编者按：2025年10月31日，由北京大学人民医院雄安医工交叉转化研究院主办，国家血液系统疾病临床医学研究中心-北京大学血液病研究所承办的“2025国际细胞治疗及生物医学前沿大会”在河北雄安盛大召开。会上，首尔圣玛丽医院Jae-Ho Yoon教授带来了《Diagnostic and therapeutic advances in Korea with acute lymphoblastic leukemia in the era of gene analysis and targeted immuno-therapy》（基因分析与靶向免疫治疗时代下韩国急性淋巴细胞白血病的诊疗进展）的精彩报告。会后，《肿瘤瞭望-血液时讯》特邀Jae-Ho Yoon教授接受采访，深入探讨韩国在ALL诊疗中的最新进展、靶向免疫治疗的临床实践经验及未来研究方向，以期为国内血液病研究与临床策略制定提供重要参考。
《肿瘤瞭望-血液时讯》基因分析和靶向免疫治疗正在改变急性淋巴细胞白血病（ALL）的诊疗格局。请您分享一下韩国在这一领域的最新进展，尤其是基因分析如何在诊断和个性化治疗方案制定中发挥重要作用？
Jae-Ho Yoon教授：基因分析不仅包括常规的基因检测，还涉及细胞遗传学和分子遗传学内容，这些都与急性淋巴细胞白血病（ALL）密切相关。风险分层的概念最初来源于急性髓系白血病（AML），在该领域中低危、中危和高危亚组的划分已相对明确。然而，在ALL领域，风险分层的建立最早应用于儿童患者，而在成人患者中尚未得到充分发展。
随着儿童ALL领域积累的经验不断丰富，我们逐渐认识到有必要在成人ALL中进行更系统的细胞遗传学风险验证。进一步的研究发现，儿童患者中已明确的一些基因异常，尤其是IKZF1、CDKN2、PAX5和EBF1等基因缺失，在成人患者中同样具有重要意义。这类额外的基因分析为ALL的预后评估提供了更为精确的信息。
基于这些研究成果，我们能够更清晰地识别出在接受造血干细胞移植或免疫治疗后仍具有不良预后风险的患者亚群。这些分子层面的发现，为成人ALL患者的精准分层管理和个体化治疗决策提供了重要依据，使临床治疗策略更加科学和精确。
Oncology Frontier-Hematology Frontier：Gene analysis and targeted immunotherapy are changing the diagnostic and treatment landscape of acute lymphoblastic leukemia (ALL). Could you share the latest advancements in this field in South Korea, particularly how gene analysis plays a critical role in diagnosis and the development of personalized treatment plans?
Professor Jae-Ho Yoon：Genetic analysis encompasses not only conventional genetic testing but also cytogenetics and molecular genetics, all of which are closely related to acute lymphoblastic leukemia (ALL). The concept of risk stratification originated from acute myeloid leukemia (AML), where the delineation of low-risk, intermediate-risk, and high-risk subgroups is relatively well-established. However, in the field of ALL, risk stratification was first applied to pediatric patients, and it has not yet been fully developed in adult patients.
As experience in pediatric ALL continues to accumulate, we have gradually recognized the necessity for more systematic cytogenetic risk validation in adult ALL. Further studies have revealed that certain genetic abnormalities well-defined in pediatric patients—particularly deletions in genes such as IKZF1, CDKN2, PAX5, and EBF1—are equally significant in adult patients. This additional genetic analysis provides more precise information for prognostic assessment in ALL.
Based on these research findings, we can more clearly identify patient subgroups with poor prognostic risks even after receiving hematopoietic stem cell transplantation or immunotherapy. These molecular-level discoveries offer an important foundation for precise stratification management and individualized treatment decisions in adult ALL patients, making clinical treatment strategies more scientific and accurate.
《肿瘤瞭望-血液时讯》随着靶向免疫治疗的不断发展，ALL的治疗策略也在不断革新。您认为靶向免疫治疗在提高治疗效果和减少副作用方面的潜力如何？目前哪些靶向免疫治疗方案在韩国临床实践中获得了显著成果？
Jae-Ho Yoon教授：在ALL的治疗中，首先需要根据费城染色体（Philadelphia chromosome，Ph）进行分型。对于Ph阳性ALL，自2010年以来，MD安德森癌症中心开展的多项临床研究表明，一线泊那替尼（ponatinib）联合常规或减毒的Hyper-CVAD化疗方案，可显著提高患者的缓解率和微小残留病（MRD）阴性率，使患者的长期生存率由既往的40%～50%提高至约70%。因此，基于泊那替尼的治疗方案已成为Ph阳性ALL生存结局改善的关键。
当前，双特异性T细胞衔接器（BiTE）时代已然到来，贝林妥欧单抗（blinatumomab）作为首个获批的BiTE药物在其中发挥着重要作用。在Ph阳性ALL领域，泊那替尼联合贝林妥欧单抗的初步数据已公布，尽管随访时间较短，但显示出极佳的生存结局。然而，需注意的是，该联合方案单用时中枢神经系统（CNS）复发风险较高。
在Ph阴性ALL中，贝林妥欧单抗的应用已彻底改变治疗格局。除已被批准用于复发/难治性及MRD阳性患者外，现已逐步应用于MRD阴性的完全缓解患者，可作为一线治疗方案。研究表明，贝林妥欧单抗相关方案可实现高缓解率与优异的生存结局，并在减少化疗强度、降低毒性方面具有显著优势。
值得关注的是，早期使用贝林妥欧单抗可在一个疗程后使约80%的患者达到MRD阴性，从而以更佳状态进入造血干细胞移植阶段。这使得减低强度预处理方案成为可能，即使在此类低毒性方案下，患者仍可获得良好的长期生存预后。
Oncology Frontier-Hematology Frontier：With the continuous development of targeted immunotherapy, the treatment strategies for ALL are also evolving. What is your perspective on the potential of targeted immunotherapy in improving treatment efficacy and reducing side effects? Which targeted immunotherapy regimens have shown significant results in clinical practice in South Korea?
Professor Jae-Ho Yoon: In the treatment of acute lymphoblastic leukemia (ALL), initial stratification is essential based on Philadelphia chromosome (Ph) status. For Ph-positive ALL, multiple clinical studies conducted at MD Anderson Cancer Center since 2010 have demonstrated that frontline ponatinib combined with conventional or attenuated Hyper-CVAD regimens significantly improves response rates and measurable residual disease (MRD) negativity rates, elevating long-term survival from the previous 40%–50% to approximately 70%. Thus, ponatinib-based regimens have become pivotal in improving survival outcomes for Ph-positive ALL.
Currently, we have entered the era of bispecific T-cell engagers (BiTEs), with blinatumomab—the first approved BiTE agent—playing a central role. In Ph-positive ALL, preliminary data on ponatinib combined with blinatumomab have been published; although follow-up remains short, the results reveal outstanding survival outcomes. However, it is noteworthy that this combination, when used alone, is associated with a higher risk of central nervous system (CNS) relapse.
In Ph-negative ALL, the application of blinatumomab has profoundly transformed the treatment landscape. Beyond its approval for relapsed/refractory disease and MRD-positive cases, it is now progressively incorporated into frontline settings for patients in complete remission with MRD negativity. Studies indicate that blinatumomab-containing regimens achieve high response rates and superior survival outcomes, while offering substantial advantages in reducing chemotherapy intensity and toxicity.
Of particular note, early administration of blinatumomab can render approximately 80% of patients MRD-negative after just one cycle, enabling entry into hematopoietic stem cell transplantation in an optimal state. This facilitates the use of reduced-intensity conditioning regimens, under which patients can still attain favorable long-term survival prognosis even with lower toxicity.
《肿瘤瞭望-血液时讯》：在基因分析和靶向治疗的双重推动下，韩国急性淋巴细胞白血病的治疗已取得了一些突破。您认为未来治疗ALL的研究重点应集中在哪些领域？尤其是在克服耐药性和提高疗效方面，哪些新的技术或策略值得关注？
Jae-Ho Yoon教授：当前，ALL的治疗正积极探索无移植治疗策略。既往未能实现这一目标的主要原因是MRD检测敏感性和可靠性不足，无法准确解读MRD阴性结果的临床意义。随着MRD检测方法的验证以及基因谱分析的完善，无移植治疗已具备可行性基础。
对于无不良风险基因谱且能在治疗早期达到深度MRD阴性的患者，可尝试实施无移植方案，并辅以贝林妥欧单抗维持治疗或常规/重复化疗维持。我认为，该方向的研究是当前最紧迫的任务，应通过前瞻性临床试验进一步明确适宜从中获益的患者群体。
另一方面，对于复发/难治性ALL患者，需重新评估异基因造血干细胞移植是否仍为标准治疗。随着多种CAR-T细胞治疗平台的快速发展，临床亟需明确复发/难治性病例中CAR-T疗法、免疫治疗维持方案与异基因移植的最优应用条件，以实现疗效最大化。
综上所述，明确无移植治疗的适用人群以及复发/难治性病例的最佳治疗路径，将是未来ALL临床研究的两大关键方向，为患者提供更加精准、安全和个体化的治疗策略。
Oncology Frontier-Hematology Frontier：Under the dual driving forces of gene analysis and targeted therapies, South Korea has achieved some breakthroughs in the treatment of acute lymphoblastic leukemia. What do you think the future research focus should be in the treatment of ALL? Specifically, what new technologies or strategies should be emphasized, especially in overcoming drug resistance and improving efficacy?
Professor Jae-Ho Yoon: Currently, the treatment of acute lymphoblastic leukemia (ALL) is actively exploring transplant-free curative strategies. The primary reason this goal was previously unattainable lies in the limited sensitivity and reliability of measurable residual disease (MRD) detection, which hindered accurate interpretation of the clinical significance of MRD-negative results. With the validation of MRD detection methods and the refinement of genomic profiling, transplant-free approaches have now gained a solid feasibility foundation.
For patients without adverse-risk genomic profiles who achieve deep MRD negativity early in treatment, transplant-free regimens can be attempted, supplemented with maintenance therapy such as blinatumomab or conventional/reintensified chemotherapy. In my view, research in this direction represents the most urgent priority at present, necessitating prospective clinical trials to precisely define the patient subgroups most likely to benefit.
On the other hand, for relapsed/refractory ALL patients, it is essential to reevaluate whether allogeneic hematopoietic stem cell transplantation remains the standard of care. With the rapid development of multiple CAR-T cell therapy platforms, clinical practice urgently requires clarification of the optimal application scenarios for CAR-T therapy, immunotherapy maintenance regimens, and allogeneic transplantation in relapsed/refractory cases to maximize therapeutic efficacy.
In summary, precisely identifying the populations suitable for transplant-free treatment and optimizing the best therapeutic pathways for relapsed/refractory cases will constitute the two key directions in future ALL clinical research, enabling more precise, safe, and individualized treatment strategies for patients.
Jae-Ho Yoon教授现场作报告