Editorial Note: Myelodysplastic syndromes (MDS) are a group of heterogeneous myeloid clonal disorders originating from hematopoietic stem cells, characterized by dysplastic development of myeloid cells, ineffective hematopoiesis, refractory cytopenia, and a potential progression to acute myeloid leukemia (AML). At the 2024 Annual Meeting of the American Society of Hematology (ASH), held from December 7 to 10 in San Diego, numerous studies on MDS were presented, showcasing significant progress in the treatment and prognostic evaluation of low-risk MDS. Oncology Frontier - Hematology Frontier invited Dr. Huaquan Wang from Tianjin Medical University General Hospital to provide expert commentary on the most impactful research in this field, delivering cutting-edge insights to our readers.

Impact of Response to Hypomethylating Agent-Based Therapy on Survival Outcomes in the Context of Baseline Clinical-Molecular Risk and Transplant Status in Patients with Myelodysplastic Syndromes/Neoplasms (MDS): An Analysis from the International Consortium for MDS (icMDS) Validate Database

At the 2024 ASH meeting, Professor Benjamin Rolles presented findings from the International MDS Alliance (icMDS) VALIDATE database (Abstract No.: 664), highlighting that baseline IPSS-M risk and allogeneic hematopoietic stem cell transplantation (allo-HCT) independently influence overall survival (OS). Meanwhile, composite complete response (cCR), as defined by the IWG 2023 criteria, independently affected OS only in non-transplanted MDS patients. Key clinical implications from this study include:

1. Failure to achieve cCR before transplantation should not preclude allo-HCT.
2. Direct transplantation without prior HMA treatment may be an option, depending on clinical circumstances and donor availability.
3. Ideally, allo-HCT should occur at the optimal time based on patient age and baseline IPSS-M risk.

Dr. Huaquan Wang：This study, based on a large dataset from the International MDS Alliance (icMDS) VALIDATE database, explored the impact of hypomethylating agent (HMA) treatment on survival outcomes in patients with myelodysplastic syndromes (MDS), particularly in the context of baseline clinical-molecular risk assessment (IPSS-M) and allogeneic hematopoietic stem cell transplantation (allo-HCT). The study addressed several key questions: whether responses defined by the IWG 2023 criteria independently affect overall survival (OS); whether HMA-induced responses improve survival in patients undergoing allo-HCT; and whether the optimal timing of transplantation significantly influences OS in MDS patients.

The study analyzed data from 762 MDS patients. The results showed that 37% of patients achieved composite complete response (cCR) after HMA treatment. Among non-transplanted patients, achieving cCR significantly improved OS compared to those who did not achieve cCR, regardless of their IPSS-M risk category. However, for transplanted patients, achieving cCR prior to allo-HCT did not provide additional OS benefits. Specifically, in the non-transplanted group, OS was significantly longer for patients who achieved cCR than for those who did not. Meanwhile, among transplanted patients, cCR achieved before HMA treatment did not further improve OS after adjusting for baseline IPSS-M risk. Furthermore, the study demonstrated that the optimal timing of transplantation was associated with better OS in patients who underwent allo-HCT.

This study provides an in-depth analysis of the independent predictive role of HMA treatment responses on the survival of MDS patients.

Firstly, the results highlight the importance of cCR for non-transplanted patients, emphasizing that patients who fail to achieve cCR should not be excluded from allo-HCT as a treatment option. This finding holds significant clinical implications for therapeutic decision-making.

Secondly, for patients who underwent allo-HCT, achieving cCR did not further improve OS, suggesting that transplantation itself is the primary determinant of survival. This observation indicates that survival outcomes may depend more critically on other factors, such as patient age and disease status, rather than on achieving a complete response.

Additionally, the study underscores the importance of optimal transplantation timing. For patients who achieved cCR following HMA treatment, undergoing allo-HCT at the optimal timing significantly improved OS. This finding provides clear guidance for clinical practice, suggesting that transplantation should be performed as early as possible in patients with a favorable treatment response to maximize survival benefits.

Despite the large sample size and the valuable insights into the relationship between HMA treatment and transplantation strategies, the study has some limitations.

Firstly, as a retrospective analysis, the results may be influenced by selection bias and variations in treatment decisions.

Secondly, although the definition of optimal transplantation timing offers valuable guidance, its application may vary across different hospitals and clinical practices. Further studies are needed to validate the survival benefits associated with different transplantation timings. Lastly, while the study emphasizes the importance of cCR for non-transplanted patients, it does not fully explore differences in efficacy among HMA agents (e.g., azacitidine vs. decitabine). Future research could further evaluate the differences between these treatment regimens.

In summary, this study provides valuable clinical data on the relationship between transplantation strategies and HMA treatment responses in MDS, offering new insights into personalized treatment decision-making. In future clinical practice, combining treatment responses with optimal transplantation timing may further optimize therapeutic outcomes and improve survival in MDS patients.

Landscape of Immune Cell States and Ecosystems in Patients with Myelodysplastic Syndrome to Refine Prognostic Assessment and Predict Treatment Response. a Study By i4MDS Consortium

At the 2024 ASH Annual Meeting, Elena Riva presented findings from the i4MDS Alliance study (Abstract #665), revealing that the immune ecosystem captures the clinical heterogeneity of myelodysplastic syndromes (MDS) across different subtypes, surpassing genotypic classification. These results provide a comprehensive system-level analysis of the MDS microenvironment and highlight opportunities for immune monitoring in clinical practice to enhance decision-making processes.

Dr. Huaquan Wang：This study highlights the critical role of the immune microenvironment in myelodysplastic syndromes (MDS) by analyzing the immune cell ecosystems of MDS patients. It introduces a novel approach for precision prognostic evaluation and predicting treatment response. Conducted by the i4MDS Alliance, the research carries significant implications for clinical practice and therapeutic decision-making.

Key Contributions

1. Identification of Five Immune Ecosystems The study’s major contribution lies in identifying five distinct immune ecosystems in MDS patients, categorized based on immune functionality and cell maturation stages. These findings underscore that MDS progression is influenced not only by tumor-related genetic mutations but also by the state of the immune microenvironment. The clear differences between healthy immune ecosystems and immunosuppressive ecosystems provide insights into disease heterogeneity and immune evasion mechanisms.
2. Prognostic Significance of Immune Ecosystems The study demonstrates the relationship between immune ecosystems and patient survival, as well as the risk of leukemic transformation. It further confirms the prognostic role of immune ecosystems within the framework of IPSS-M risk stratification and ICC/WHO 2022 classifications. The independent prognostic impact of immune ecosystems in multivariable analysis suggests their potential as novel biomarkers for more accurate prognostic assessment. This stratification not only aids clinical decision-making but also points to new directions for individualized treatment approaches in MDS.
3. Association with HMA Treatment Response The study explores the correlation between immune ecosystems and HMA treatment response, revealing that baseline immune ecosystems can effectively predict complete remission probabilities, with significant differences across groups. Intervening in immune dysfunction allowed some patients to achieve long-term responses, presenting new possibilities for MDS immunotherapy. The dynamic changes in immune ecosystems and their association with treatment responses provide a practical reference for clinical immune monitoring.
4. Development of Immune Monitoring Panels The research also showcases the clinical application potential of immune monitoring panels. By designing a pre-configured dry antibody panel, the study offers a feasible solution for clinical detection of immune ecosystems. This non-invasive method greatly simplifies clinical applications and enhances real-time monitoring of the immune status in MDS patients.

Conclusion

Through a systematic analysis of the immune microenvironment in MDS patients, this study provides novel theoretical support for disease prognosis and therapeutic decision-making. The discovery of immune ecosystems not only paves the way for new immunotherapeutic strategies in MDS but also holds potential implications for other hematologic diseases.

However, as this is a prospective study, further clinical validation is required to solidify the role of immune ecosystems in predicting treatment response and long-term survival outcomes. Additionally, the development and standardization of tools for evaluating immune ecosystems in clinical practice face technical and practical challenges that need to be addressed.

Huaquan Wang

Chief Physician, Department of Hematology Tianjin Medical University General Hospital Doctoral Supervisor, Vice Director

• Member and Secretary of the Anemia Subgroup, Chinese Society of Hematology, Ninth, Tenth, and Eleventh Committees
• Vice Leader of the Anemia Subgroup, Tenth Committee
• Member of the Leukemia and Lymphoma Subgroup, Eleventh Committee
• Member, Fifth Committee of the Hematology Branch, Chinese Medical Doctor Association
• Member, First Committee of the Hematology Branch, Chinese Geriatrics Society
• Member, MDS Academic Work Committee
• Member, Second Committee of the MDS/MPN Working Group, Hematologic Oncology Branch, Chinese Anti-Cancer Association