Myelodysplastic Syndromes (MDS) are blood cancers originating in the bone marrow, characterized by impaired production of healthy, mature blood cells. The disease involves an abnormal population of blood-forming cells that fail to develop correctly. The most serious complication of MDS is its transformation into Acute Myeloid Leukemia (AML). This progression occurs in about one-third of MDS patients, shifting the disease from a chronic disorder to a rapidly progressing, life-threatening acute leukemia. The risk of this transition is the primary factor guiding treatment strategy for many MDS patients.
The Nature of Myelodysplastic Syndromes
MDS is a clonal disorder of hematopoietic stem cells, the body’s earliest blood-forming cells. The disease starts from a single abnormal stem cell that replicates, forming a clone of defective cells. The bone marrow, the factory for blood production, exhibits ineffective hematopoiesis, where cells are produced but are abnormal and often die prematurely.
This failure of proper maturation, called dysplasia, can affect red cells, white cells, or platelets. The resulting condition, cytopenia, leads to various clinical issues. Patients commonly experience anemia (low red blood cells), causing fatigue, or frequent infections due to a lack of functional white blood cells (neutropenia). Low platelet counts (thrombocytopenia) can cause increased bruising or bleeding.
The bone marrow in MDS patients is often hypercellular, containing many cells, but most are abnormal. These dysplastic cells are unable to exit the marrow and perform their functions in the bloodstream. This process creates an unstable environment where the abnormal cell clone can gradually evolve into a more aggressive malignancy.
Biological Drivers of AML Transformation
The transition from MDS to AML is driven by clonal evolution, involving the acquisition of successive genetic changes within the abnormal stem cell clone. The initial MDS clone typically harbors mutations that impair blood production. Over time, this clone acquires secondary mutations that confer a growth advantage, allowing the abnormal cells to proliferate uncontrollably.
A key threshold in this progression is the accumulation of immature white blood cells, known as blasts, in the bone marrow. MDS is diagnosed when the percentage of blasts is less than 20 percent of the total bone marrow cells. Transformation to AML occurs once the blast percentage reaches or exceeds the 20 percent mark. This increase signals that the malignant clone has gained enough genetic alterations to block cell differentiation entirely.
Specific genetic mutations are strongly associated with high-risk progression. Mutations in the TP53 gene, a tumor suppressor, are linked to aggressive disease and poor outcomes. Other frequently implicated genes regulate epigenetics (ASXL1, EZH2) or transcription factors (RUNX1). Complex karyotypes, which involve multiple chromosomal abnormalities, also represent a poor prognostic factor, indicating genomic instability that facilitates AML development.
Clinical Assessment and Risk Stratification
Physicians use clinical and biological data to assess a patient’s likelihood of progression and overall survival through risk stratification. The primary tool is the Revised International Prognostic Scoring System (IPSS-R), which assigns a weighted score based on five factors:
- The percentage of blasts in the bone marrow.
- The presence and type of chromosome abnormalities (cytogenetics).
- The severity of cytopenias (levels of hemoglobin, platelets, and absolute neutrophil count).
The IPSS-R refines older systems by classifying cytogenetic abnormalities into five prognostic groups. It recognizes that certain chromosomal changes, like a complex karyotype or monosomy 7, carry a much higher risk. The system also scores the depth of cytopenias, distinguishing between mild and severe low blood counts.
The total score places the patient into one of five risk categories: Very Low, Low, Intermediate, High, or Very High. Patients in the Very Low and Low-risk groups have a lower chance of AML transformation and are managed with less aggressive therapies. Conversely, High and Very High-risk groups face a significantly higher risk of progression. This system guides the decision to proceed with observation, low-intensity treatment, or curative approaches.
Treatment Approaches to Prevent Progression
For patients categorized as higher-risk by the IPSS-R, treatment focuses on delaying or preventing AML transformation. The standard first-line treatment is the use of Hypomethylating Agents (HMAs), such as azacitidine and decitabine. These drugs target the epigenetic changes that contribute to disease progression.
HMAs are nucleoside analogs that incorporate into the DNA of abnormal cells, inhibiting the enzyme DNA methyltransferase. This inhibition causes the removal of methyl groups from the DNA (hypomethylation), which can restore the function of silenced tumor suppressor genes. By changing the gene expression pattern, HMAs promote the maturation and differentiation of abnormal blood cells, slowing the malignant clone’s growth and reducing the blast count.
While HMAs extend survival and reduce the rate of transformation, Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) remains the only potentially curative option for MDS. HSCT replaces the patient’s diseased blood-forming cells with healthy donor cells. This intensive procedure is generally reserved for younger, medically fit patients with higher-risk disease due to significant risks of mortality and complications.