What is the best course of treatment for a patient with myelodysplastic syndrome (MDS)?

Treatment of Myelodysplastic Syndrome

Treatment for MDS must be stratified by risk category using IPSS-R scoring, with higher-risk patients receiving azacitidine or allogeneic stem cell transplantation, and lower-risk patients receiving supportive care with erythropoiesis-stimulating agents or lenalidomide for del(5q) cases. 1

Risk Stratification is Mandatory

IPSS-R scoring is required for all MDS patients before initiating treatment. 1 This scoring system incorporates:

• Cytogenetic risk category (very good to very poor) 1
• Bone marrow blast percentage 1
• Hemoglobin level 1
• Platelet count 1
• Absolute neutrophil count 1

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

Fit Patients ≤70 Years with Donor Available

Allogeneic stem cell transplantation is the treatment of choice for fit patients ≤70 years with a donor, as it represents the only potentially curative therapy. 1 This applies to IPSS-R very high, high, and some intermediate-risk patients. 1

• Transplantation may be preceded by chemotherapy or hypomethylating agents to reduce blast percentage, particularly when marrow blasts are >10%. 1
• This approach is especially important for non-myeloablative transplantation. 1

Patients >70 Years or Without Donor

Azacitidine is the first-line reference treatment for higher-risk MDS patients not immediately eligible for allogeneic transplantation. 1

Dosing regimen: 1, 2

• Azacitidine 75 mg/m²/day subcutaneously for 7 consecutive days every 28 days
• Alternative "5-2-2" regimens are acceptable for practical reasons 1
• At least 6 cycles are required before assessing efficacy, as most patients respond only after several courses 1

Achievement of hematological improvement (HI) according to IWG 2006 criteria is associated with prolonged survival compared to supportive care. 1

AML-Like Intensive Chemotherapy

Intensive chemotherapy has limited indication and 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 transplantation. 1

• MDS patients with unfavorable karyotype show few complete remissions and shorter CR duration. 1
• Suggested regimens include cytarabine combinations with idarubicin or fludarabine. 1

Very Frail Patients

Supportive care with RBC transfusions and antibiotics is appropriate for very frail patients with higher-risk MDS. 1 Consider clinical trials or symptomatic treatment in case of failure or relapse. 1

Lower-Risk MDS Treatment Algorithm

First-Line Treatment for Anemia Without del(5q)

Erythropoiesis-stimulating agents (ESAs), particularly EPO alpha, are recommended as first-line treatment for anemia in lower-risk MDS patients without del(5q). 1

• Response rates range from 15-40% with median duration of 8-23 months. 3
• ESA efficacy can be improved by adding G-CSF. 1
• Responses occur within 8-12 weeks of treatment. 1
• Median duration of response is approximately 2 years. 1

Lower-Risk MDS with del(5q)

Lenalidomide is the most effective treatment for transfusion-dependent anemia in lower-risk MDS with del(5q). 1

• Response rate: 60-65% with median RBC transfusion independence duration of 2-2.5 years 1
• Recommended initial dose: 10 mg/day, 3 weeks out of every 4 weeks 1
• Cytogenetic response achieved in 50-75% of patients (including 30-45% complete cytogenetic response) 1
• TP53 mutations (found in ~20% of del(5q) MDS) confer resistance to lenalidomide and higher AML progression risk. 1

Common pitfall: Grade 3-4 neutropenia and thrombocytopenia occur in ~60% of patients during first weeks—close blood count monitoring with dose reduction and/or G-CSF addition is required. 1

Second-Line Treatments After ESA Failure

For patients without del(5q): 1

• Anti-thymocyte globulin (ATG) with or without cyclosporine is recommended for specific cohorts: relatively young (<65 years), low-risk MDS with RBC transfusion history <2 years, normal karyotype (or trisomy 8), no excess blasts, HLA DR15 genotype, and possibly thrombocytopenia in addition to anemia. 1
• Hypomethylating agents yield RBC transfusion independence in 30-40% of patients. 1
• Lenalidomide yields RBC transfusion independence in 25-30% of lower-risk MDS without del(5q) resistant to ESA. 1
• Combination of lenalidomide and ESA may yield higher response rates than lenalidomide alone. 1

For patients with del(5q) resistant to lenalidomide: 1

• These patients have poor prognosis, especially with TP53 mutations. 1
• Consider hypomethylating agents or allogeneic transplantation whenever possible. 1

Supportive Care Measures

Iron Chelation

Iron chelation is strongly recommended in candidates for allogeneic transplantation, as even moderate iron overload before transplantation is associated with increased transplant-related mortality. 1

For non-transplant candidates with lower-risk MDS:

• Strongly recommended in patients with major iron overload (e.g., significantly reduced cardiac T2* by MRI) 1
• Consider starting chelation in patients with relatively favorable prognosis (low or intermediate-1 risk) who have received 20-60 RBC concentrates or serum ferritin >1000-2500 U/L 1
• Oral deferasirox is preferred over parenteral deferoxamine for ease of administration 1

Transfusion Support

RBC transfusions remain a cornerstone of supportive care for symptomatic anemia. 1 Prophylactic antibiotics should be considered during periods of severe neutropenia. 1

Key Clinical Pitfalls

Do not substitute azacitidine for injection for oral azacitidine—the indications and dosing regimens differ. 2

Do not discontinue azacitidine prematurely—at least 6 cycles are required to properly evaluate efficacy, as most patients respond only after several courses. 1

Monitor for tumor lysis syndrome in MDS patients receiving azacitidine, as it may cause fatal or serious tumor lysis syndrome. 2

Assess baseline renal function before azacitidine therapy, as azacitidine and its metabolites are primarily excreted by the kidneys. 2