What is the primary goal and treatment approach for patients with myelodysplastic syndromes (MDS)?

Treatment Goals and Approach for Myelodysplastic Syndromes

The primary goal of MDS treatment is risk-stratified: for higher-risk disease, the priority is prolonging survival and delaying progression to acute myeloid leukemia, while for lower-risk disease, the focus is managing cytopenias (especially anemia) and improving quality of life. 1

Risk Stratification Determines Treatment Strategy

The IPSS-R (Revised International Prognostic Scoring System) is mandatory for determining treatment approach and must be calculated at diagnosis 1. This scoring system incorporates cytogenetics, bone marrow blast percentage, hemoglobin, platelet count, and absolute neutrophil count to classify patients into very low, low, intermediate, high, and very high-risk categories 1.

Higher-Risk MDS (IPSS-R High, Very High, and Some Intermediate)

Primary Treatment Goals

• Alter the natural history of disease by prolonging overall survival 1
• Delay or prevent progression to acute myeloid leukemia 2
• Achieve hematologic response (complete or partial remission) 1

Treatment Algorithm for Higher-Risk Disease

For fit patients ≤70 years with an available donor:

• Allogeneic stem cell transplantation (allo-SCT) is the only potentially curative treatment and should be pursued 1
• Patients aged <55 years without comorbidities should receive myeloablative conditioning rather than reduced-intensity conditioning due to lower relapse rates 1
• HLA-identical or single antigen mismatched siblings/matched unrelated donors are preferred, though haploidentical donors are now acceptable alternatives 1
• Bridging therapy with azacitidine or chemotherapy to reduce blast count may be used before transplant, particularly when marrow blasts exceed 10% 1

For patients >70 years or those without a transplant donor:

• Azacitidine 75 mg/m² subcutaneously for 7 consecutive days every 28 days is the standard first-line treatment 1, 3
• At least six cycles should be administered before assessing response, as responses often occur after multiple courses 1
• Azacitidine has demonstrated a 74% improvement in survival despite modest complete response rates 2
• Alternative "5-2-2" regimens (5 days, 2-day break, 2 days) are acceptable for practical administration 1

For very frail patients:

• Supportive care with RBC transfusions and antibiotics is appropriate 1

Second-Line Treatment After Hypomethylating Agent Failure

Patients who fail azacitidine have extremely poor survival (median <6 months) and should be enrolled in clinical trials with investigational agents 1. If they become eligible for allo-SCT during this period, proceed immediately to transplant 1. Retreatment with AML-like chemotherapy or low-dose cytarabine yields dismal results and should be avoided 1.

Lower-Risk MDS (IPSS-R Very Low, Low, and Some Intermediate)

Primary Treatment Goals

• Treat cytopenias, particularly anemia (the predominant cytopenia) 1
• Improve quality of life 1
• Reduce transfusion requirements and prevent iron overload 1

Treatment Algorithm for Anemia in Lower-Risk Disease

For patients WITHOUT del(5q) deletion:

• Erythropoiesis-stimulating agents (ESAs) are first-line treatment 1
• Recombinant EPO 30,000-80,000 units weekly OR darbepoetin 150-300 μg weekly 1
• ESAs achieve 40-60% erythroid response rates when baseline EPO level is <200-500 U/L and transfusion requirement is absent or limited 1
• Adding G-CSF improves efficacy 1
• Response occurs within 8-12 weeks; median duration of response is 20-24 months 1
• ESAs are an independent favorable prognostic factor for survival without increasing AML progression risk 1

For patients WITH del(5q) deletion:

• Lenalidomide 10 mg daily for 3 weeks every 4 weeks is first-line treatment 1
• Achieves 60-65% response rates with median RBC transfusion independence of 2-2.5 years 1
• Produces cytogenetic response in 50-75% of patients (30-45% complete cytogenetic response) 1
• Critical caveat: TP53 mutations (present in ~20% of del(5q) MDS) confer resistance to lenalidomide and higher AML progression risk; these patients require intensified surveillance 1

Transfusion Support and Iron Overload Management

Chronic RBC transfusions are associated with:

• Excess morbidity from chronic anemia 1
• Incomplete correction of impaired quality of life 1
• Iron overload causing organ damage (particularly cardiac, hepatic, and endocrine dysfunction) 1
• Increased treatment-related mortality in patients proceeding to allo-SCT 1

Iron chelation therapy should be initiated in transfusion-dependent patients to preserve quality of life and organ function, and must be given to transplant candidates until conditioning begins 1.

Response Evaluation Criteria

Response assessment should include four levels based on treatment intent 1:

• Hematologic response (for low-intensity therapies aimed at palliation) 1
• Altering natural history (survival, progression-free survival for disease-modifying therapies) 1
• Cytogenetic response (particularly valuable for transplant and intensive therapies) 1
• Quality of life assessment (using instruments like WHO Performance Score or FACT Questionnaire) 1

Complete blood counts should be evaluated at least monthly to establish durability of responses 1.

Critical Pitfalls to Avoid

• Do not substitute azacitidine for injection for oral azacitidine formulations—they have different indications and dosing regimens 3
• Do not discontinue azacitidine before 6 cycles in higher-risk patients, as responses are often delayed 1
• Do not use intensive chemotherapy in higher-risk patients who fail azacitidine unless proceeding to transplant 1
• Do not overlook TP53 mutation testing in del(5q) patients before starting lenalidomide 1
• Do not delay transplant evaluation in eligible higher-risk patients—it should occur at diagnosis 1