Myelodysplastic Syndromes (MDS) are blood cancers where the bone marrow produces defective or immature blood cells, leading to low counts of red cells, white cells, and platelets. This is characterized by ineffective hematopoiesis, meaning the body attempts to make blood cells, but the process is faulty. Hypoplastic Myelodysplastic Syndrome (H-MDS) is a distinct variant, making up approximately 10% to 15% of all MDS cases.
Defining Hypoplastic Myelodysplastic Syndromes
H-MDS is defined by a paradox: the peripheral blood lacks mature cells, yet the bone marrow looks sparse. Most classical forms of MDS are hypercellular, packed with cells failing to mature fully. In contrast, H-MDS features hypocellularity, an abnormally low number of blood-forming cells within the marrow space, often defined as cellularity below 25% for adults under 70.
Despite this reduced cellularity, the few blood-forming cells present still display signs of dysplasia, the hallmark of MDS. This means the cells have abnormal shapes, sizes, and structures, indicating a fundamental defect in their development. The presence of these dysplastic, yet sparse, cells distinguishes H-MDS from other bone marrow failure disorders.
H-MDS is considered an overlap syndrome because it shares features with both standard MDS and Aplastic Anemia (AA). The hypocellularity and potential immune-mediated component link it closely to AA. However, the presence of true dysplasia and clonal abnormalities confirms its classification as a myeloid neoplasm.
The Diagnostic Process and Ruling Out Aplastic Anemia
Distinguishing H-MDS from Aplastic Anemia (AA) is a significant challenge because both present with pancytopenia—low counts of all three blood cell lines—and hypocellular bone marrow. The definitive diagnostic tool is the bone marrow biopsy and aspiration, allowing a detailed look at cellularity and cell morphology. Aspiration may be difficult in hypocellular cases, resulting in a “dry tap” and necessitating reliance on the biopsy core sample.
The presence of dysplasia is a key differentiating factor, with H-MDS showing abnormal morphology in at least 10% of cells in one or more hematopoietic lineages. The percentage of myeloblasts, which are immature blood cells, also tends to be higher in H-MDS than in AA. In H-MDS, the blast percentage is typically between 1% and 5%, serving as a measure of disease severity, but is rarely seen in AA.
Cytogenetic analysis provides another differentiation point by examining the chromosomes of the bone marrow cells. While AA typically features a normal karyotype, H-MDS often presents with specific, abnormal chromosomal changes. Detecting an MDS-defining abnormality, such as monosomy 7 or deletion 5q, confirms H-MDS even if dysplasia is subtle. Molecular testing for somatic mutations in genes like SF3B1 or TET2 further confirms a clonal disorder, as these mutations are much more frequent in H-MDS than in AA.
Treatment Options for Hypoplastic MDS
The treatment approach for H-MDS is highly individualized, depending on the patient’s health, age, and risk stratification. For many patients, especially those resembling Aplastic Anemia (AA), Immunosuppressive Therapy (IST) is often the first-line treatment. IST, typically involving anti-thymocyte globulin (ATG) and cyclosporine, aims to suppress an overactive immune system that may be attacking blood-forming cells. This treatment is often effective in H-MDS due to the underlying immune-mediated component shared with AA.
Growth factors are also used to manage symptomatic low blood counts. Erythropoiesis-Stimulating Agents (ESAs) increase red blood cell production and reduce the need for transfusions. For low platelet counts, thrombopoietin receptor agonists, such as eltrombopag, may stimulate platelet production in the marrow.
Hypomethylating Agents (HMAs), such as azacitidine and decitabine, are the standard treatment for higher-risk MDS, but they are generally less effective in H-MDS than in hypercellular MDS. They are typically reserved for H-MDS patients who fail IST or present with higher-risk features, such as a higher blast count or unfavorable cytogenetics. These agents modify the DNA of cancer cells, attempting to restore normal gene function and maturation.
Allogeneic Stem Cell Transplantation (SCT) remains the only potentially curative option for H-MDS. This procedure replaces the patient’s diseased bone marrow with healthy donor cells, but it carries considerable risk. SCT is generally reserved for younger patients or those with higher-risk disease features who are healthy enough to withstand the intensive conditioning regimen.
Prognosis and Risk Stratification
The prognosis for H-MDS is widely variable, but it is generally considered more favorable than for normo- or hypercellular MDS. Risk stratification uses the Revised International Prognostic Scoring System (IPSS-R), which assesses five factors: bone marrow blast percentage, cytogenetic abnormalities, and the severity of peripheral blood cytopenias. H-MDS cases often fall into the lower-risk IPSS-R categories due to typically lower blast counts and fewer complex cytogenetic abnormalities.
The main long-term concern is the potential for disease progression to Acute Myeloid Leukemia (AML). The rate of transformation to AML in H-MDS is notably lower than in higher-risk hypercellular MDS, contributing to the better outlook. For patients categorized in the lower-risk groups by IPSS-R, the focus of care is often on managing symptoms and improving quality of life.
Ongoing monitoring is an important aspect of care to track disease stability and detect progression. This typically involves regular complete blood counts and periodic repeat bone marrow biopsies. Overall survival for lower-risk H-MDS patients is often measured in years, with outcomes closely tied to the specific genetic and cellular features identified at diagnosis.