Low-risk myelodysplastic syndromes (LR-MDS) are complex blood disorders characterized by the abnormal proliferation and dysfunction of marrow cells, leading to increased risks of anemia, bleeding, and infection. Although the progression of LR-MDS is relatively slow, the treatment of this disease still faces significant challenges. Existing therapeutic options, such as erythropoiesis-stimulating agents (ESAs) and immunomodulators, may alleviate symptoms to some extent but often struggle to achieve long-term disease control and can be associated with significant side effects. Against this backdrop, Dr. Valeria Santini explored the potential of Imetelstat, a first-in-class oligonucleotide telomerase inhibitor, in treating patients with LR-MDS through the IMerge trial. The 12th Annual Meeting of the Society for Hematologic Oncology (SOHO 2024) took place in Houston, USA, from September 4 to 7, 2024, bringing together top experts in the field of hematologic oncology worldwide to share the latest research findings and discuss new treatment strategies. Hematology Frontier specially invited Dr. Valeria Santini from the University of Florence, MDS Unit, Hematology, DMSC, AOUC, Florence, Italy, to delve into the research outcomes of this Phase III clinical trial, discussing the significant progress achieved by Imetelstat in improving the precision and effectiveness of LR-MDS patient treatment, and how this discovery may provide a new direction for future strategies in the MDS treatment field.

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.

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.

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.