The 29th European Hematology Association (EHA) Annual Meeting was grandly held in Madrid, Spain, from June 13-16, 2024. As the largest international conference in the field of hematology in Europe, it attracts experts and scholars from around the world every year to share and discuss innovative ideas and the latest scientific and clinical research findings in hematology. At this year's conference, the latest classification standards and clinical research outcomes for MDS received widespread attention. "Oncology Frontier - Hematology Frontier" invited Professor Hongyan Tong from The First Affiliated Hospital, Zhejiang University School of Medicine to provide an in-depth interpretation of the key updates in the latest WHO MDS classification standards and share her team's groundbreaking research achievements in MDS, particularly in the MDS-f subtype.

Oncology Frontier – Hematology Frontier: MDS is a highly heterogeneous clonal hematologic malignancy, and its classification standards are continuously updated. What are the significant updates and adjustments in the 2022 (fifth edition) WHO MDS classification compared to the 2016 version?

Professor Hongyan Tong: In the field of hematology, the classification standards for myelodysplastic syndromes (MDS) have been evolving to accommodate our increasing understanding of this heterogeneous disease. The fifth edition of the WHO MDS classification, released in 2022, includes several important updates and adjustments compared to the 2016 version:

1. Emphasis on Genetic and Molecular Classification

The 2022 classification places greater emphasis on the importance of genetic and molecular characteristics in the diagnosis and classification of MDS. Specific genetic abnormalities define certain MDS subtypes, such as SF3B1 mutation (MDS-SF3B1) and 5q- syndrome (5q- MDS), which have relatively better prognoses, primarily presenting as anemia with longer survival times. There are also targeted treatments for anemia in these subtypes, such as lenalidomide and luspatercept. The new classification particularly highlights MDS with TP53 mutations and biallelic inactivation mutations (MDS-biTP53), which have a very poor prognosis. This finding underscores the need to pay special attention to identifying and distinguishing these specific molecular types of MDS in diagnosis and treatment.

1. Further Refinement of Lower-Risk MDS

The new classification continues to use 5% bone marrow blasts as a critical cutoff value. Among MDS with less than 5% blasts, one special type is hypoplastic MDS. Although this subtype has been mentioned in the past, it is now separately distinguished from lower-risk MDS in the new standards. This year’s EHA meeting also featured research on hypoplastic MDS, exploring interventions for its immune disorders, immune dysregulation, and chronic inflammatory responses.

1. Independent Classification of MDS with Bone Marrow Fibrosis

MDS with bone marrow fibrosis has been separately classified to emphasize its severe prognosis. Even among MDS types with more than 5% blasts, patients with bone marrow fibrosis have a poor prognosis, and fibrosis significantly impacts their outcomes. This independent classification helps us more accurately identify this subtype and explore corresponding treatment methods.

Oncology Frontier – Hematology Frontier: At this year’s EHA conference, your team presented a study on the reclassification of 420 patients based on the 2022 fifth edition of the WHO MDS classification, with a particular focus on the impact of bone marrow fibrosis (MF). Could you briefly introduce this study and its main findings?

Professor Hongyan Tong: At this year’s EHA conference, our team presented a cohort study based on the 2022 fifth edition of the WHO MDS classification, reclassifying 420 MDS patients to observe the clinical characteristics of bone marrow fibrosis (MF). We found that over 40% of patients had varying degrees of bone marrow fibrosis, with about one-third of these patients having grade 2 or 3 fibrosis. Specifically, the proportion of grade 3 fibrosis in MDS was about 5%, and these patients had very poor prognoses, with a progression-free survival (PFS) of only 8 months and a median overall survival (mOS) of only 12 months. This indicates that in higher-risk MDS, bone marrow fibrosis is one of the subtypes with a poor prognosis. Additionally, we observed that patients with fibrosis often had significantly elevated levels of lactate dehydrogenase (LDH) and C-reactive protein (CRP), suggesting that chronic inflammatory responses may be involved in the pathogenesis of MDS.

Oncology Frontier – Hematology Frontier: Your research mentioned a new subtype, MDS-f, which accounts for approximately 5.4% of MDS patients. How do you think the proposal of the MDS-f subtype will promote clinical research in MDS?

Professor Hongyan Tong: The MDS-f subtype was independently classified in the WHO 2022 guidelines. MDS with fibrosis has been reported in several international research centers. Professors Zhijian Xiao from the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences, and Changkang Chang from the Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University have also published relevant research findings.

Based on data from our center at the First Affiliated Hospital of Zhejiang University School of Medicine, the MDS-f subtype has a poor prognosis among high-risk MDS, characterized by significant bone marrow fibrosis. Patients with grade 2 or 3 fibrosis account for about 10-15%. Currently, treating this subtype remains challenging, with traditional hypomethylating agents (HMA) monotherapy or “HMA+X” regimens still presenting issues of bone marrow suppression and unpredictable side effects when treating patients with fibrosis.

Therefore, I believe that future treatment strategies need to start from the pathological mechanism, exploring new treatments specific to MDS-f. For example, research into JAK inhibitors or anti-fibrotic drugs may offer new therapeutic options for MDS patients with fibrosis.

Oncology Frontier – Hematology Frontier: Looking to the future, what do you think are the major unresolved issues or challenges in the field of MDS research? How do you plan to continue advancing research in this area?

Professor Hongyan Tong: At this EHA conference, the MDS field updated several important clinical research outcomes, focusing on immune-related mechanisms such as Tim-3 and CD47. Although the two global phase III studies on Tim-3 and CD47 did not meet their primary endpoints, they provided extensive data and showed some therapeutic potential.

The reason these studies did not meet expectations may be related to patient stratification. The conference emphasized the need to more accurately distinguish which patient groups can benefit from immunotherapy in MDS. Therefore, there was a significant focus on discussing the complex immune abnormalities associated with MDS. To better identify these mechanisms, prospective studies need to be conducted to carefully sort and stratify them, so personalized treatment plans can be designed and implemented based on different immune mechanisms.