Myelodysplastic Syndrome Management
Risk Stratification is Mandatory Before Treatment
IPSS-R scoring must be performed before initiating any therapy to stratify patients into lower-risk versus higher-risk categories, as this fundamentally determines treatment goals and selection 1, 2. Lower-risk patients (IPSS-R very low, low, intermediate) focus on treating cytopenias and improving quality of life, while higher-risk patients (IPSS-R high, very high) require disease-modifying therapy aimed at prolonging survival 1, 2.
- Molecular analysis should be added, particularly TP53 mutations in del(5q) MDS and SF3B1 mutations in patients with <5% blasts, as these provide additional prognostic value 1.
Higher-Risk MDS Treatment Algorithm
First-Line Therapy: Azacitidine
For higher-risk MDS patients without major comorbidities who are not immediately eligible for allogeneic stem cell transplantation, azacitidine 75 mg/m² subcutaneously for 7 consecutive days every 28 days is the first-line reference treatment 1, 2.
- At least 6 cycles are mandatory before evaluating 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 acceptable for logistical reasons, though the 7-day regimen is preferred 1.
- Hematologic improvement (HI) in cytopenias—not just complete or partial remission—is a valid response endpoint associated with survival prolongation 1.
Common pitfall: Discontinuing azacitidine prematurely before 6 cycles. Response may not be apparent until cycle 4-6, and early discontinuation denies patients potential benefit 1.
Allogeneic Stem Cell Transplantation
Allogeneic SCT is the only potentially curative treatment and should be considered for fit patients ≤70 years with a suitable donor 1, 2.
- Azacitidine can be used for 2-6 cycles before transplant to reduce blast percentage or for logistical reasons while arranging transplantation 1.
- Patients with unfavorable cytogenetics show poor responses to chemotherapy and should proceed directly to transplant evaluation 1.
AML-Like Intensive Chemotherapy
Intensive chemotherapy has limited indication and should be restricted to fit patients <70 years without unfavorable cytogenetics, >10% marrow blasts, and preferably as a bridge to allogeneic SCT 1.
- Combinations of cytarabine with idarubicin or fludarabine are suggested regimens 1.
- Patients with unfavorable karyotypes (especially complex cytogenetics or chromosome 7 abnormalities) show few complete remissions and shorter CR duration, making chemotherapy inappropriate 1.
Decitabine Alternative
Decitabine is FDA-approved for all MDS subtypes and IPSS risk groups 3, though azacitidine is preferred based on demonstrated survival advantage in randomized trials 1. Decitabine may be considered when azacitidine is unavailable or not tolerated 3.
Lower-Risk MDS Treatment Algorithm
Anemia Management
For symptomatic anemia in lower-risk MDS, erythropoiesis-stimulating agents (ESAs) are first-line treatment when serum erythropoietin is <500 U/L and transfusion requirement is <2 RBC units/month 1, 2.
- Response rates are 15-40% with ESAs alone, increasing to approximately 60% when combined with G-CSF 1, 4, 5.
- Median response duration is 8-23 months 5.
For lower-risk MDS with del(5q) and transfusion-dependent anemia, lenalidomide is the treatment of choice, achieving RBC transfusion independence in 60-65% of patients with median duration of 2-2.5 years 2.
For RBC transfusion-dependent lower-risk MDS with ring sideroblasts (MDS-RS) or SF3B1 mutation refractory to ESA, luspatercept is approved, achieving erythroid response in 63% and RBC transfusion independence in 38% of patients 2.
Immunosuppressive Therapy
Antithymocyte globulin (ATG) plus cyclosporine A should be considered for hypoplastic MDS, particularly in patients <60 years, HLA-DR15 positive, or with short transfusion duration 6, 4.
- Response rate is approximately 30% in appropriately selected patients, occurring within 3-6 months 6, 4.
- ATG plus cyclosporine also achieves platelet response in 35-40% of cases in addition to erythroid responses 1.
Neutropenia Management
G-CSF can improve neutropenia in 60-75% of cases and should be added to anti-infective drugs during severe infections, but prolonged prophylactic use has not demonstrated survival impact 1.
- Prophylactic antibiotics and G-CSF are not recommended for neutropenia; instead, mandate rapid onset of broad-spectrum antibiotics for fever or infection symptoms 1.
- Neutrophils <1500/mm³ occur in only 7% of lower-risk MDS and rarely cause life-threatening infections unless drugs worsening neutropenia are used 1.
Thrombocytopenia Management
Thrombopoietin receptor agonists (TPO-RAs) like romiplostim and eltrombopag are not approved for MDS in Europe and cannot be recommended outside clinical trials 1.
- In phase II trials, romiplostim achieved 55% platelet response but caused transient rise in marrow blasts in 15% of patients 1.
- Eltrombopag showed 47% platelet response with no observed rise in marrow blasts, but remains investigational 1.
- High-dose androgens can improve thrombocytopenia in one-third of patients, but response is generally transient 1.
Supportive Care Requirements for All Patients
Transfusion Support
RBC transfusions should maintain hemoglobin ≥8 g/dL, or 9-10 g/dL in patients with comorbidities or poor functional tolerance 1, 2.
- Transfuse sufficient RBC concentrates over 2-3 days if needed to increase hemoglobin above 10 g/dL and limit chronic anemia effects on quality of life 1.
- Use leukocyte-reduced blood products 1.
Prophylactic platelet transfusions are not commonly used except in patients receiving myelosuppressive drugs 1.
Iron Chelation Therapy
Iron chelation should be started in lower-risk MDS patients with relatively favorable prognosis who have received 20-60 RBC concentrates, serum ferritin >1000-2500 U/L, or cardiac T2 significantly reduced on CMR imaging* 1.
- The TELESTO trial showed significant improvement in event-free survival with chelation in lower-risk MDS 1.
- Future allogeneic SCT candidates should be chelated early, as even moderate iron overload before transplant is associated with increased transplant-related mortality 1, 6, 4.
- Deferasirox is the preferred oral chelator, though it causes gastrointestinal side-effects and cannot be used in renal failure 1.
Psychosocial Support
Psychosocial support and contact with patient support groups should be offered to all patients 1, 2.
Monitoring and Response Assessment
Complete blood count with platelets should be performed at baseline, prior to each cycle, and as needed to monitor response and toxicity 3.
- Myelosuppression and worsening neutropenia may occur more frequently in the first or second treatment cycles and do not necessarily indicate MDS progression 3.
- Response criteria follow IWG 2006 definitions, including complete remission, partial remission, and hematologic improvement in erythroid, platelet, and neutrophil lineages 1.
Common pitfall: Interpreting early worsening of cytopenias during azacitidine cycles 1-2 as treatment failure or disease progression, leading to premature discontinuation 3.