Myelodysplastic Syndromes (MDS) are heterogeneous bone marrow disorders where defective blood-forming stem cells produce abnormal, immature, and non-functional blood cells. This results in cytopenia, a persistent deficiency of mature cell types in the peripheral blood. MDS can progress to Acute Myeloid Leukemia (AML). The clinical course of MDS is highly variable, ranging from a stable illness requiring only supportive care to a rapidly progressing disease with a poor prognosis. Because of this wide spectrum of outcomes, risk stratification is employed to accurately predict the disease’s trajectory and guide appropriate treatment.
Key Biological Factors Determining Risk
Risk stratification in MDS focuses on three specific cellular and hematological inputs.
The most significant factor is the bone marrow blast percentage, which measures the proportion of immature white blood cells (blasts) in the bone marrow or peripheral blood. Blasts are non-functional cells, and their elevated presence is the strongest predictor of transformation into AML. Even a small increase in blast percentage significantly worsens the prognosis.
The second factor involves cytogenetics, the study of structural or numerical abnormalities (karyotypes) within the MDS cells. These chromosomal changes are fundamental indicators of disease behavior. Favorable outcomes are associated with specific deletions like isolated loss of chromosome 5q (\(\text{del(5q)}\)) or the loss of the Y chromosome \((-\text{Y})\). Conversely, complex karyotypes or the loss of chromosome 7 \((-\text{7})\) predict a poorer prognosis and higher risk of AML evolution.
The third factor relates to the depth of peripheral blood cytopenias, which quantifies the severity of low blood cell counts. Physicians assess hemoglobin (anemia), platelets (thrombocytopenia), and the absolute neutrophil count (ANC, neutropenia). Modern risk models assign different weights based on the degree of reduction in each cell line, emphasizing that the severity of the cytopenia directly contributes to the overall risk.
The Standardized Prognostic Scoring Systems
Clinicians use standardized prognostic scoring systems to combine biological factors into a unified risk assessment. The International Prognostic Scoring System (IPSS) was the historical standard, but it was limited by grouping patients into only three broad cytogenetic categories and not adequately accounting for cytopenia severity. This led to the development of the Revised International Prognostic Scoring System (R-IPSS), which is now the gold standard for prognostication.
The R-IPSS refined the assessment by assigning statistically weighted numerical points to five input variables. It introduced a more granular categorization for blast percentage and expanded the cytogenetic classification from three to five distinct prognostic groups: Very Good, Good, Intermediate, Poor, and Very Poor. The cumulative score is calculated by adding points for blast percentage, the specific cytogenetic category, hemoglobin level, platelet count, and absolute neutrophil count. This weighted approach ensures that factors with the highest prognostic impact, particularly cytogenetics and blast percentage, exert a greater influence on the final risk category.
Interpreting the Risk Categories
The numerical score generated by the R-IPSS translates into five distinct risk categories: Very Low, Low, Intermediate, High, and Very High. Each category is linked to two primary prognostic outcomes: overall survival time and the probability of transformation to AML.
For example, a patient classified as Very Low risk has an estimated median overall survival of approximately 8.8 years, with a low likelihood of AML transformation. Conversely, a patient in the Very High risk category faces a significantly shorter prognosis, with a median overall survival of less than one and a half years and a high probability of rapid progression to AML. The Intermediate category exhibits outcomes between these extremes, with a median survival of about three years. This clear stratification allows physicians to communicate the expected disease behavior with greater precision.
Connecting Risk to Treatment Decisions
The R-IPSS risk category is the main determinant for selecting the appropriate intensity of treatment, defining a clear risk-adapted therapeutic approach.
Lower-Risk MDS Treatment
Patients in the Very Low and Low risk categories are grouped as “lower-risk MDS” and are typically managed with supportive care strategies. The primary goal is to manage symptoms related to cytopenias and improve quality of life. This includes providing red blood cell transfusions for anemia or administering erythropoiesis-stimulating agents (ESAs) to boost red blood cell production. For patients with the specific \(\text{del(5q)}\) abnormality, the immunomodulatory drug lenalidomide is often highly effective in achieving transfusion independence.
Higher-Risk MDS Treatment
For patients categorized as High or Very High risk (“higher-risk MDS”), the focus shifts to aggressive, disease-modifying therapies aimed at prolonging life and reducing the risk of AML transformation. These patients are often candidates for hypomethylating agents (HMAs), such as azacitidine or decitabine, which work by altering gene expression to encourage normal blood cell development. The only potentially curative option for MDS is an Allogeneic Stem Cell Transplantation (alloSCT). This procedure is typically reserved for younger, fitter patients in the higher-risk groups where the potential benefit of a cure outweighs the significant risks.