Clinical Characteristics and Prognostic Implication for Myelodysplastic Syndromes/Neoplasms Patients with or without Cytogenetic Abnormalities or Gene Mutations
Authors: Lee Wan Hsuan , Lin Chien-Chin , Tsai Cheng-Hong , Tien Feng-Ming , Lo Min Yen , Tseng Mei-Hsuan , Kuo Yuan-Yeh , Yu Shan-Chi , Liu Ming-Chih , Yuan Chang-Tsu , Tien Hwei-Fang , Hou Hsin-An , Chou Wen-Chien 
Published: December 2024

Myelodysplastic syndromes/neoplasms (MDS) comprise a diverse set of clonal myeloid disorders marked by ineffective hematopoiesis, recurrent chromosomal aberrations, and gene mutations, leading to cytopenias and dysplastic hematopoietic cells. Cytogenetic abnormalities are found in 40-50% of MDS cases and only 10-30% of patients diagnosed through standard workup have no detectable mutations on next generation sequencing (NGS). The clinical characteristics and outcomes had not been well explored between patients with at least one gene mutation or cytogenetic changes and those without any molecular abnormalities. Thus, we conducted a retrospective study that comprised 758 patients with primary MDS, diagnosed and treated in National Taiwan University Hospital. Patients with a history of chemotherapy, radiotherapy, or hematologic malignancies were excluded. Cytogenetic analyses were performed and interpreted according to the International System for Human Cytogenetic Nomenclature. The TruSight myeloid sequencing panel (Illumina, San Diego, CS, USA) and HiSeq platform (Illumina, San Diego, CA, USA) were used to analyze alterations in 54 myeloid-neoplasm-related genes.

Overall, 20.4% of patients did not have any gene mutation or cytogenetic abnormalities at diagnosis. For clinical characteristics, female (55.5% vs. 31.2%, P&lt;0.001) and younger (58 vs. 69 years old, P&lt;0.001) patients had higher proportion of not harboring these molecular abnormalities. Patients without cytogenetic abnormalities or gene mutations had higher absolute neutrophil count, lower bone marrow blast percentage, and lower-risk group of IPSS-R or IPSS-M at diagnosis and more of them received only supportive care for MDS. Based on 2022 World Health Organization classification, 43.0% of patients without cytogenetic abnormalities or gene mutations were classified as MDS with low blasts and 38.4% of patients with hypoplastic MDS did not have cytogenetic change or gene mutation. While categorized patients with International Consensus Classification, 85.8% of patients without cytogenetic abnormalities or gene mutations were in group of MDS, not otherwise specified, single lineage or multilineage dysplasia. At the same time, 61.0%, 44.0% and 25.4% of patients with increased/excess blasts, based on 2016 WHO, 2022 WHO or ICC respectively had at least one gene mutation or chromosomal abnormalities. Survival analysis showed that patients without cytogenetic abnormalities or gene mutations had lower two-year (1.3% vs. 21.8%, P&lt;0.001) and five-year (1.3% vs. 26%, P&lt;0.001) leukemic transformation rate. Furthermore, these patients had longer overall survival (250.7 vs. 28.3 months, P&lt;0.001) and leukemia-free survival (218.7 vs. 22.3 months, P&lt;0.001). Subgroup analysis for patients in the same group of IPSS-R or IPSS-M revealed that individuals without cytogenetic abnormalities or gene mutations had superior outcomes than those without.

In conclusion, cytogenetics abnormalities and gene mutations at diagnosis play a crucial role in predicting outcomes. However, the survival differences between patients with or without cytogenetic abnormalities or gene mutations within the same category of IPSS-R or IPSS-M suggest that these two scoring systems may not fully capture the prognostic implications of cytogenetics change or gene mutations. Further studies examining immune dysregulation, or the microenvironment may be warranted to enhance current risk stratification tools and improve our understanding of the pathophysiology of MDS.