
Oncology Frontier-Hematology Frontier：Could you share some preliminary results from the ASC4FIRST study and their potential impact on the field of CML treatment?
Dr. Jorge E. Cortes：The ASC4FIRST study was a randomized trial comparing Asciminib to any available treatment as a frontline therapy for CML. It had two primary endpoints: major molecular response at 48 weeks and a comparison of Asciminib versus Imatinib, as well as Asciminib versus other TKIs. Before randomization, physicians had to decide whether they would use Imatinib or a second-generation TKI if assigned to the control group. The results showed that both primary endpoints were met, with a significantly better rate of major molecular response for Asciminib against all TKIs, with a difference of almost 20%, and against Imatinib specifically, with a difference of almost 30%. This indicates a significant improvement in the primary endpoint. Secondary endpoints, such as early molecular response and deep molecular response (MR4, MR4.5), also demonstrated Asciminib's efficacy. The safety and tolerability of Asciminib were equal to or better than other TKIs, with fewer patients discontinuing therapy due to adverse events. The safety profile showed fewer adverse events compared to other TKIs. Overall, this suggests that Asciminib could represent an additional improvement in the already effective treatments for CML, potentially advancing the outcomes for patients.
《肿瘤瞭望-血液时讯》您认为ASC4FIRST研究对于当前CML治疗模式有何重要意义？
Jorge E. Cortes教授：尽管目前针对CML有很好的治疗方法，但仍有改进的空间。CML患者已经达到了几乎正常的预期寿命，但仍然存在远期毒副作用，患者生活质量仍有改善空间，许多患者无法终止治疗。这些都是我们应该努力解决的问题。我认为，尽管ASC4FIRST研究的随访时间还不足，但它已经显示出克服目前治疗局限的潜力。因此，我认为ASC4FIRST研究在CML领域具有重要意义，Asciminib有望突破CML的治疗瓶颈，解决仍存在的治疗难题。
Oncology Frontier-Hematology Frontier：What significance does the ASC4FIRST study hold for the current paradigm of CML treatment?
Dr. Jorge E. Cortes：I think the significance lies in the fact that, although we have very effective treatments for CML, there are still areas where we can make improvements. We've almost reached a normal life expectancy, which is already an achievement, but there are still long-term side effects and an impact on quality of life. Additionally, many patients still don't qualify for treatment discontinuation. We can and should try to improve all of these aspects. I believe that these results, although preliminary, show the potential to overcome some or all of these deficiencies present in our current therapies. Therefore, I consider this study to be important in that regard. It may help us to surpass the limitations we still face in CML treatment.
《肿瘤瞭望-血液时讯》ASC4FIRST研究作为一项关键的III期临床试验，如何指导临床实践？
Jorge E. Cortes教授：Asciminib可能成为新诊断CML患者的治疗选择。目前已有多种治疗药物，因此在治疗开始时必须根据患者的需求为其选择最合适的治疗方案，例如对终止治疗更有需求的患者和更关注不良反应的患者。而Asciminib多提供了一个治疗选项。此外，疾病治疗需要在启动治疗时就选择疗效、安全性潜在最佳的治疗方案，因此Asciminib可能改变一线治疗的格局。ASC4FIRST研究为Asciminib成为一线治疗的优选提供了依据。
Oncology Frontier-Hematology Frontier：As a pivotal Phase 3 clinical trial, how will the ASC4FIRST study guide clinical practice?
Dr. Jorge E. Cortes：I think what it can do is become the treatment of choice for patients with newly diagnosed CML. Currently, we have many treatment options, so we will need to decide who the right patient is for these options versus others. It certainly offers an option for patients more interested in treatment discontinuation and for those concerned about adverse events. It may also change the paradigm by starting to use these drugs as our initial therapy. Obviously, in cancer, our aim is to use the best potential treatment available from the start. This study could provide us with the opportunity to begin with the best treatment, using the most effective drug we've identified so far, and introduce it as part of the initial therapy.