Low Hemoglobin, IDH2 Mutation Indicative of Poor Survival in MDS

A retrospective study published in Leukemia and Lymphoma suggested the presence of predictive biomarkers for outcomes of myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) with plasma cell neoplasms (PCN), as well as gave insights into the clinical features of MDS.¹

Genetic mutation may play a role in survival outcomes in MDS | image credit: Justlight - stock.adobe.com

MDS is a group of heterogeneous clonal hematopoietic stem cell disorders that are characterized by cytopenias leading to ineffective hematopoiesis and increased blast production, resulting in bone marrow failure.² There is also a risk of progression to acute myeloid leukemia (AML). MDS is more common in the elderly, possibly due to a state of inflammation brought about with aging. The most common MDS subtype associated with PCN is MDS with low blasts, followed by MDS with increased or excess blasts or MDS with 5q deletion. Very rarely, MDS/MPN are associated with PCN.

A total of 225 patients whose bone marrow biopsies were submitted were identified over 8 years from the medical archives of the pathology department of the University of Virginia Health System. Twenty-six of these patients were identified to have MDS or MDS/MPN along with PCN while 68 had MDS/MPN without PCN.¹

Twenty-one out of 26 patients had MDS with PCN while 5 had MDS/MPN with PCN. The MDS components of the 21 patients were further classified based on the findings at the time of diagnosis: 11 had MDS with low blasts, 7 had MDS with excess blasts, 2 had MDS with 5q mutations and 1 had MDS with SF3B1 mutation. The researchers noted that 88% of patients had PCN diagnosed at the same time as their MDS or MDS/MPN while 2 patients developed MDS months after their diagnosis of smoldering multiple myeloma without previously receiving cytotoxic therapy. Therapy-induced MDS has been previously seen in patients with plasma cell myeloma or multiple myeloma.

In this study, the complete treatment information was available only for 20 patients. Five patients with MDS were given azacytidine, 2 patients were treated with darbepoetin alpha, while the remaining 6 received hypomethylating agents or regular blood transfusions. The patients with MDS/MPN mainly received hydroxyurea while 1 was treated with hematopoietic stem cell transplant.

Patients with MDS are categorized into different risk groups. Lower-risk MDS patients are those who have a risk of very low, low, or intermediate disease with a score of 3.5 points or less on the Revised International Prognostic Scoring System (IPSS-R) scale.³ Higher risk patients are patients with a risk of intermediate disease (>3.5 points), high, or very high risk. In this study, only 7 patients were classified as high risk or very high risk with the rest being lower risk patients.¹

Genetic mutations are an important driver of diseases. While there isn’t a specific mutation to define these diseases, they can help in establishing a diagnosis. The most commonly mutated gene observed in the MDS-PCN subgroup was DNMT3A followed by ASXL1. The most commonly mutated gene in the MDS/MPN-PCN subgroup was SRSF2. Co-mutation with TET2 was a highly specific indicator of MDS/MPN phenotype. However, there were no common mutations in both of these subgroups that would explain their association with PCN.

The study also sought to find out indications of poor survival. Hemoglobin less than 8 g/dL, IPSS-R category of intermediate or higher, blast percentage of ≥ 5% and somatic mutations in IDH2 were all associated with poor survival. Hemoglobin less than 8 g/dL and mutation in IDH2 were found to be independent predictors of poor survival. The findings likely explain the high mortality rate in patients with MDS/MPN-PCN compared to MDS-PCN. Patients with MDS/MPN-PCN also had increased fibrosis which may contribute to poor survival. Increased fibrosis was only seen in patients of the MDS/MPN-PCN subgroup. A possible explanation given by the study was that the PCN augments the fibrosis already present in patients with MDS/MPN. Moreover, MDS/MPN-PCN was associated with a worse overall survival

References

1. Adekunle F, Ko K, Craig J, et al. Concurrent myelodysplastic malignancies and plasma cell neoplasms; a clinicopathological study with prognostic implications. Leuk Lymphoma. 2024:1-8. doi:10.1080/10428194.2024.2391905

2. Arellano-Ballestero H, Sabry M, Lowdell MW. A killer disarmed: natural killer cell impairment in myelodysplastic syndrome. Cells. 2023;12(4):633. doi:10.3390/cells12040633

3. Giagounidis A. Current treatment algorithm for the management of lower-risk MDS. Hematology Am Soc Hematol Educ Program. 2017;2017(1):453-459. doi:10.1182/asheducation-2017.1.453