What are the treatment options for myelodysplastic syndromes (MDS)?

Treatment of Myelodysplastic Syndromes

Treatment of MDS is fundamentally determined by risk stratification using IPSS-R, which divides patients into lower-risk (very low, low, intermediate) and higher-risk (intermediate, high, very high) categories, with each requiring distinct therapeutic approaches aimed at different outcomes. 1

Risk Stratification is Mandatory

• IPSS-R scoring is required for prognostic evaluation and treatment planning before initiating any therapy. 1
• Molecular analysis adds prognostic value, particularly TP53 mutations in del(5q) MDS and SF3B1 mutations in patients with <5% blasts. 1
• The IPSS-R incorporates cytogenetic risk, bone marrow blast percentage, hemoglobin, platelet count, and absolute neutrophil count to stratify patients into five risk groups with distinct survival outcomes. 1

Higher-Risk MDS Treatment Algorithm

For higher-risk MDS (IPSS-R intermediate, high, or very high), the treatment goal is to modify disease course and prolong survival, not merely improve cytopenias. 1

Fit Patients ≤70 Years with Donor Available

• Allogeneic stem cell transplantation (allo-SCT) is the only potentially curative treatment and should be pursued in eligible patients. 1
• Allo-SCT may be preceded by chemotherapy or hypomethylating agents (HMAs) to reduce blast percentage, though this remains debated. 1
• Patients aged <55 years without comorbidities should receive myeloablative conditioning rather than reduced-intensity conditioning due to higher relapse rates with the latter. 1
• 2-6 cycles of azacitidine are commonly used before transplantation to reduce bone marrow blasts or for logistical reasons. 1, 2

Patients >70 Years or Without Donor

Azacitidine is the first-line reference treatment for higher-risk MDS patients without major comorbidities who are not immediately eligible for allo-SCT. 1

Azacitidine Dosing Regimen

• Administer azacitidine 75 mg/m² subcutaneously daily for 7 consecutive days every 28 days. 1, 2
• At least 6 cycles are mandatory before evaluating treatment efficacy, as most patients only respond after several courses. 1, 2
• The "5-2-2" regimen (5 days on, 2 days off, 2 days on) is acceptable and often easier to apply, though it has not demonstrated survival advantage over the 7-day regimen. 1, 2
• Hematological improvement according to IWG 2006 criteria is associated with prolonged survival compared to supportive care. 1, 2

Common Pitfall: Do not discontinue azacitidine before 6 cycles unless there is clear disease progression or unacceptable toxicity, as delayed responses are common. 1, 2

Alternative: Decitabine

• Decitabine is FDA-approved for MDS including intermediate-1, intermediate-2, and high-risk IPSS groups. 3
• Two regimens exist: 15 mg/m² IV over 3 hours every 8 hours for 3 days (repeat every 6 weeks) or 20 mg/m² IV over 1 hour daily for 5 days (repeat every 4 weeks). 3

Intensive Chemotherapy

• AML-like chemotherapy (anthracycline-cytarabine combinations) has limited indication in higher-risk MDS. 1
• Consider only for younger patients (generally <60-65 years) with favorable cytogenetics and marrow blasts >10%, preferably as a bridge to allo-SCT. 1
• Suggested regimens include cytarabine with idarubicin, fludarabine, or topotecan. 1

Low-Dose Cytarabine

• Low-dose cytarabine (20 mg/m²/day for 14-21 days every 4 weeks) is significantly inferior to azacitidine in terms of response and survival. 1
• May be considered only in patients with normal karyotype who are not candidates for intensive chemotherapy or allo-SCT when azacitidine is not available. 1
• Achieves CR/PR in only 15-20% of cases with significant myelosuppressive effects. 1

Very Frail Patients

• Supportive care with RBC transfusions, antibiotics, and platelet transfusions as needed. 1
• In case of failure or relapse, consider clinical trial or symptomatic treatment. 1

Second-Line Treatment After HMA Failure

• Patients who fail azacitidine or are primary refractory to HMAs have extremely poor survival (median <6 months). 1
• The recommended approach is enrollment in a clinical trial with investigational agents. 1
• If the patient becomes eligible for allo-SCT, proceed to transplant. 1

Lower-Risk MDS Treatment Algorithm

For lower-risk MDS (IPSS-R very low, low, or some intermediate), the primary goal is treating cytopenias (mainly anemia) and improving quality of life, not modifying disease course. 1

Symptomatic Anemia Management

Patients WITHOUT del(5q)

For patients with serum EPO <500 U/L and requiring <2 RBC concentrates/month:

• Erythropoiesis-stimulating agents (ESAs) are first-line treatment. 1
• Weekly doses of 30,000-80,000 units of EPO or 150-300 μg darbepoetin alfa yield ~60% erythroid response rates. 1
• ESAs with or without G-CSF achieve responses in 40-60% of patients with median response duration of 20-24 months. 1
• Responses occur within 8-12 weeks of treatment. 1
• ESA treatment is an independent favorable prognostic factor for survival in lower-risk MDS. 1

For patients with serum EPO ≥500 U/L or requiring ≥2 RBC concentrates/month:

• ESAs have low success rates in this population. 1
• Consider second-line options including antithymocyte globulin (ATG) ± cyclosporine, azacitidine (if approved), or lenalidomide ± EPO. 1

Patients WITH del(5q)

Lenalidomide is the treatment of choice for lower-risk MDS with del(5q) and transfusion-dependent anemia. 1

• Lenalidomide achieves RBC transfusion independence in 60-65% of patients with median duration of 2-2.5 years. 1
• Recommended initial dose is 10 mg/day for 3 weeks every 4 weeks. 1
• Cytogenetic response occurs in 50-75% of patients (including 30-45% complete cytogenetic response). 1
• Critical Caveat: TP53 mutations (found in ~20% of del(5q) lower-risk MDS) confer resistance to lenalidomide and higher risk of AML progression. 1
• Patients with del(5q) harboring or developing TP53 mutations require intensified disease surveillance with regular bone marrow assessment. 1
• Grade 3-4 neutropenia and thrombocytopenia occur in ~60% during first weeks; close blood count monitoring with dose reduction and/or G-CSF addition is required. 1
• In the EU, lenalidomide is approved only after ESA failure or ineligibility. 1

MDS with Ring Sideroblasts (MDS-RS) or SF3B1 Mutation

Luspatercept is approved for RBC transfusion-dependent, lower-risk MDS-RS or SF3B1 mutation refractory to ESA. 1

• Achieves erythroid response in 63% and RBC transfusion independence in 38% of patients. 1
• Particularly effective in patients with MDS-RS or SF3B1 mutation. 1

Symptomatic Neutropenia Management

• Broad-spectrum antibiotics if fever develops. 1
• Short-term G-CSF during severe infections can be useful but prolonged use has not demonstrated survival impact. 1
• ATG if favorable features present. 1
• Azacitidine if approved for this indication. 1

Symptomatic Thrombocytopenia Management

• Platelet transfusions for severe thrombocytopenia or bleeding. 1
• Thrombopoietin receptor agonists (TPO-RAs) if marrow blasts <5%: romiplostim or eltrombopag achieve ~55% platelet responses. 1
• Important Caveat: Transient rise in marrow blasts (~15%) can occur with romiplostim but is reversible after discontinuation. 1
• High-dose androgens improve thrombocytopenia in about one-third of cases but response is generally transient. 1
• ATG and HMAs yield platelet response in 35-40% of cases. 1

Supportive Care for All Patients

• RBC transfusions should maintain hemoglobin ≥8 g/dL, or 9-10 g/dL in patients with comorbidities worsened by anemia or poor functional tolerance. 1
• Transfuse sufficient RBC concentrates to increase hemoglobin >10 g/dL to limit chronic anemia effects on quality of life. 1
• Iron chelation should be considered for patients with heavy transfusion requirements at risk for end-organ complications. 4
• Prophylactic antibiotics and G-CSF are not recommended for neutropenia, but rapid broad-spectrum antibiotics are mandatory with fever or infection symptoms. 1
• Psychosocial support and patient support group contacts should be systematically offered. 1