Treatment Options for Myelodysplastic Syndromes
Risk Stratification Determines Treatment Strategy
Treatment for MDS must be stratified by IPSS-R risk category, which divides patients into lower-risk (very low, low, intermediate) and higher-risk (high, very high) groups requiring fundamentally different therapeutic approaches and goals. 1, 2
IPSS-R scoring 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 and must be performed before initiating any therapy 2. Molecular analysis adds prognostic value, particularly TP53 mutations in del(5q) MDS and SF3B1 mutations in patients with <5% blasts 1.
Higher-Risk MDS Treatment Algorithm
Primary Goal: Modify Disease Course and Prolong Survival
For fit patients ≤70 years with a donor, allogeneic stem cell transplantation (allo-SCT) is the only potentially curative treatment and should be pursued as first-line therapy. 1, 2
Allo-SCT can be preceded by chemotherapy or hypomethylating agents (HMAs) to reduce blast percentage, though this is optional 1. The use of 2-6 cycles of azacitidine before transplantation is common to reduce bone marrow blasts or for logistical reasons to allow time to find an adequate donor 1.
For Patients >70 Years or Without a 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, 2
- Dosing regimen: 75 mg/m² subcutaneously daily for 7 consecutive days every 28 days 1, 2
- Critical requirement: At least 6 cycles are mandatory before evaluating treatment efficacy, as most patients only respond after several courses 1, 2
- Alternative "5-2-2" regimens (5 days on, 2 days off, 2 days on) are often easier to apply and considered acceptable 1
- Doses can be reduced in relatively frail patients 1
Decitabine is FDA-approved for all MDS subtypes including intermediate-1, intermediate-2, and high-risk IPSS groups, with dosing options of either 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.
AML-Like Intensive Chemotherapy
AML-like intensive chemotherapy has limited indication and should only be considered for fit patients (generally <70 years) without unfavourable cytogenetics (especially those with normal karyotype) and >10% marrow blasts, preferably as a bridge to allo-SCT. 1
MDS patients with unfavourable karyotype show few complete responses and shorter CR duration than those with normal karyotype 1. Suggested regimens include combinations of cytarabine with idarubicin or fludarabine 1. A direct comparison suggested superiority of HMAs over AML-like chemotherapy in terms of survival (but not CR rate), though the study was underpowered 1.
Very Frail Patients
Supportive care with RBC transfusions and antibiotics is appropriate, with consideration of clinical trials or symptomatic treatment in case of failure or relapse 1.
Lower-Risk MDS Treatment Algorithm
Primary Goal: Treat Cytopenias and Improve Quality of Life
For symptomatic anemia with serum EPO <500 U/L and requiring <2 RBC concentrates/month, erythropoiesis-stimulating agents (ESAs) with or without G-CSF are first-line treatment. 1, 2
ESAs have a low success rate but should be attempted before more aggressive therapies in appropriate candidates 1, 4. The European Society for Medical Oncology advises against using lenalidomide as first-line therapy before attempting ESAs in appropriate candidates 4.
For Del(5q) MDS with Transfusion-Dependent Anemia
Lenalidomide is the treatment of choice for lower-risk MDS with del(5q) cytogenetic abnormality, achieving 60-65% transfusion independence with median duration of 2-2.5 years. 4, 2
- Dosing: 10 mg daily for 21 days every 28 days as the starting dose 4
- Cytogenetic response: Occurs in 50-75% of patients, including 30-45% complete cytogenetic responses, which correlates with extended survival and delayed AML progression 4
- Critical caveat: TP53 mutations, found in approximately 20% of del(5q) MDS patients, confer resistance to lenalidomide and higher risk of AML progression 4. The American Society of Hematology recommends testing for TP53 mutations before starting lenalidomide, as these patients have poor outcomes and may benefit from alternative approaches including allogeneic transplant 4.
- Response assessment: Assess response by 4 months and consider alternative therapies if no improvement; do not continue indefinitely without response 4
For Ring Sideroblasts or SF3B1 Mutation
Luspatercept is approved for very low-, low-, or intermediate-risk MDS with ring sideroblasts (≥15%) or SF3B1 mutation refractory to ESA, achieving 38% transfusion independence ≥8 weeks. 4, 2
Note that luspatercept is administered subcutaneously, not orally 4.
For Patients Requiring ≥2 RBC Concentrates/Month and Serum EPO >500 U/L
Treatment options include 1:
- Azacitidine (if approved or in clinical trial)
- For del(5q): lenalidomide
- For non-del(5q): second-line treatment options
Immunosuppressive Therapy
Antithymocyte globulin (ATG) can be considered if favorable features are present 1.
Supportive Care for All Patients
Transfusion Management
RBC transfusions should maintain hemoglobin ≥8 g/dL, or 9-10 g/dL in patients with cardiovascular comorbidities or poor functional tolerance. 2, 5
Administer sufficient RBC concentrates over 2-3 days if necessary to increase hemoglobin >10 g/dL to limit chronic anemia effects on quality of life 1, 2, 5. Prophylactic platelet transfusions are less commonly used than RBC transfusions in MDS, especially long-term, except in patients receiving myelosuppressive drugs 1.
Infection Management
Rapid onset of broad-spectrum antibiotics is mandatory in neutropenic patients with fever or symptoms of infection. 1, 5
Prophylactic antibiotics and/or G-CSF are not recommended for neutropenia, as they have not shown survival impact 1. Short-term use of G-CSF during severe infections could be useful in neutropenic patients, improving neutropenia in 60-75% of cases, but this indication has not been formally validated 1, 5.
Iron Chelation Therapy
Iron chelation should be considered in patients with relatively favorable prognosis (low or intermediate-1-risk MDS) who have received 20-60 RBC concentrates, or if serum ferritin raises above 1000-2500 U/L, or if cardiac T2* is significantly reduced 1. Future candidates to allo-SCT should be chelated early, as even relatively moderate iron overload before allo-SCT is associated with increased transplant-related mortality 1.
Deferasirox is an oral iron chelator option, though frequently associated with gastrointestinal side-effects and cannot be used in patients with renal failure 1.
Psychosocial Support
Psychosocial support and contacts with patient support groups should be systematically offered to all patients 1, 2.
Critical Treatment Considerations
Response criteria to treatment in MDS are based on International Working Group (IWG) 2006 recommendations, defining responses aimed at modifying disease course and improvement of cytopenias (haematological improvement or HI) in one or several lineages. 1
For lower-risk patients, the major therapeutic goal is hematologic improvement, whereas alteration of disease natural history is paramount for higher-risk patients 1. Achievement of HI according to IWG 2006 criteria is associated with prolongation of survival compared with supportive care or low-dose cytarabine 1.
Most patients with therapy-related MDS have poorer prognoses than those with primary MDS, including a substantial proportion with poor-risk cytogenetics, and are generally managed as having higher-risk disease. 1