What is the initial treatment approach for myelodysplastic syndrome (MDS)?

Initial Treatment Approach for Myelodysplastic Syndrome

The initial treatment approach for MDS is determined by risk stratification using IPSS-R scoring, with lower-risk patients receiving supportive care and symptom-directed therapy (erythropoiesis-stimulating agents for anemia, lenalidomide for del(5q)), while higher-risk patients should receive hypomethylating agents (azacitidine or decitabine) as first-line therapy, with allogeneic stem cell transplantation considered for eligible patients at diagnosis. 1

Risk Stratification Drives Treatment Selection

The foundation of MDS treatment begins with IPSS-R (Revised International Prognostic Scoring System) risk categorization, which is mandatory for prognostic evaluation and treatment planning 1. This system stratifies patients into five risk groups (very low, low, intermediate, high, very high) based on:

• Cytogenetic risk category 1
• Bone marrow blast percentage 1
• Hemoglobin level 1
• Platelet count 1
• Absolute neutrophil count 1

Patients are then divided into two major treatment groups: lower-risk (IPSS-R very low, low, intermediate) and higher-risk (IPSS-R intermediate, high, very high). 1 The intermediate category can be managed as either group depending on additional factors including age, performance status, serum ferritin, and LDH levels 1.

Lower-Risk MDS: Symptom-Directed Therapy

For lower-risk patients, the primary goal is hematologic improvement, reducing transfusion requirements, and preventing progression to higher-risk disease 1, 2.

Anemia Management

• Erythropoiesis-stimulating agents (ESAs) such as recombinant human erythropoietin or darbepoetin alfa, with or without G-CSF, are first-line for symptomatic anemia, achieving erythroid response rates of 40-60% in lower-risk patients 1, 2.
• Response rates of 15-40% can be expected, with median response duration of 8-23 months 2.

Del(5q) MDS

• Lenalidomide is specifically indicated for patients with deletion 5q cytogenetic abnormality 1, 3, 4.
• However, TP53 mutations are associated with diminished response or relapse after lenalidomide treatment 1.

Supportive Care

All lower-risk patients should receive appropriate supportive care including:

• Red blood cell transfusions as needed 1
• Platelet transfusions for severe thrombocytopenia 1
• Antibiotics for infections 1

Higher-Risk MDS: Disease-Modifying Therapy

For higher-risk patients, treatment aims to alter the natural disease course and prolong survival 1.

Hypomethylating Agents (First-Line Standard)

Azacitidine is the recommended first-line treatment for higher-risk MDS patients without major comorbidities who are not immediately eligible for allogeneic stem cell transplantation. 1

Azacitidine Dosing

• 75 mg/m² subcutaneously daily for 7 consecutive days every 28 days 1, 5
• Alternative "5-2-2" regimens (5 days on, 2 days off, 2 days on) are considered acceptable and often easier to implement 1
• At least 6 cycles are recommended before assessing response, as most patients only respond after several courses 1, 5

Decitabine Alternative

• 15 mg/m² intravenously every 8 hours for 3 days every 6 weeks is an alternative hypomethylating agent regimen 6
• Oral decitabine/cedazuridine combination is also FDA-approved 3, 4

Allogeneic Stem Cell Transplantation

For fit patients ≤70 years with a donor, allogeneic stem cell transplantation should be considered at diagnosis as it represents the only potentially curative therapy. 1, 2, 3, 4

• Transplant may be preceded by chemotherapy or hypomethylating agents to reduce blast percentage 1
• 2-6 cycles of azacitidine are commonly used before HSCT to reduce blasts or for logistical reasons 1

Intensive Chemotherapy

• Intensive anthracycline-cytarabine combinations are used less frequently than hypomethylating agents 1
• Reserved for select patients, particularly those proceeding to transplant 1

Critical Monitoring Requirements

Hematologic Monitoring

• Complete blood counts with differential must be monitored at baseline, prior to each cycle, and as needed to assess response and toxicity 6.
• Myelosuppression (anemia, neutropenia, thrombocytopenia) is the most frequent cause of dose reduction, delay, and discontinuation with hypomethylating agents 6.

Response Assessment

• Response criteria are based on IWG 2006 recommendations, defining both disease-modifying responses and hematologic improvement 1.
• Achievement of hematologic improvement is associated with prolonged survival compared to supportive care 1.

Important Clinical Pitfalls

Molecular Testing Considerations

• TP53 mutation status should be assessed, particularly in del(5q) MDS, as it predicts diminished lenalidomide response 1.
• SF3B1 mutations provide prognostic value in patients with <5% blasts 1.
• However, molecular markers should not preclude use of hypomethylating agents nor influence selection between them 1.

Treatment Duration

• Continue hypomethylating agents as long as the patient continues to benefit 5.
• Early discontinuation before 6 cycles is a common error, as responses often occur after multiple courses 1.

Dose Modifications

• For azacitidine: doses can be reduced in relatively frail patients 1.
• For decitabine: dose delays, reductions, and use of growth factors may be needed to manage myelosuppression 6.

Very Frail Patients

For very frail higher-risk patients, supportive care alone (RBC transfusions, antibiotics) may be most appropriate 1.