Myelodysplastic Syndromes (MDS) are a group of bone marrow disorders where the body fails to produce enough healthy, mature blood cells. This condition is characterized by the production of abnormal, immature cells in the bone marrow. Unlike solid tumors, which are assigned numerical stages based on size and spread, MDS is not staged using a system like Stage I through IV. Instead, a patient’s disease is first categorized based on the appearance of the cells and then stratified into risk groups to determine the course of the disease and guide treatment decisions.
Understanding the Diagnostic Classification (WHO)
The World Health Organization (WHO) classification system provides the descriptive diagnostic framework for MDS, focusing on the underlying cellular pathology. This system categorizes the disease based on what the cells look like under a microscope and increasingly incorporates specific genetic abnormalities. The classification relies on three main components: low blood cell counts, the degree of dysplasia, and the percentage of immature cells, or blasts, found in the bone marrow.
Dysplasia refers to the abnormal shape, size, and appearance of blood cell precursors in the bone marrow. The WHO system accounts for how many cell lines (red blood cells, white blood cells, or platelets) are affected. Subtypes are defined by this morphological assessment, such as MDS with single lineage dysplasia or MDS with multilineage dysplasia, where two or three cell lines are affected.
Another element is the count of blast cells, which are normally less than 5% in healthy bone marrow. When the blast percentage increases, the subtype changes to MDS with excess blasts (MDS-EB), which is further divided into MDS-EB-1 (5–9% blasts) and MDS-EB-2 (10–19% blasts).
The WHO system also recognizes specific genetic subtypes, such as MDS with isolated deletion 5q, which often responds uniquely to certain therapies. This classification system serves as the initial step, defining the specific type of MDS a patient has before their prognosis is evaluated.
The Prognostic Staging System (IPSS-R)
The most widely used method for determining the outlook and functional “staging” of MDS is the Revised International Prognostic Scoring System (IPSS-R). This system moves beyond the descriptive classification to quantify a patient’s risk level, predicting both survival and the likelihood of the disease progressing to acute myeloid leukemia (AML). The IPSS-R combines multiple clinical and genetic factors, assigning different weights to each to generate a comprehensive risk score. This score then places a patient into one of five distinct prognostic categories.
The IPSS-R calculation is based on five separate components. The first is the percentage of blast cells found in the bone marrow, which is highly predictive of disease progression. The most heavily weighted component is cytogenetics, which involves analyzing the chromosomes for abnormalities, as specific changes can indicate a particularly aggressive disease course. The system has refined this component by defining five distinct cytogenetic prognostic subgroups.
The remaining three factors assess the depth of the patient’s cytopenias, or low blood cell counts, which directly impact symptoms and the need for supportive care. These include the patient’s hemoglobin level, the absolute neutrophil count, and the platelet count. The score assigned to each of these five variables is added together to generate a total risk score.
This final score then places the patient into one of the five categories: Very Low, Low, Intermediate, High, or Very High risk. The IPSS-R provides a more precise estimation of prognosis than previous systems by incorporating the severity of the low blood counts and more detailed cytogenetic findings. For example, a patient with a very low blast count but an unfavorable chromosomal abnormality may be categorized as a higher risk than a patient with a slightly higher blast count but normal chromosomes. This stratification is crucial because it allows physicians to tailor the treatment approach to the predicted risk level.
How Risk Levels Guide Treatment
The risk category assigned by the IPSS-R is the primary determinant for the choice of treatment strategy, moving the management of MDS to a highly personalized plan. Patients categorized as Very Low or Low risk are typically managed with a less aggressive approach focused on improving quality of life and managing symptoms. This often involves supportive care, such as regular blood transfusions to address anemia, or the use of growth factors to stimulate the production of blood cells.
For these lower-risk patients, the goal is often to reduce the need for transfusions and monitor the disease closely, a strategy sometimes referred to as “watchful waiting.” Certain specific lower-risk subtypes, particularly those with the isolated deletion 5q cytogenetic abnormality, may benefit from targeted oral therapies like lenalidomide.
In contrast, patients in the High or Very High risk categories require immediate and aggressive disease-modifying therapy due to the increased probability of rapid progression and shorter survival. The standard first-line treatment for these patients involves hypomethylating agents, such as azacitidine or decitabine, which work to change how the cancer-causing genes are expressed. The only potentially curative option is allogeneic hematopoietic stem cell transplantation, which is generally reserved for High and Very High risk patients who are fit enough to tolerate the procedure. The IPSS-R score thus acts as a clinical roadmap, directing the physician toward either a supportive or a curative strategy.
Progression to Acute Myeloid Leukemia
MDS is often considered a pre-leukemic condition, meaning there is a risk that the bone marrow disorder will evolve into a more aggressive form of blood cancer called Acute Myeloid Leukemia (AML). The likelihood of this transformation is directly predicted by the IPSS-R score, with patients in the High and Very High risk categories facing the greatest chance of progression. The underlying cause of this transformation is the accumulation of further genetic mutations that drive uncontrolled cell growth.
The official threshold for the disease to be reclassified as AML is reached when the percentage of myeloblasts in the bone marrow or peripheral blood exceeds 20%. Below this 20% mark, the disease is classified as MDS; at or above this level, the diagnosis shifts to AML. This transition signifies a major change in disease behavior, moving from a chronic bone marrow failure disorder to a fast-growing acute leukemia. For patients who progress to AML, the treatment strategy must be rapidly adjusted to reflect the more aggressive nature of the new diagnosis.