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

Treatment Options for Myelodysplastic Syndrome

Treatment for MDS is stratified by risk category: lower-risk patients (IPSS low/INT-1, IPSS-R very low/low/intermediate) receive therapies targeting hematologic improvement and symptom management, while higher-risk patients (IPSS INT-2/high, IPSS-R intermediate/high/very high) require disease-modifying treatments aimed at altering natural history and delaying AML transformation. 1

Risk Stratification Framework

Risk assessment using IPSS or IPSS-R scoring systems is mandatory before selecting treatment, as this determines the therapeutic approach (category 2A recommendation). 1 Additional critical determinants include:

• Age and performance status - directly influence ability to tolerate intensive treatments 1
• Comorbidities - impact treatment selection and transplant eligibility 1
• TP53 mutation status - particularly in del(5q) patients, as mutations confer resistance to lenalidomide and higher AML progression risk 1
• Transfusion dependence - negative prognostic factor incorporated in WPSS scoring 1

Lower-Risk MDS Treatment Algorithm

For Symptomatic Anemia

First-line therapy depends on serum erythropoietin levels and del(5q) status:

Patients WITHOUT del(5q):

• If serum EPO <500 U/L: Erythropoiesis-stimulating agents (ESAs) such as recombinant human erythropoietin or darbepoetin alfa, with or without G-CSF, achieve erythroid response rates of 40-60% 1
• Response occurs within 8-12 weeks; median response duration is 20-24 months 1
• If serum EPO ≥500 U/L or requiring ≥2 RBC concentrates/month: ESAs have low success rates; consider second-line options 1

Patients WITH del(5q):

• Lenalidomide 10 mg/day for 3 weeks every 4 weeks is first-line therapy (after ESA failure/ineligibility in EU), achieving RBC transfusion independence in 60-65% with median duration of 2-2.5 years 1
• Cytogenetic response occurs in 50-75% (including 30-45% complete responses) 1
• Critical pitfall: 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 mandatory 1
• TP53 mutations (present in ~20% of del(5q) patients) predict lenalidomide resistance and require intensified disease surveillance 1

Second-line options for lower-risk MDS:

• Luspatercept for MDS with ring sideroblasts: achieves erythroid response in 63% and RBC transfusion independence in 38% 1
• Antithymocyte globulin (ATG) ± cyclosporine in select patients with favorable features 1
• Azacitidine if approved for lower-risk disease 1

For Symptomatic Neutropenia

• Broad-spectrum antibiotics immediately upon fever or infection symptoms - this is mandatory and directly impacts survival 1, 2, 3
• Short-term G-CSF during severe active infections improves neutropenia in 60-75% of cases 2, 3
• Critical pitfall: Prophylactic G-CSF or antibiotics are NOT recommended outside active infection, as they have not demonstrated survival benefit 1, 3

For Symptomatic Thrombocytopenia

• Platelet transfusions for severe thrombocytopenia or active bleeding 1, 2
• Thrombopoietin receptor agonists if marrow blasts <5% 1
• Prophylactic platelet transfusions are generally not used long-term except when receiving myelosuppressive drugs 1, 2

Higher-Risk MDS Treatment Algorithm

First-Line Therapy

Azacitidine 75 mg/m² subcutaneously for 7 consecutive days every 28 days is the reference first-line treatment for IPSS INT-2/high risk patients not eligible for transplant. 1, 2 This is the only hypomethylating agent with proven survival advantage over conventional care in randomized trials. 1

Key implementation points:

• Minimum 6 cycles required before assessing efficacy, as most patients respond only after several courses 1, 2
• Hematologic improvement (not just CR/PR) indicates response and associates with prolonged survival 1
• Alternative 5-day regimens have not demonstrated survival advantage in higher-risk MDS 1

Decitabine is FDA-approved for all MDS subtypes (including intermediate-1, intermediate-2, and high-risk IPSS groups) but lacks clear survival advantage over conventional treatment in phase III trials. 4, 1 Dosing options include:

• 15 mg/m² IV over 3 hours every 8 hours for 3 days, repeated every 6 weeks 4
• 20 mg/m² IV over 1 hour daily for 5 days, repeated every 4 weeks 4

Allogeneic Hematopoietic Cell Transplantation

Allogeneic HCT should be proposed to all fit patients ≤70 years with higher-risk disease who have a donor, as this is the only potentially curative option. 1, 2 Azacitidine use before transplantation appears promising and is under evaluation. 1

Critical consideration: Even moderate iron overload before alloSCT associates with increased transplant-related mortality; future transplant candidates should receive early iron chelation. 1

AML-Like Intensive Chemotherapy

Intensive chemotherapy has limited indication in higher-risk MDS, particularly in patients with unfavorable cytogenetics. 1 This approach is generally reserved for select younger patients without poor-risk features.

Universal Supportive Care Measures

All MDS patients require comprehensive supportive care regardless of risk category:

Transfusion Management

• RBC transfusions (leukocyte-reduced) to maintain hemoglobin ≥8 g/dL, or 9-10 g/dL with cardiovascular comorbidities 1, 2, 5
• Consider transfusing sufficient units over 2-3 days to increase hemoglobin above 10 g/dL to limit chronic anemia effects on quality of life 1, 2, 5
• Monitor for citrate toxicity (hypocalcemia, hypomagnesemia) when multiple units given rapidly 2, 5

Iron Overload Management

• Monitor serum ferritin in chronically transfused patients 5
• Consider iron chelation (deferasirox or deferoxamine) in lower-risk patients with favorable prognosis who have received 20-60 RBC concentrates or ferritin >1000-2500 U/L 1
• Heart MRI showing T2* <20 ms indicates iron overload risk for heart failure 1
• All future transplant candidates should receive early chelation 1

Quality of Life Support

• Clinical monitoring, psychosocial support, and quality-of-life assessment addressing physical, functional, emotional, spiritual, and social domains 1, 5
• Contact with patient support groups when available 1

Therapy-Related MDS

Patients with therapy-related MDS have poorer prognoses than primary MDS, with substantial proportion having poor-risk cytogenetics; manage as higher-risk disease regardless of IPSS score. 1

Clinical Trial Participation

Clinical trial enrollment should be considered for all MDS patients, particularly those with higher-risk disease or those who have failed standard therapies. 1