Myelodysplastic Syndromes: Symptoms, Types, Causes and Treatment

Myelodysplastic syndromes (MDS) are a diverse group of blood cancers that begin in the bone marrow and are characterized by ineffective blood cell production and a risk of progression to acute myeloid leukemia (AML). While MDS may sound complex and intimidating, understanding its symptoms, types, causes, and treatments can empower patients, families, and caregivers to better navigate the journey. In this article, we dive into the essential aspects of MDS, drawing upon recent research and clinical insights.

Symptoms of Myelodysplastic Syndromes

Recognizing the symptoms of MDS can be challenging because its early signs often mimic other, less serious conditions. However, being aware of what to look for can lead to earlier diagnosis and better management.

Symptom	Description	Impact	Source(s)
Fatigue	Persistent tiredness, weakness	Reduced daily functioning	2 3 5
Anemia	Low red blood cell count	Shortness of breath, pallor, dizziness	1 3 4
Infections	Frequent or severe infections	Due to neutropenia	1 4 13
Bleeding	Easy bruising, nosebleeds, petechiae	Due to low platelets	1 4 13

Table 1: Key Symptoms of Myelodysplastic Syndromes

Fatigue and Anemia: The Most Common Complaints

Fatigue is the most distressing and prevalent symptom for people with MDS, often arising from anemia—a hallmark of the disease. Patients may describe severe tiredness, weakness, and difficulty maintaining social relationships or daily activities. Blood transfusions can help alleviate these symptoms, leading to noticeable improvements within days 2 3 5. Shortness of breath and pallor are also common, particularly during exertion 1 3.

Infections and Bleeding Tendencies

MDS often causes neutropenia (low white blood cell counts), which makes patients more susceptible to infections—sometimes severe or recurrent. Thrombocytopenia (low platelet counts) can result in easy bruising, frequent nosebleeds, or the appearance of small red spots on the skin (petechiae). In advanced cases, bleeding can be life-threatening 1 4 13.

The Subtlety of Early Symptoms

Early symptoms of MDS can be subtle and are sometimes mistaken for normal aging, especially in elderly patients. Chronic, unexplained anemia should never be dismissed as a natural consequence of aging. Persistent cytopenias, especially macrocytic anemia, warrant further investigation and referral to a hematologist for bone marrow assessment 4.

Types of Myelodysplastic Syndromes

MDS is not a single disease but rather a group of related disorders, each with distinct features and risks. Classification is essential for determining prognosis and guiding treatment.

Type/Subtype	Key Features	Risk/Prognosis	Source(s)
MDS with Single Lineage Dysplasia (SLD)	Dysplasia in one blood cell line	Lower risk	8 10 16
MDS with Multilineage Dysplasia (MLD)	Dysplasia in ≥2 lineages	Intermediate risk	8 10 16
MDS with Ring Sideroblasts (RS)	Abnormal RBCs with ringed iron	Often indolent	7 10
MDS with Isolated del(5q)	Deletion of chromosome 5q	Good prognosis, unique treatment	3 7 10
MDS with Excess Blasts (EB)	>5% blasts in marrow or blood	Higher risk of AML	1 8 10 16
Secondary/therapy-related MDS	After chemo/radiation exposure	Poorer prognosis	1 8 13 16

Table 2: Main Types of Myelodysplastic Syndromes

Classification Systems

The World Health Organization (WHO) classification integrates morphological, cytogenetic, and molecular features to define MDS subtypes. The Revised International Prognostic Scoring System (IPSS-R) is commonly used for risk stratification and determines whether a patient is considered lower or higher risk 8 10 16.

Unique Subtypes: del(5q) and SF3B1-mutant MDS

MDS with isolated del(5q) is notable for its distinct genetic abnormality—a deletion on the long arm of chromosome 5. It generally has a favorable prognosis and responds well to specific treatments like lenalidomide 3 7 10. Another emerging entity is SF3B1-mutant MDS, characterized by ring sideroblasts and a relatively indolent course. Luspatercept may abolish transfusion requirements in this subtype 7.

Therapy-Related and Secondary MDS

Some patients develop MDS after chemotherapy or radiation therapy for other cancers. These therapy-related cases tend to behave more aggressively and are associated with a higher risk of progression to AML 1 8 13 16.

Blast Percentage and Risk

A key determinant of prognosis is the proportion of blasts (immature blood cells) in the bone marrow. MDS with excess blasts (MDS-EB) signals a higher risk for transformation into AML and requires more intensive treatment 1 8 10 16.

Causes of Myelodysplastic Syndromes

Understanding what leads to MDS sheds light on both prevention and targeted approaches. While the exact cause often remains elusive, several risk factors and underlying mechanisms are now recognized.

Cause/Factor	Description	Clinical Implication	Source(s)
Aging	Most common in elderly	Increases incidence	1 4 6 8
Prior chemo/radiation	Therapy-related MDS	Aggressive course	1 8 13 16
Genetic mutations	Somatic/germline mutations (e.g., TP53, SF3B1)	Prognosis, treatment	7 9 11 12 15
Environmental toxins	Benzene, pesticides	Modifiable risk	4 8
Inherited syndromes	Familial MDS, bone marrow failure syndromes	Early onset, screening	9
Epigenetic changes	DNA methylation, histone modification	Affects gene expression	1 12 14 15

Table 3: Causes and Risk Factors for Myelodysplastic Syndromes

Age and Environmental Exposures

The incidence of MDS rises sharply with age, making it one of the most common hematologic malignancies in the elderly. Exposure to certain chemicals (e.g., benzene), pesticides, or prior cancer therapies can also increase risk, often leading to more aggressive disease 1 4 6 8 13.

Genetic and Epigenetic Alterations

MDS arises from acquired mutations in hematopoietic stem cells, affecting genes involved in:

• RNA splicing (e.g., SF3B1, SRSF2)
• Epigenetic regulation (e.g., TET2, DNMT3A, ASXL1)
• Tumor suppression (e.g., TP53, RUNX1)

These mutations disrupt normal blood cell development, leading to cytopenias and dysplasia 7 11 12 15 17. Epigenetic changes, such as abnormal DNA methylation, further alter gene expression and disease behavior 1 12 14 15.

Inherited Predispositions

Though rare, some cases of MDS run in families. Germline mutations in genes like RUNX1, DDX41, and others are now recognized as causes of familial MDS and bone marrow failure syndromes, especially in younger patients 9.

Immune and Inflammatory Dysregulation

Recent research highlights the role of chronic inflammation and innate immune signaling abnormalities in driving ineffective blood cell production and marrow failure in MDS 14.

Treatment of Myelodysplastic Syndromes

The treatment of MDS is highly individualized, reflecting the disease’s heterogeneity and the patient’s health status. While some therapies aim to cure, most focus on improving quality of life and blood counts.

Treatment	Indication/Use	Key Notes	Source(s)
Supportive Care	All patients	Transfusions, growth factors	1 2 3 16 18
ESAs	Lower-risk, symptomatic anemia	Not always effective	3 10 16 18
Lenalidomide	Lower-risk, del(5q) subtype	Can induce transfusion independence	3 7 10 18
Hypomethylating agents (HMA)	Higher-risk, or ESA-refractory cases	Azacitidine, decitabine; may delay AML	1 10 16 17 18 19 20
Luspatercept	SF3B1-mutant/ring sideroblasts	Reduces transfusion need	7 10
Allogeneic Stem Cell Transplant (ASCT)	Fit, higher-risk, younger patients	Only curative option	1 10 16 17 18 19 20
Clinical trials	Especially for high-risk or refractory disease	Access to novel therapies	17 20

Table 4: Main Treatment Strategies for Myelodysplastic Syndromes

Supportive Care: The Foundation

Nearly all patients benefit from supportive measures, including:

• Red blood cell and platelet transfusions
• Use of growth factors (e.g., ESAs, G-CSF) to stimulate blood cell production
• Infection prevention and prompt treatment
• Psychosocial support to help with fatigue and emotional burden 1 2 3 16 18

Disease-Modifying Therapies

For Lower-Risk MDS

• Erythropoiesis-Stimulating Agents (ESAs): Improve anemia in many patients, though responses are variable 3 10 16 18.
• Lenalidomide: Highly effective in lower-risk MDS with isolated del(5q), often eliminating the need for transfusions 3 7 10 18.
• Luspatercept: Particularly useful for patients with ring sideroblasts and SF3B1 mutations 7 10.

For Higher-Risk MDS

• Hypomethylating Agents (HMAs): Azacitidine and decitabine are standard for higher-risk patients or those progressing despite other therapies. They can delay progression to AML and improve survival in some cases but are not curative 1 10 16 17 18 19 20.
• Allogeneic Stem Cell Transplant (ASCT): The only potentially curative therapy, but limited to younger, fit patients due to risks of transplant-related complications 1 10 16 17 18 19 20.

Novel and Investigational Approaches

Patients who do not respond to standard treatments or who relapse are encouraged to participate in clinical trials. New drugs targeting specific mutations, immune pathways, or epigenetic mechanisms are under active investigation 17 20.

Choosing the Right Therapy

Treatment is tailored according to:

• Disease risk (IPSS-R score)
• Patient age and overall health
• Presence of specific genetic mutations
• Patient preferences and goals 1 10 16 18

Conclusion

Myelodysplastic syndromes are complex disorders requiring nuanced understanding and individualized care. Advances in genetics and classification have improved diagnosis and risk assessment, but treatment remains challenging—especially for older adults. Here’s what you need to remember:

• Symptoms: Fatigue, anemia, infections, and bleeding are the most common and impact quality of life 1 2 3 4 5.
• Types: MDS includes several subtypes, each with unique features and prognoses; genetic findings play an increasing role in classification 3 7 8 10.
• Causes: Aging, prior chemo/radiation, genetic and epigenetic changes, environmental exposures, and rare inherited syndromes all contribute 1 4 7 9 12 15.
• Treatment: Options range from supportive care and ESAs to lenalidomide, HMAs, and stem cell transplantation; clinical trials are vital for refractory cases 1 3 7 10 16 17 18 19 20.

In summary:

• MDS is a diverse group of stem cell disorders mainly affecting older adults.
• Early recognition of symptoms, especially persistent anemia, is key.
• Diagnosis and classification rely on blood, bone marrow, and genetic studies.
• Treatment is risk-adapted, with curative options limited to a minority.
• Ongoing research and clinical trials offer hope for better targeted therapies in the future.

By staying informed about these aspects, patients and loved ones can be proactive partners in care and decision-making.