Myelodysplastic Syndromes (MDS) are a group of bone marrow failure disorders where blood-forming cells become abnormal and ineffective. Classified as a type of cancer, MDS is characterized by the production of immature, dysfunctional blood cells that fail to mature properly. This results in a deficiency of healthy red blood cells, white blood cells, and platelets in the bloodstream. MDS exists on a spectrum, ranging from an indolent course to a highly aggressive form. A formal risk assessment stratifies the disease into lower-risk and higher-risk categories, with High Risk MDS requiring immediate and intensive therapeutic intervention due to its rapid progression.
Understanding Myelodysplastic Syndromes
MDS originates from a clonal disorder within hematopoietic stem cells, the precursor cells in the bone marrow responsible for creating all blood components. This abnormality causes ineffective hematopoiesis, where the bone marrow is often overactive but fails to successfully release sufficient numbers of mature, functional cells into the peripheral blood. Although the bone marrow may be hypercellular (overly crowded with cells), the patient experiences low counts in the circulating blood, a state known as cytopenia.
A diagnosis of MDS requires integrating clinical findings with detailed laboratory analysis, particularly a bone marrow biopsy and aspirate. The bone marrow sample is examined to identify dysplasia, which is the abnormal size, shape, and appearance of blood cells across one or more cell lines. Cytopenias are defined by specific thresholds, such as a hemoglobin level below 10 g/dL, a platelet count below 100 x 10⁹/L, or a low absolute neutrophil count.
Defining High Risk Status
High-risk status is determined by the Revised International Prognostic Scoring System (IPSS-R), the standard tool used to predict disease trajectory and guide treatment decisions. This scoring system evaluates five biological factors, assigning points to calculate a total score that places the patient into one of five risk groups. High Risk MDS falls into the two most severe categories: High Risk (IPSS-R score >4.5 to 6) and Very High Risk (score >6).
The most heavily weighted factor is the percentage of blasts, which are immature, abnormal blood cells found in the bone marrow. A bone marrow blast percentage between 5% and 10% contributes significantly to a higher score, while a percentage greater than 10% typically pushes a patient into the High or Very High Risk range. The second major determinant is the presence of specific cytogenetic abnormalities, which are structural or numerical changes in the chromosomes. Complex karyotypes (three or more chromosomal changes) and the loss of all or part of chromosome 7 are considered poor-risk changes that strongly indicate an aggressive disease course. Finally, the severity of cytopenias, such as very low hemoglobin, platelet, or neutrophil counts, also contributes to the final high-risk score.
Disease Progression and Prognosis
The primary concern with High Risk MDS is the rapid progression to Acute Myeloid Leukemia (AML), a much more aggressive form of blood cancer. Transformation to AML occurs when the percentage of blasts in the bone marrow or blood reaches 20% or higher, a transition that happens in up to 40% of high-risk patients within two years. Once this transformation occurs, the prognosis worsens considerably, and the median overall survival time is significantly reduced.
The High and Very High Risk categories are associated with a substantially shorter life expectancy compared to lower-risk groups. For patients with a High Risk classification, the median overall survival is noted to be around 1.5 years, though individual outcomes can vary widely based on specific genetics and overall health. The IPSS-R score indicates that these patients face a much more immediate threat from the disease itself. Therefore, the treatment strategy shifts from supportive care to actively modifying the disease course to delay AML progression and extend survival.
Treatment Strategies
The management of High Risk MDS focuses on active disease modification to improve survival and delay the onset of AML. The initial standard treatment involves Hypomethylating Agents (HMAs), such as azacitidine and decitabine. These medications target the abnormal process of DNA methylation, helping blood cells mature normally and encouraging the death of abnormal cells.
Azacitidine has been shown in clinical trials to offer a survival benefit compared to conventional supportive care, making it a common first-line therapy. While HMAs can improve blood counts and delay AML transformation, they are not typically curative; the median overall survival for patients on these therapies remains around 18 months. The goal of HMA therapy is to achieve remission or a reduction in blast counts, which can serve as a bridge to more intensive treatment.
Allogeneic Hematopoietic Stem Cell Transplantation (HSCT), also known as bone marrow transplant, is the only therapeutic option that offers a potential cure for High Risk MDS. This procedure replaces the patient’s diseased bone marrow with healthy blood-forming stem cells from a matched donor. HSCT is a high-intensity treatment associated with significant risks, including treatment-related mortality and graft-versus-host disease.
The decision to proceed with HSCT requires a careful assessment of the patient’s age, overall health, and the availability of a suitable donor, as many MDS patients are elderly. For patients who are not candidates for HSCT, or whose disease has progressed rapidly toward AML, more intensive chemotherapy regimens may be considered. These treatments are often similar to those used for acute leukemia, sometimes involving a combination of drugs like HMAs and BCL-2 inhibitors to achieve a deeper reduction in the blast population.