Myelodysplastic syndromes (MDS) encompass a diverse group of hematopoietic neoplasms caused by acquired mutations that disrupt the normal maturation of myeloid progenitors, leading to cytopenias in the peripheral blood. In MDS, hematopoiesis is ineffective and the cells produced are often malformed or dysplastic. MDS is primarily confined to the elderly, with a peak incidence in individuals more than 70 years of age.

Clinical Manifestations of MDS

Most patients with MDS present with vague symptoms related to the slow onset of anemia, neutropenia, or thrombocytopenia as the disease progression is not acute. Anemia can manifest as fatigue, shortness of breath, pale skin, and dizziness. Additionally, patients may experience easy bruising and excessive bleeding due to a lack of functional platelets. In severe cases, recurrent infections may occur as a consequence of neutropenia.

However, MDS does not always announce its arrival with such blatant pronouncements. Some individuals may experience vague, non-specific symptoms such as weight loss, fatigue, and fever. These seemingly trivial symptoms, when considered in conjunction with other factors like age and family history, can raise suspicion of underlying MDS.

Causes Related to MDS

MDS arises sporadically, but some cases are related to exposure to DNA-damaging agents. While the exact mechanisms are still under investigation, several key contributors have emerged as leading suspects in this medical detective story.

1. Acquired genetic mutations: The most significant culprit in MDS is the presence of acquired genetic mutations within blood stem cells. These mutations disrupt the normal process of blood cell development, leading to abnormal and dysfunctional cells. Age is a major risk factor for acquiring these mutations, as the accumulation of genetic errors over time increases the likelihood of developing MDS.

2. Exposure to certain toxins and chemicals: Certain environmental exposures have been linked to an increased risk of developing MDS. These include:

Benzene: a chemical found in gasoline and tobacco smoke
Pesticides and herbicides: commonly used in agriculture and gardening
Radiation: exposure to high doses of radiation, such as during cancer treatment

3. Previous cancer treatment: Individuals who have undergone chemotherapy or radiation therapy for other cancers are at a higher risk of developing MDS as a secondary complication. This risk is related to the damage these treatments can inflict on bone marrow and blood stem cells.

4. Certain inherited conditions: While uncommon, some genetic disorders can increase the risk of developing MDS. These include Fanconi anemia, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome.

5. Smoking: Tobacco smoking is a well-established risk factor for various cancers, and it is also associated with an increased risk of MDS. This is likely due to the presence of harmful chemicals in tobacco smoke that can damage DNA and contribute to the development of cancer and other blood disorders.

6. Unknown factors: In many cases, the specific cause of MDS remains elusive. Several other factors, such as dietary deficiencies, autoimmune disorders, and viral infections, are being investigated for their potential role in the development of this disease.

WHO Classifications of MDS Based on Morphology

The World Health Organization (WHO) classification system for myelodysplastic syndromes (MDS) utilizes morphology, meaning the microscopic appearance of blood and bone marrow cells, as a key diagnostic and prognostic tool. This approach provides a framework for understanding the diverse presentations of MDS and guiding therapeutic decisions.

Here’s a detailed breakdown of the WHO classification based on morphology:

MDS with Single Lineage Dysplasia (MDS-SLD)

Characterized by dysplasia affecting only one cell line: erythroid, myeloid, or megakaryocytic.
Subtypes include:
- RA (refractory anemia): affecting erythroid lineage.
- RC (refractory cytopenia): affecting either the myeloid or megakaryocytic lineage.
- 5q- syndrome: characterized by isolated del(5q) cytogenetic abnormality and dysplastic erythropoiesis.

MDS with Multilineage Dysplasia (MDS-MLD)

Features dysplasia in two or more cell lines.
Requires at least 10% dysplastic cells in at least two lineages to meet diagnostic criteria.

MDS with Ring Sideroblasts (MDS-RS)

Defined by the presence of ring sideroblasts, which are red blood cell precursors with iron deposits surrounding the nucleus.
This subtype is further categorized based on the percentage of ring sideroblasts:
- MDS-RS with single lineage dysplasia (RS-SLD): <50% ring sideroblasts and dysplasia in only one lineage.
- MDS-RS with multilineage dysplasia (RS-MLD): <50% ring sideroblasts and dysplasia in two or more lineages.
- MDS-RS with ring sideroblasts and thrombocytosis (RS-T): >50% ring sideroblasts and thrombocytosis.

MDS with Excess Blasts (MDS-EB)

Defined by the presence of 5-9% blasts in the bone marrow.
Subtypes include:
- MDS-EB1: 5-9% blasts and dysplasia in one or more cell lines.
- MDS-EB2: 5-9% blasts with multilineage dysplasia and Auer rods (abnormal cytoplasmic granules) in blasts.

MDS with Myelofibrosis (MDS/MF)

Occurs when MDS co-exists with myelofibrosis, a condition characterized by excessive bone marrow fibrosis.

Unclassifiable MDS (MDS-U)

Cases that do not meet the criteria for any other MDS subtype.

Benefits of WHO Classification

Provides a standardized approach to diagnosis and prognostication.
Guides therapeutic decisions.
Improves communication and collaboration among healthcare professionals.

Limitations of WHO Classification

Relies primarily on morphology, which can be subjective and prone to observer bias.
May not fully capture the molecular heterogeneity of MDS.

MDS Defining Abnormalities

MDS-defining abnormalities are specific genetic mutations or chromosomal changes that play a significant role in the development and progression of myelodysplastic syndromes (MDS). These abnormalities help differentiate MDS from other blood disorders and influence prognosis and treatment decisions.

Here are some of the most common MDS-defining abnormalities:

Cytogenetic abnormalities

Deletion 5q: This is the most common and well-characterized MDS-defining abnormality. It is associated with a relatively favorable prognosis and can be treated with less intensive therapies.
Deletion 20q: This abnormality is also associated with a relatively good prognosis and can be responsive to immune-modulating agents.
Trisomy 8: This abnormality is associated with an intermediate prognosis and may require more aggressive treatment.
Monosomy 7/Deletion 7q: This abnormality is associated with a poor prognosis and often requires stem cell transplantation.
Complex karyotype: This refers to the presence of multiple chromosomal abnormalities and is associated with a poor prognosis.

Gene mutations

SF3B1 mutations: These mutations are the most common genetic mutations in MDS and are associated with a favorable prognosis. They may be responsive to specific targeted therapies.
TP53 mutations: These mutations are associated with a poor prognosis and often indicate a higher risk of progression to acute myeloid leukemia (AML).
TET2 mutations: These mutations are relatively common in MDS and are associated with a variable prognosis.
ASXL1 mutations: These mutations are associated with a poor prognosis and may be indicative of a higher risk of AML.

It’s important to note that the presence of an MDS-defining abnormality does not necessarily mean that a person will develop MDS. However, these abnormalities are significant risk factors for the disease and should be considered in the context of other clinical features when making a diagnosis.

The identification of MDS-defining abnormalities plays a crucial role in the management of MDS by:

Providing prognostic information: Helping to predict the course of the disease and guide treatment decisions.
Identifying patients eligible for targeted therapies: Some targeted therapies are only effective for patients with specific genetic mutations.
Informing clinical trial enrolment: Patients with certain abnormalities may be eligible to participate in clinical trials testing new therapies.

Laboratory Investigations Related to MDS

Atypical granulocytic lineage cells in a patient with myelodysplasia. “File:Granulocytic Dysplasia.jpg” by Emily Patonay is licensed under CC BY-SA 4.0.

The diagnostic hallmark of this disorder is dysplasia which can affect all three lineages or just one or two.

1. Complete Blood Count (CBC): Presence of anemia, neutropenia or thrombocytopenia. It also helps in assessing the severity of cytopenias, which plays a crucial role in determining the appropriate course of treatment.

2. Peripheral Blood Smear: Dysplastic changes in red blood cells (macrocytosis, poikilocytosis), white blood cells (hypogranularity, vacuoles), and platelets (hypogranularity, giant platelets) can be observed, providing valuable clues to the diagnosis of MDS.

3. Bone Marrow Aspiration and Biopsy: Characteristic dysplastic findings include erythroid elements with misshapen nuclei or ring sideroblasts, neutrophils with only 2 nuclear lobes or abnormal cytoplasmic granulation, and multinucleated or small megakaryocytes with simple nuclei.

4. Cytogenetic Analysis: Specific chromosomal abnormalities, such as del(5q) or trisomy 8, can provide prognostic information and guide treatment decisions.

5. Flow Cytometry and Immunophenotyping: By employing flow cytometry and immunophenotyping techniques, researchers can identify, quantify, and characterize distinct populations of hematopoietic cells at various stages of development within the bone marrow and peripheral blood.

6. Molecular Testing: The presence of mutations in genes like SF3B1, TP53, and TET2 can influence prognosis and guide the selection of targeted therapies.

Hallmark Characteristics of MDS in Laboratory Investigations:

Cytopenias in one or more cell lines (anemia, neutropenia, thrombocytopenia)
Dysplastic changes in blood and bone marrow cells
Specific chromosomal abnormalities
Gene mutations associated with MDS

Prognosis of MDS

The International Prognostic Scoring System (IPSS) and its revised version, IPSS-R (Revised IPSS), are two important tools used to assess the prognosis and guide treatment decisions in patients with myelodysplastic syndromes (MDS). Both systems assign risk scores based on specific clinical and laboratory features, allowing for a more objective and standardized approach to risk stratification.

IPSS

Developed in 1997, the IPSS relies on three factors to predict overall survival:

Cytopenia: Number of cytopenias (anemia, neutropenia, thrombocytopenia)
Blast percentage: Percentage of immature blast cells in the bone marrow
Cytogenetic risk category: Based on specific chromosomal abnormalities

Patients are assigned points based on these factors, and the total score determines their risk group:

Very low risk: 0 points
Low risk: 0.5-1 points
Intermediate-1 risk: 1.5-2 points
Intermediate-2 risk: 2.5-3 points
High risk: ≥3.5 points

IPSS-R

Published in 2012, the IPSS-R incorporates additional factors to refine risk stratification:

Sideroblasts: Percentage of ring sideroblasts in the bone marrow
Serum lactate dehydrogenase (LDH) level: An indicator of disease activity
Karyotype complexity: Presence of multiple chromosomal abnormalities

The IPSS-R assigns points based on these factors and classifies patients into five risk groups:

Very low risk: ≤1.5 points
Low risk: >1.5-3 points
Intermediate risk: >3-4.5 points
High risk: >4.5-6 points
Very high risk: >6 points

Benefits of IPSS and IPSS-R

Standardized prognostic assessment: Enhances comparison between patients and facilitates treatment decisions.
Guidance for clinical trials: Helps stratify patients for eligibility and evaluate treatment efficacy.
Improved patient counseling: Provides realistic expectations about disease course and prognosis.

Limitations of IPSS and IPSS-R

Relies solely on clinical and cytogenetic data, potentially overlooking molecular factors.
May not fully capture the complexities of individual cases.

The IPSS and IPSS-R systems provide valuable tools for risk stratification in MDS. Despite their limitations, they remain widely used in clinical practice and contribute significantly to improving the management of this complex group of disorders.

Treatment and Management of MDS

The primary goal of treatment is to alleviate symptoms, improve quality of life, and prolong survival. Here’s an overview of the various treatment options:

Supportive care

Blood transfusions: For managing anemia and thrombocytopenia.
Growth factors: Stimulating the production of red blood cells and platelets.
Antibiotics: To prevent infections in patients with neutropenia.
Iron chelation therapy: For patients with chronic transfusion dependence.

Hypomethylating agents (HMAs)

Medications like azacitidine and decitabine that work by reprogramming gene expression to promote the differentiation of immature blast cells into mature blood cells, induce programmed cell death in abnormal blood cells and trigger DNA damage pathways, leading to cell cycle arrest and apoptosis.
Primarily used for lower-risk MDS and intermediate-risk MDS without del(5q).
Can improve symptoms and prolong survival.

Chemotherapy

Used for higher-risk MDS and some patients with intermediate-risk MDS.
Aims to destroy rapidly dividing cells, including abnormal blood cells.
Aggressive chemotherapy is usually not effective, although it initially clears the marrow of tumor cells, the MDS progenitors typically grow back quickly after chemotherapy is stopped and most patients never achieve a true remission.

Immunomodulatory drugs (IMiDs)

Medications like lenalidomide that modulate the immune system and promote red blood cell production. One key mechanism of action involves hijacking the “garbage disposal” system of the cell, the ubiquitin-proteasome system. By binding to a key protein, lenalidomide directs the destruction of specific harmful proteins in MDS cells. This includes IKZF1/3, a protein that hinders blood cell development, and CK1α, which promotes cell growth.
Used for some patients with lower-risk MDS with del(5q).
Can improve anemia and reduce transfusion dependence.

Stem cell transplantation (SCT)

The only potentially curative treatment option for MDS.
Involves replacing the patient’s diseased bone marrow with healthy stem cells from a donor.
Only suitable for younger patients with good performance status.

Choosing the right treatment approach depends on various factors, including

MDS subtype and risk category
Patient’s age and health status
Availability of a suitable donor for SCT
Patient’s preferences and goals of treatment

Despite these diverse therapies, the overall prognosis is poor. Many patients progress to AML with those with higher-risk disease doing so more rapidly and more frequently. When AML supervenes, it usually responds poorly to chemotherapy and is associated with median survival times of only a few months.

Key Points of MDS

Definition

A heterogeneous group of hematopoietic malignancies due to impaired maturation of myeloid progenitors leading to cytopenias and dysplasia of myeloid-lineage cells.

Signs and symptoms

Fatigue, shortness of breath
Neutropenia
Thrombocytopenia

Causes

Sporadic
DNA-damaging agents e.g. radiation, chemotherapy, toxins

Incidence

> 70 years old

Classifications

Classification	Dysplastic lineages	Cytopenias	Bone marrow (BM) and peripheral blood (PB) blasts	Cytogenetics
MDS with single lineage dysplasia	1	1 or 2	BM <5%, PB <1%, no Auer rods	Any, unless meets criteria for MDS with isolated (del)5q
MDS with multilineage dysplasia	2 or 3	1 – 3	BM <5%, PB <1%, no Auer rods	Any, unless meets criteria for MDS with isolated (del)5q
MDS with isolated del(5q)	1 – 3	1 -2	BM <5%, PB <1%, no Auer rods	(del)5q alone or with 1 additional abnormality except -7 or del(7q)
MDS with ring sideroblasts (MDS-RS)
MDS-RS with single lineage dysplasia	1	1 or 2	BM <5%, PB <1%, no Auer rods	Any, unless meets criteria for MDS with isolated (del)5q
MDS-RS with multilineage dysplasia	2 or 3	1 – 3	BM <5%, PB <1%, no Auer rods	Any, unless meets criteria for MDS with isolated (del)5q
MDS with excess blasts (MDS-EB)
MDS-EB-1	0 – 3	1 – 3	BM 5-9% or PB 2-4%, no Auer rods	Any
MDS-EB-2	0 – 3	1 – 3	BM 10-19% or PB 5-19%, Auer rods	Any
MDS, unclassifiable (MDS-U)
MDS-U with 1% blood blasts	1 – 3	1 – 3	BM <5%, PB <1%, no Auer rods	Any
MDS-U with single lineage dysplasia and pancytopenia	1	3	BM <5%, PB <1%, no Auer rods	Any
MDS-U based on defining cytogenetic abnormality	0	1 – 3	BM <5%, PB <1%, no Auer rods	MDS-defining abnormality*
Refractory cytopenia of child	1 – 3	1 – 3	BM <5%, PB <2%	Any

*MDS-defining abnormality:

Loss of chromosome 7 or del(7q)
del(5q)
Isochromosome 17q or t(17p)
Loss of chromosome 13 or del(13q)
del(11q)
del(12p) or t(12p)
del(9q)
idic(X)(q13)
t(11;16)(q23.3;p13.3)
t(3;21)(q26.2;q22.1)
t(1;3)(p36.3;q21.2)
t(2;11)(p21;q23.3)
inv(3)(q21.3;q26.2)/ t(3;3)(21.3;q26.2)
t(6;9)(p23;q34.1)

Laboratory Investigations

PBF: Dysplasia of myeloid lineage including erythroblasts with misshapen nucleus, ringed sideroblasts, bilobed neutrophils or abnormal cytoplasmic granules or multinucleated or small megakaryocytes

Treatment and management

Allogeneic stem cell transplantation
Lenalidomide for MDS with anemia and 5qdel only
Many patients progress to AML

Disclaimer: This article is intended for informational purposes only and is specifically targeted towards medical students. It is not intended to be a substitute for informed professional medical advice, diagnosis, or treatment. While the information presented here is derived from credible medical sources and is believed to be accurate and up-to-date, it is not guaranteed to be complete or error-free. See additional information.

References

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