低风险骨髓增生异常综合征（LR-MDS）是一种复杂的血液疾病，其特点是骨髓细胞的异常增生和功能障碍，导致贫血、出血和感染风险增加。尽管LR-MDS的进展速度相对较慢，但这种疾病的治疗仍然面临重大挑战。现有的治疗手段，如红细胞生成刺激剂（ESAs）和免疫调节剂，虽然在一定程度上能够缓解症状，但往往难以实现长期的疾病控制，且可能伴随显著的副作用。在这一背景下，Valeria Santini教授通过IMerge试验，探索了Imetelstat——一种首创的寡核苷酸端粒酶抑制剂——在治疗LR-MDS患者中的潜力。第12届美国血液肿瘤学会年会（SOHO 2024）于2024年9月4日至7日在美国休斯顿举行，汇聚了全球血液肿瘤领域的顶尖专家，交流最新研究成果，探讨治疗新策略。《血液时讯》特邀意大利佛罗伦萨大学附属医院Valeria Santini教授，深入剖析这项III期临床试验的研究成果，探讨Imetelstat在提高LR-MDS患者治疗的准确性和有效性方面取得的重大进展，以及这一发现如何为MDS治疗领域未来的策略提供新的方向。
《肿瘤瞭望-血液时讯》：您在SOHO会议上的报告涉及了Imetelstat在低风险骨髓增生异常综合征（LR-MDS）中的疗效。在您的这项IMerge III期试验中，Imetelstat治疗对提高患者的总体生存率有怎样的影响？
Valeria Santini教授：IMerge试验是一项多中心、随机、双盲、安慰剂对照的III期试验，共纳入178例依赖输血的成人LR-MDS患者，每4周1次7.5mg/kg Imetelstat（n=118）或安慰剂（n=60）给药。主要终点为8周的红细胞输血独立性（RBC-TI），次要终点为24周的RBC-TI、TI持续时间、血液学改善-红系（HI-E）和安全性。
本项试验达到了预期的主要终点，约有40%的患者在治疗后达到至少连续8周RBC-TI，其中25%的患者能够维持这一状态超过6个月，而18%的患者能够维持超过一年。这表明了Imetelstat在促进RBC-TI方面的持久效果。
我们在评估这一治疗方案的疗效时，重点关注了RBC-TI和总生存率。研究结果显示，Imetelstat治疗并未显著提升总体生存率，但考虑到当前的随访时间较短，我们有理由相信，随着时间的推移，治疗所带来的持续响应将可能对患者的生活质量以及总体生存率产生积极作用。因此，我们将继续开展进一步的研究和深入分析，以更全面地评估Imetelstat治疗在LR-MDS中的长期临床疗效。
Hematology Frontier：Your presentation at this conference deals with the efficacy of Imetelstat in lower-risk myelodysplastic syndromes (LR-MDS). In your IMerge Phase 3 trial, what significant impacts did Imetelstat treatment have on improving the overall survival rate of patients?
Dr. Valeria Santini：The IMerge trial was meant with the treatment to induce red blood cell transfusion independence. The evaluation of overall survival was only a secondary objective, so the primary objective was met, meaning that 40% of the patients achieved a stable transfusion independence longer than 8 weeks, and a quarter of them longer than 6 months and 18% longer than 1 year. So a long transfusion independence. When we evaluated the impact of this very long transfusion independence on overall survival, in fact, there was no significant effect in prolongation of overall survival. As far as we know, now the follow up may be still too short, but the durability of the response should prompt for an improvement, of course in quality of life, but also in overall survival. That's why we will have to run further research on these and further analysis.
《血液时讯》：您的研究使用了哪些创新性的方法和策略，以提升LR-MDS患者治疗的准确性和有效性？
Valeria Santini教授：Imetelstat是一款全球首创的寡核苷酸端粒酶抑制剂，作为一种首创的治疗方法，通过抑制端粒酶的活性来发挥作用。在患者筛选方面，我们并未基于端粒长度来进行筛选。我们的筛选标准是针对那些根据国际预后评分系统（IPSS）定义的、伴有输血依赖性贫血、对红细胞生成刺激剂（ESAs）无应答或产生耐药或不适合使用ESAs、非del(5q)、未经来那度胺和去甲基化药物（len/HMA）治疗的LR-MDS患者，这些患者需要持续输注红细胞，具体来说，需在8周内输入4个或更多单位红细胞。
通过这种严格的患者筛选流程，我们确保了入组的患者群体具有均质性，均为低风险且有输血依赖性的患者。这种创新有助于我们更准确地评估Imetelstat的疗效。目前，我们正在考虑如何利用IMerge试验的结果来进一步优化患者选择，以便为LR-MDS患者提供更加个性化和有效的治疗方案。
Hematology Frontier：What innovative approaches or strategies were used in your research to enhance the precision and effectiveness of treatment for LR-MDS patients?
Dr. Valeria Santini：This treatment imetelstat is a completely new drug and new approach. We are not sure that the mechanism of action is the telomerase inhibition, but in fact, this drug has this activity. We didn't select the patients on the basis of the telomere length or telomerase activity. We just selected lower risk MDS patients, according to IPSS who were transfusion dependent with a heavy transfusion burden from four to more than six. And the median was six red blood cell transfusion in 8 weeks. What was more selective for the patient was that they couldn't have received any other treatment before the erythropoiesis-stimulating factors. So they could not have received lenalidomide and hypomethylating agents. That were the two exclusion criteria. The patients were all transfusion dependent, lower risk. And in fact, this was the way we went on. And now we have to evaluate whether we can select patients on the basis of results obtained in the IMerge trial.
《血液时讯》：您如何评价Imetelstat治疗在临床上的获益，特别是在实现RBC-TI方面？
Valeria Santini教授：我们根据国际工作组（IWG）2000年的标准，以及最新的临床指南，对患者的RBC-TI进行了评估。这意味着患者需要达到连续超过8周RBC-TI，进一步的目标是实现连续6个月以及连续一年的RBC-TI。
达到超过一年的RBC-TI意义重大，可显著改善患者的日常生活质量。最重要的疗效评估在于，这些患者不再需要频繁前往医院接受输血治疗，这一改变显著减轻了他们的身体和心理负担。因此，我们认为Imetelstat治疗在临床上提供了显著的益处，特别是在减少LR-MDS患者对红细胞输血的依赖性方面。
Hematology Frontier：How do you assess the clinical benefits of Imetelstat treatment, particularly in achieving durable RBC-TI?
Dr. Valeria Santini：To evaluate the activity and efficacy of the imetelstat, we evaluated the length of transfusion independence according to IWG criteria 2,000. But we also applied the most recent criteria as well, meaning that the patients had to have transfusion independence longer than 8 weeks continuously without interruption. And then also 6 months transfusion independence in a continuous way and more than 1 year transfusion independence. So achieving more than 1 year transfusion independence was a great goal, because a great objective was reached. These really changes the life of our patients. They don't have to go to the hospital, and this was the main assessment of efficacy.