What are the treatment options for a patient with Myelodysplastic Syndrome (MDS)?

Treatment of Myelodysplastic Syndromes (MDS)

Treatment for MDS is fundamentally determined by IPSS-R risk stratification, which divides patients into lower-risk and higher-risk categories requiring completely different therapeutic strategies with distinct goals: lower-risk MDS focuses on treating cytopenias and improving quality of life, while higher-risk MDS aims to modify disease course and prolong survival. 1, 2

Risk Stratification: The Critical First Step

IPSS-R scoring is mandatory before initiating any MDS therapy, incorporating cytogenetic risk, bone marrow blast percentage, hemoglobin, platelet count, and absolute neutrophil count to stratify patients into five risk groups (very low, low, intermediate, high, very high) with distinct survival outcomes ranging from 8.8 years median survival in very low risk to 0.8 years in very high risk. 1, 2

• Molecular analysis adds critical prognostic value, particularly TP53 mutations in del(5q) MDS and SF3B1 mutations in patients with <5% blasts. 1, 2
• TP53 mutations confer resistance to standard therapies and warrant consideration of allogeneic transplantation even in otherwise lower-risk patients. 3

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Higher-Risk MDS Treatment Algorithm

First-Line Treatment Selection

For fit patients ≤70 years with a donor: proceed directly to allogeneic stem cell transplantation (allo-SCT), which is the only potentially curative treatment. 1, 2

• Allo-SCT may be preceded by 2-6 cycles of azacitidine or chemotherapy to reduce blast percentage, though this is optional. 1

For patients >70 years, younger patients without a donor, or those with comorbidities: azacitidine 75 mg/m² subcutaneously daily for 7 consecutive days every 28 days is the first-line reference treatment. 1, 2, 4

• Alternative "5-2-2" regimens (5 days on, 2 days off, 2 days on) are acceptable for logistical convenience, though the 7-day regimen remains standard. 1
• At least 6 cycles are mandatory before evaluating efficacy, as most patients only respond after several courses—do not abandon therapy prematurely. 1, 2
• Doses can be reduced in relatively frail patients. 1
• Decitabine is an alternative hypomethylating agent (HMA) approved for all MDS subtypes and IPSS risk groups, though azacitidine has stronger survival data. 4, 5

AML-Like Intensive Chemotherapy: Limited Role

AML-like intensive chemotherapy should only be considered for fit patients (generally <70 years) with favorable cytogenetics (especially normal karyotype) and >10% marrow blasts, preferably as a bridge to allo-SCT. 1

• Avoid intensive chemotherapy in patients with unfavorable karyotype, as they show few complete remissions and shorter remission duration. 1
• Suggested regimens include cytarabine combined with idarubicin or fludarabine. 1
• Direct comparisons suggest HMAs may provide survival advantage over intensive chemotherapy, though data is limited. 1

Very Frail Patients

For very frail patients: supportive care only, including RBC transfusions to maintain hemoglobin ≥8 g/dL (or 9-10 g/dL in patients with cardiac/pulmonary comorbidities), antibiotics, and psychosocial support. 1, 2

Second-Line Treatment After HMA Failure

Patients who fail to respond to azacitidine or are primary refractory have extremely poor survival (median <6 months) unless eligible for allo-SCT. 1

• The recommended approach is enrollment in a clinical trial with investigational agents. 1
• If the patient becomes eligible for allo-SCT after HMA failure, proceed to transplant. 1
• Retreatment with AML-like chemotherapy or low-dose cytarabine yields dismal results and should be avoided. 1

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Lower-Risk MDS Treatment Algorithm

Anemia Management

For patients with serum erythropoietin (EPO) <500 U/L requiring <2 RBC units/month: erythropoiesis-stimulating agents (ESAs) are first-line treatment, achieving response in 15-40% of patients for a median of 8-23 months. 2, 3, 5

For patients with del(5q) cytogenetic abnormality and transfusion-dependent anemia: lenalidomide 10 mg daily for 21 days every 28 days is the treatment of choice after ESA failure or ineligibility, achieving 60-65% transfusion independence with median duration of 2-2.5 years. 2, 3

• Cytogenetic response occurs in 50-75% of patients, including 30-45% complete cytogenetic responses, which correlates with extended survival and delayed AML progression. 3
• Critical pitfall: Test for TP53 mutations before starting lenalidomide in del(5q) patients, as approximately 20% harbor these mutations, which confer resistance and higher AML progression risk. 3
• Do not use lenalidomide as first-line therapy before attempting ESAs in appropriate candidates (serum EPO <500 U/L). 3
• Assess response by 4 months and consider alternative therapies if no improvement—do not continue indefinitely without response. 3

For patients with ring sideroblasts (≥15%) or SF3B1 mutation who are refractory to ESA: luspatercept is approved, achieving erythroid response in 63% and RBC transfusion independence in 38% of patients. 2, 3

Supportive Care Standards

RBC transfusions should maintain hemoglobin ≥8 g/dL, or 9-10 g/dL in patients with comorbidities worsened by anemia or poor functional tolerance. 2

• Transfuse sufficient RBC concentrates to increase hemoglobin >10 g/dL to limit chronic anemia effects on quality of life. 2
• Psychosocial support and patient support group contacts should be systematically offered to all patients. 2

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IPSS-R Intermediate-Risk MDS: The Gray Zone

For IPSS-R intermediate-risk patients, the decision to treat as lower-risk versus higher-risk MDS depends on age, comorbidities, severity of cytopenias, somatic mutations, and response to first-line treatment. 1

• This requires individualized assessment incorporating molecular data and clinical trajectory. 1

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Common Pitfalls to Avoid

• Do not abandon azacitidine before 6 cycles—premature discontinuation is the most common error, as response often requires several courses. 1, 2
• Do not use intensive chemotherapy in unfavorable cytogenetics—these patients have poor outcomes and should receive HMAs or allo-SCT. 1
• Do not skip TP53 mutation testing in del(5q) patients—these patients will not respond to lenalidomide and need alternative strategies. 3
• Do not use lenalidomide before ESAs in appropriate candidates—this violates guideline recommendations and may expose patients to unnecessary toxicity. 3