Treatment of Myelodysplastic Syndrome
Treatment of MDS is fundamentally determined by risk stratification using IPSS or IPSS-R, which divides patients into lower-risk (IPSS low/intermediate-1) and higher-risk (IPSS intermediate-2/high) categories, with each requiring distinct therapeutic approaches prioritizing survival and quality of life. 1
Risk Stratification Framework
Risk assessment must incorporate the IPSS-R system, which stratifies patients into five groups (very low, low, intermediate, high, very high) based on bone marrow blast percentage, cytogenetics, and cytopenias 1, 2. Patient-related factors including age, ECOG performance status, and comorbidities are critical for treatment selection, particularly in lower-risk disease 1. Transfusion dependence is an independent negative prognostic factor that influences treatment decisions 1.
Higher-Risk MDS Treatment Algorithm
Fit Patients ≤70 Years with Donor Available
Allogeneic stem cell transplantation (allo-SCT) is the only curative option and should be offered to all higher-risk MDS patients under 70 years without major comorbidities who have a donor 1. This may be preceded by 2-6 cycles of azacitidine or chemotherapy to reduce blast percentage, though this is optional 1.
Patients >70 Years or Without Donor
Azacitidine 75 mg/m²/day subcutaneously for 7 consecutive days every 28 days is the first-line standard of care 1. This recommendation is based on a randomized phase III trial demonstrating survival advantage over conventional care regimens 1. Alternative "5-2-2" regimens (5 days on, 2 days off, 2 days on) are acceptable for logistical reasons 1.
At least six cycles of azacitidine must be administered before assessing efficacy, as most patients respond only after several courses 1. Achievement of hematological improvement (HI) in cytopenias, not just complete remission, is associated with prolonged survival and should be considered a meaningful response 1.
Azacitidine is preferred over decitabine because azacitidine demonstrated survival benefit in randomized trials, while decitabine showed no clear survival advantage over conventional treatment in two phase III trials 1. Decitabine is FDA-approved for all IPSS risk groups but lacks the survival data supporting azacitidine 3.
AML-Like Intensive Chemotherapy
Intensive chemotherapy has limited indication in higher-risk MDS 1. It should only be considered for fit patients (generally <70 years) without unfavorable cytogenetics (especially normal karyotype) and >10% marrow blasts, preferably as a bridge to allo-SCT 1. MDS patients with unfavorable karyotypes show few complete responses and shorter remission duration 1.
Suggested regimens include cytarabine combined with idarubicin or fludarabine 1. A small randomized trial suggested survival superiority of azacitidine over intensive chemotherapy, though not statistically significant due to sample size 1.
Very Frail Patients
Supportive care alone is appropriate for very frail patients, including RBC transfusions (generally at hemoglobin ≥8 g/dL, higher with comorbidities), platelet transfusions for bleeding, and antibiotics 1, 2.
Lower-Risk MDS Treatment Algorithm
Anemia Management
For anemia without del(5q), erythropoiesis-stimulating agents (ESAs) are first-line treatment at weekly doses of 30,000-60,000 units epoetin alfa or darbepoetin 150-300 μg 1, 2. Response rates are approximately 15-20% with ESA monotherapy 4. Predictors of response include serum erythropoietin <500 mU/mL, low transfusion burden (<2 units/month), and IPSS low/intermediate-1 risk 1.
For non-responders after 8 weeks, add G-CSF 300 mg/week in 2-3 divided doses, which increases response rates to approximately 40% 1, 4.
For anemia with del(5q), lenalidomide is the most effective first-line treatment with 60-65% response rates and median transfusion independence of 2-2.5 years 2. This represents a dramatic improvement over ESAs in this cytogenetic subgroup.
Thrombocytopenia Management
TPO receptor agonists (romiplostim, eltrombopag) are recommended for severe thrombocytopenia, but only in patients with marrow blasts <5% 2. A phase 1/2 study showed 46% durable platelet response with romiplostim, but treatment-related serious adverse events occurred in 11% 1.
Neutropenia Management
G-CSF or GM-CSF should not be used for routine infection prophylaxis 1. Consider use only for recurrent or resistant infections in neutropenic patients 1.
Supportive Care Essentials
RBC transfusions should be leuko-reduced for symptomatic anemia 1. CMV-negative products are recommended for CMV-negative transplant candidates 1. Irradiated products are suggested for transplant candidates 1.
Iron chelation therapy is indicated for:
- Transplant candidates with iron overload 2
- Non-transplant candidates with major iron overload 2
- Patients with favorable prognosis who received 20-60 RBC units or serum ferritin >1000-2500 ng/mL 1, 2
Deferoxamine subcutaneously or deferasirox orally are the chelation options 1.
Critical Pitfalls to Avoid
Do not stop azacitidine before 6 cycles unless clear disease progression, as delayed responses are common 1. Patients who fail hypomethylating agents have median survival <6 months unless eligible for allo-SCT 1.
Do not use intensive chemotherapy in patients with unfavorable cytogenetics outside of transplant bridging, as outcomes are poor 1.
Do not use TPO agonists in patients with ≥5% blasts due to safety concerns 2.