Myelodysplastic Syndromes (MDS) are a group of heterogeneous myeloid clonal disorders originating from hematopoietic stem cells, characterized by dysplastic development of myeloid cells, manifested as ineffective hematopoiesis, refractory cytopenia, and the potential to transform into acute myeloid leukemia (AML). At the 2024 American Society of Hematology (ASH) Annual Meeting held in San Diego, USA from December 7th to 10th, numerous studies in the field of MDS were announced, with significant progress particularly in the treatment and prognosis assessment of low-risk MDS. "Hematology Frontier" specially invited Dr. Huaquan Wang from the Department of Hematology, Tianjin Medical University General Hospital, to select and comment on the key studies, in hopes of bringing cutting-edge information and unique insights to everyone.

Early Versus Late Onset of ESA in Lower Risk Anemic MDS Patients: Results of the GFM Randomized Phase III EPO-Pretar Trial

Number: 349 Presenter: Sophie Park

Dr. Huaquan Wang：This study presents the findings of the Phase III EPO-PRETAR trial, which aimed to evaluate the impact of early versus late initiation of erythropoiesis-stimulating agents (ESA) in patients with low-risk anemic myelodysplastic syndromes (MDS). The trial assessed various endpoints, including the time to RBC transfusion dependence (TD), hematologic improvement (HI-E), progression-free survival (PFS), overall survival (OS), and quality of life.

The study’s multicenter, open-label design included 84 patients with baseline hemoglobin levels between 9 and 10.5 g/dL. Patients were randomized into two groups: an early initiation group (ESA started within six months of diagnosis) and a late initiation group (ESA started when RBC transfusion criteria were met). Results demonstrated that early ESA initiation significantly improved the incidence and duration of HI-E compared to late initiation. However, the time to TD, PFS, and OS were similar across the two groups, indicating that early intervention does not necessarily delay disease progression or improve survival outcomes.

The key takeaway is that while early ESA therapy provides short-term benefits in anemia management, its advantages in slowing disease progression and extending survival are limited. This underscores the importance of a nuanced approach in clinical decision-making, balancing short-term benefits against long-term outcomes.

Furthermore, the study highlights the predictive role of biomarkers such as serum EPO levels, IPSS-M scores, and SF3B1 mutations in determining ESA response. These findings provide valuable insights for clinicians when selecting candidates for ESA therapy and optimizing treatment timing.

Despite its contributions, the study has limitations. The median follow-up of 34 months may not adequately capture long-term outcomes, and the predominantly elderly cohort (median age: 84 years) restricts the applicability of findings to younger populations. Future studies should explore ESA in combination with other therapeutic strategies, such as immunosuppressive therapy or chemotherapy, and assess their impact on different patient subgroups.

In conclusion, early ESA initiation appears effective for managing anemia in low-risk MDS patients but has limited impact on delaying TD or improving long-term outcomes. Treatment decisions should be tailored to individual patient profiles, considering disease characteristics, treatment tolerance, and long-term prognosis.

Combining ESA and Luspatercept in Non-RS MDS Patients Having Failed ESA – Results of the Phase 1-2 Part a of the GFM Combola Study

Number: 351 Presenter: Lionel Ades

Dr. Huaquan Wang：This study reports the Phase I/II Part A findings from the COMBOLA trial, exploring the safety and efficacy of luspatercept combined with ESA in low-risk (LR) non-ring sideroblast (non-RS) MDS patients. While luspatercept is already approved for RS-positive MDS patients with transfusion-dependent anemia, its role in non-RS MDS has been unclear.

The trial identified the recommended Phase II dose (RP2D) as luspatercept 1.75 mg/kg every 21 days combined with EPO 60,000 UI weekly. Although no DLTs were observed, efficacy was modest, with only 29% of patients achieving an erythroid response. Importantly, responses were longer in low transfusion burden patients, highlighting the potential benefit in select populations.

The study also demonstrated the manageable safety profile of this combination, despite some severe adverse events such as infections and cardiac issues. These findings provide valuable preliminary data on the potential of luspatercept and ESA combination therapy.

However, the study’s small sample size and short follow-up period limit its conclusions. Larger randomized trials, such as Part B of the COMBOLA trial, are needed to validate these findings and further evaluate the long-term outcomes and potential benefits of this therapeutic approach.

In summary, this study establishes a foundation for luspatercept and ESA combination therapy in non-RS low-risk MDS patients, offering new possibilities for improving treatment outcomes in this challenging subgroup.

Professor Huaquan Wang

• Chief Physician and Administrative Deputy Director, Department of Hematology, Tianjin Medical University General Hospital
• Doctoral Supervisor

Professional Affiliations:

• Member and Secretary, Red Cell Disease (Anemia) Group, 9th, 10th, and 11th Committees of the Hematology Branch of the Chinese Medical Association; Vice Chair of the 10th Committee
• Member, Leukemia and Lymphoma Group, 11th Committee of the Hematology Branch of the Chinese Medical Association
• Member, 5th Committee of the Hematology Physician Branch of the Chinese Medical Doctor Association
• Member, 1st Committee of the Hematology Branch of the Chinese Geriatrics Society
• Member, MDS Academic Working Committee
• Member, 2nd Committee of the Chinese MDS/MPN Working Group under the Hematologic Oncology Professional Committee of the Chinese Anti-Cancer Association