High-Risk MDS: Classification, Bone Marrow, and Prognosis

Myelodysplastic syndromes (MDS) are bone marrow disorders that lead to ineffective blood cell production. High-risk MDS is particularly concerning due to its likelihood of progressing to acute myeloid leukemia (AML). Understanding this condition is crucial for guiding treatment and improving outcomes.

Several factors influence the severity and progression of high-risk MDS, including bone marrow characteristics, genetic markers, and blood cell changes. Prognostic scoring systems help assess risk and predict disease trajectory, aiding clinical management.

Classification

High-risk myelodysplastic syndromes (MDS) are categorized based on hematologic and cytogenetic criteria. The World Health Organization (WHO) and the International Prognostic Scoring System (IPSS) provide widely accepted classification frameworks, incorporating blast percentage, cytogenetic abnormalities, and cytopenia severity. The WHO classification, updated in 2022, emphasizes molecular and genetic features, while the IPSS and its revised version (IPSS-R) stratify patients based on prognostic variables.

A defining characteristic of high-risk MDS is an increased proportion of myeloblasts in the bone marrow, typically 10-19%, distinguishing it from AML, which is diagnosed when blasts exceed 20%. The presence of excess blasts signals a more aggressive disease course, often requiring intensive treatment. High-risk MDS frequently exhibits complex karyotypic abnormalities, such as deletions in chromosome 7 (del(7q)) or monosomal karyotypes, which are associated with poor outcomes. These cytogenetic findings influence both prognosis and therapeutic approaches.

Beyond blast percentage and chromosomal alterations, classification also considers the severity of cytopenias. Patients often present with significant reductions in one or more blood cell lineages, including anemia, neutropenia, or thrombocytopenia. The WHO system further refines classification by incorporating morphologic features of dysplasia, distinguishing between subtypes such as MDS with excess blasts (MDS-EB) and MDS with multilineage dysplasia (MDS-MLD), each with distinct prognostic implications.

Bone Marrow Features

The bone marrow in high-risk MDS exhibits profound abnormalities. One of the most defining features is the elevated presence of myeloblasts, which typically range from 10-19% of marrow cells. This increase disrupts normal marrow function, impairing blood cell production and contributing to cytopenias. These immature cells often display dysplastic morphology, characterized by irregular nuclear shapes, aberrant chromatin patterns, and defective granulation, signaling progression toward leukemic transformation.

Beyond blast proliferation, the marrow microenvironment is altered, with fibrosis and increased cellularity being frequent findings. Reticulin and collagen fibrosis, detected through specialized staining techniques, create a fibrotic scaffold that hinders normal hematopoiesis and reduces the effectiveness of therapies like hypomethylating agents. Hypercellularity, often seen in early stages, reflects a compensatory response to ineffective hematopoiesis, while advanced disease may lead to hypocellularity due to marrow failure.

Dysplastic changes in erythroid, myeloid, and megakaryocytic lineages are another hallmark. Erythroid precursors often exhibit nuclear budding, multinucleation, and megaloblastic changes. Myeloid precursors may present with hypogranulation or abnormal nuclear segmentation, including pseudo-Pelger-Huët cells, which indicate defective maturation. Megakaryocytes, responsible for platelet production, frequently appear as micromegakaryocytes with hypolobulated or mononuclear forms, contributing to thrombocytopenia and an increased bleeding risk. These morphological abnormalities, assessed through bone marrow aspirates and biopsies, provide critical diagnostic and prognostic insights.

Genetic Markers

High-risk MDS is shaped by genetic mutations that influence disease progression and therapeutic response. Unlike lower-risk forms, which may harbor isolated or less aggressive mutations, high-risk MDS often involves multiple genetic alterations. Among the most frequently implicated genes are TP53, ASXL1, RUNX1, and EZH2. TP53 mutations, found in 10-20% of cases, are particularly concerning due to their association with resistance to conventional therapies and rapid progression to AML. These mutations compromise the tumor suppressor function of p53, diminishing apoptosis and allowing malignant clones to survive.

ASXL1 and RUNX1 mutations further complicate the genetic landscape. ASXL1 mutations, occurring in about 15-20% of cases, impair chromatin remodeling, disrupting gene expression essential for hematopoietic differentiation. Patients with ASXL1 mutations often exhibit poor responses to hypomethylating agents. RUNX1 mutations interfere with transcriptional regulation of myeloid differentiation, contributing to ineffective hematopoiesis and an increased risk of leukemic transformation.

Chromosomal abnormalities frequently co-occur with specific mutations. Complex karyotypes, defined by three or more chromosomal alterations, are often seen in patients with TP53 mutations and are linked to poor outcomes. Monosomy 7 leads to defective hematopoiesis by eliminating key tumor suppressor genes, while deletions in chromosome 5q (del(5q)) disrupt ribosomal protein function, impairing bone marrow activity. These structural changes, combined with high-risk mutations, foster disease progression and limit treatment efficacy.

Blood Cell Alterations

High-risk MDS disrupts normal blood cell production, leading to severe hematologic abnormalities. Anemia, often macrocytic, results from ineffective erythropoiesis, where defective progenitor cells fail to mature properly, leading to premature destruction within the bone marrow. Patients frequently experience fatigue, pallor, and shortness of breath, with some requiring regular transfusions. Repeated transfusions can result in iron overload, further exacerbating organ dysfunction.

Neutropenia increases susceptibility to bacterial and fungal infections. Impaired production of mature neutrophils weakens the immune response, leaving patients vulnerable to recurrent infections, including pneumonia and sepsis. Even circulating neutrophils often exhibit reduced chemotaxis and phagocytic activity. Absolute neutrophil counts (ANC) below 500 cells/µL signal a heightened risk of life-threatening complications.

Disease Trajectory

High-risk MDS progresses with worsening cytopenias and a heightened risk of transformation into AML. Unlike lower-risk cases, which may remain stable for years, high-risk MDS often declines rapidly. Accumulating genetic mutations and chromosomal abnormalities drive malignant evolution, outcompeting normal hematopoietic stem cells and increasing myeloblast populations. As immature cells proliferate, bone marrow failure worsens, leading to recurrent infections, severe anemia, and bleeding complications.

The transition to AML is driven by additional mutations that enhance cellular proliferation and survival. Nearly 30-40% of high-risk MDS cases progress to AML within one to two years, with mutations like TP53 and RUNX1 accelerating transformation. Patients who develop AML often exhibit resistance to standard therapies, complicating treatment. External factors, including comorbidities and prior treatments, also influence survival and therapeutic options. Understanding these patterns allows for early intervention strategies that may delay or mitigate disease advancement.

Prognostic Scoring

Accurately assessing disease severity in high-risk MDS is essential for guiding treatment. Prognostic scoring systems integrate clinical and genetic variables to classify patients into risk categories. The International Prognostic Scoring System (IPSS) and its revised version (IPSS-R) incorporate bone marrow blast percentage, cytogenetic abnormalities, and cytopenia severity. IPSS-R refines this approach by assigning weighted scores to specific chromosomal alterations and blood count values, improving risk stratification. Patients with high-risk scores often have a median survival of less than two years, necessitating aggressive treatment such as allogeneic stem cell transplantation.

Newer models, such as the Molecular International Prognostic Scoring System (IPSS-M), integrate genetic mutations for greater predictive accuracy. This system accounts for recurrent mutations in genes like TP53, ASXL1, and SF3B1, which independently influence prognosis. Incorporating molecular data improves survival predictions and treatment response assessments. Clinicians increasingly rely on these models to personalize therapy, selecting candidates for intensive interventions or clinical trials based on molecular risk profiles. These advancements refine management strategies, ensuring tailored treatment based on individual risk factors.