Treatment of Myelodysplastic Syndrome
Treatment of MDS must be stratified by IPSS-R risk category, with lower-risk disease managed primarily with supportive care and agents targeting cytopenias, while higher-risk disease requires hypomethylating agents (azacitidine or decitabine) as first-line therapy, with allogeneic stem cell transplantation reserved for eligible patients as the only potentially curative option. 1
Risk Stratification Framework
All patients must be risk-stratified using the IPSS-R scoring system, which incorporates cytogenetic risk category, bone marrow blast percentage, hemoglobin level, platelet count, and absolute neutrophil count to classify patients into five risk groups: very low, low, intermediate, high, and very high 1. The IPSS-R provides median overall survival estimates ranging from 8.8 years for very low-risk to 0.8 years for very high-risk disease 1.
IPSS-R intermediate-risk patients may be managed as either lower-risk or higher-risk depending on additional factors including age, performance status, serum ferritin, lactate dehydrogenase levels, severity of cytopenias, and response to initial therapy 1, 2.
Molecular analysis adds prognostic value, particularly TP53 mutations in del(5q) MDS and SF3B1 mutations in patients with <5% blasts 1. TP53 mutations predict poor response to lenalidomide and shorter overall survival 1, 3.
Lower-Risk MDS Treatment (IPSS-R Very Low, Low, Intermediate)
Primary Goal
The therapeutic aim is hematologic improvement—specifically treating symptomatic cytopenias, improving quality of life, and reducing transfusion burden—rather than altering disease natural history 1, 2.
First-Line Anemia Management
For symptomatic anemia with serum erythropoietin ≤500 mU/mL, initiate erythropoiesis-stimulating agents (ESAs) such as recombinant erythropoietin or darbepoetin alfa, with or without granulocyte-colony stimulating factor (G-CSF) 1, 2. ESAs achieve erythroid response rates of 40-60% when baseline EPO is low (<200-500 U/L) and transfusion requirements are modest (<2 units/month) 1, 2.
Predictors of favorable ESA response include: low baseline serum erythropoietin, low marrow blast percentage, and minimal prior transfusions 2.
Del(5q) MDS-Specific Therapy
For isolated del(5q) with symptomatic anemia, lenalidomide 10 mg daily for 21 out of 28 days is recommended 1. However, test for TP53 mutations before initiating lenalidomide, as TP53 alterations predict reduced response or early relapse 1, 2, 3. Lenalidomide should not be used as primary therapy in TP53-mutated MDS even with del(5q) present 3.
Immunosuppressive Therapy
Immunosuppressive therapy with equine anti-thymocyte globulin (ATG) ± cyclosporin A is most effective in relatively young patients (≤60 years) with ≤5% marrow blasts, hypocellular marrows, HLA-DR15 positivity, PNH clone positivity, or STAT-3 mutant cytotoxic T-cell clones 1, 2.
Supportive Care
Red blood cell transfusions should maintain hemoglobin >8-10 g/dL based on symptoms 1, 2. Platelet transfusions are indicated for active bleeding or severe thrombocytopenia 2. G-CSF is recommended for recurrent infections in neutropenic patients 2.
Iron chelation therapy should be considered for transfusion-dependent patients, as iron overload increases infection-related mortality 2. Monitor serum ferritin with goal <1000 mcg/L 2.
Higher-Risk MDS Treatment (IPSS-R Intermediate, High, Very High)
Primary Goal
Treatment aims to modify disease course by delaying AML progression and prolonging overall survival, with objectives including complete remission, partial remission, and hematologic improvement 1, 2.
First-Line Hypomethylating Agent Therapy
Azacitidine 75 mg/m² subcutaneously for 7 consecutive days every 28 days is the reference first-line treatment for higher-risk patients without major comorbidities who are not immediately eligible for allogeneic stem cell transplantation 1, 2, 3. Alternative "5-2-2" dosing schedules (5 days on, 2 days off, 2 days on) are acceptable for logistical reasons 1.
A minimum of six treatment cycles must be completed before assessing response, as most patients only respond after several courses 1, 2, 3. Azacitidine improves overall survival by up to 74% compared with conventional care, with complete response rates of 15-20% 2.
Decitabine 20 mg/m² IV over 1 hour daily for 5 days every 4 weeks is an alternative hypomethylating agent, with overall response rates (CR+PR) of approximately 17% 4. Oral decitabine/cedazuridine represents a newer oral formulation option 5, 6.
Allogeneic Stem Cell Transplantation
Allogeneic stem cell transplantation is the only potentially curative treatment and should be evaluated at diagnosis for all higher-risk patients ≤70 years old (or fit patients >70 years) with an HLA-identical sibling or matched unrelated donor 1, 2.
Fit patients ≤55 years without significant comorbidities should receive myeloablative conditioning, whereas older or less-fit patients should receive reduced-intensity conditioning 2.
Administering 2-6 cycles of azacitidine before transplant can reduce blast burden and provide time to secure a donor 1, 2, 3.
Intensive Chemotherapy
**Intensive AML-like chemotherapy (cytarabine + anthracycline combinations) is reserved for fit patients <70 years** with favorable cytogenetics (especially normal karyotype), >10% marrow blasts, and when used as a bridge to allogeneic transplantation 1, 2. Patients with unfavorable cytogenetics derive few complete remissions and shorter remission durations with intensive chemotherapy 2.
Low-dose cytarabine is significantly less effective than azacitidine and should only be used when hypomethylating agents are unavailable, preferably in patients with normal karyotype 2.
Very Frail Patients
Very frail higher-risk patients should receive supportive care only (transfusions, antibiotics, growth factors) rather than disease-modifying therapy 1, 2.
Management After Hypomethylating Agent Failure
Patients refractory to hypomethylating agents have a median survival <6 months; enrollment in clinical trials or proceeding directly to allogeneic stem cell transplantation (if eligible) is recommended 2, 3. Retreatment with intensive chemotherapy or low-dose cytarabine after HMA failure yields dismal outcomes 2.
Response Assessment
Response evaluation follows International Working Group (IWG) 2006 criteria, defining complete remission (CR), partial remission (PR), and hematologic improvement (HI) 1, 2, 3. Achievement of hematologic improvement is associated with prolonged survival compared with supportive care alone 1, 3.
Critical Pitfalls to Avoid
Do not discontinue azacitidine before completing six cycles unless clear disease progression is documented 2.
Do not employ intensive AML-like chemotherapy in patients with unfavorable cytogenetics outside of clinical trials, as outcomes are poor 2.
Do not postpone allogeneic transplant evaluation in eligible higher-risk patients; transplant assessment should occur at diagnosis 2, 3.
Do not use lenalidomide as primary treatment for TP53-mutated MDS, even in the presence of del(5q), as TP53 alterations predict resistance and poor outcomes 3.
Special Considerations
Therapy-related MDS is associated with high frequency of poor-risk cytogenetics and should be managed as higher-risk disease irrespective of IPSS-R score 2.
Patient-related factors including age, performance status, and comorbidities are critical determinants of treatment tolerance and should guide therapy selection 1.