What are the treatment options for a patient diagnosed with myelodysplastic syndrome (MDS)?

Treatment Options for Myelodysplastic Syndrome (MDS)

Treatment for MDS is fundamentally determined by risk stratification using the International Prognostic Scoring System-Revised (IPSS-R), which divides patients into lower-risk and higher-risk categories with completely different therapeutic goals and approaches. 1, 2

Risk Stratification First

Before any treatment decision, you must obtain IPSS-R scoring incorporating cytogenetic risk, bone marrow blast percentage, hemoglobin, platelet count, and absolute neutrophil count. 2 This stratifies patients into five risk groups (very low, low, intermediate, high, and very high) with distinct survival outcomes ranging from 8.8 years median survival for very low risk to 0.8 years for very high risk. 1

For treatment purposes, IPSS low and intermediate-1 are grouped as "lower-risk MDS" while intermediate-2 and high-risk are "higher-risk MDS." 1

Higher-Risk MDS Treatment Algorithm

First-Line: Azacitidine

For higher-risk MDS patients without major comorbidities who are not immediately eligible for allogeneic stem cell transplantation, azacitidine 75 mg/m² subcutaneously daily for 7 consecutive days every 28 days is the first-line reference treatment. 1, 2, 3

Critical implementation details:

• You must administer at least 6 cycles before evaluating efficacy, as most patients only respond after several courses. 1, 2
• Alternative 5-day regimens have NOT demonstrated survival advantage in higher-risk MDS despite similar response rates in lower-risk disease. 1
• Response includes not just complete remission (CR) and partial remission (PR), but also hematological improvement (HI) in cytopenias, which is associated with prolonged survival. 1

Azacitidine demonstrated superiority over conventional care regimens (supportive care, low-dose cytarabine, and AML-like chemotherapy) in randomized trials, whereas decitabine showed no clear survival advantage in two phase III trials. 1

Curative Option: Allogeneic Stem Cell Transplantation

Allogeneic stem cell transplantation is the only potentially curative treatment for MDS and should be considered for all eligible higher-risk patients at diagnosis. 2, 4, 5

Azacitidine before transplantation appears promising and is being evaluated in clinical trials. 1

Limited Role for Intensive Chemotherapy

AML-like intensive chemotherapy has limited indication in higher-risk MDS, particularly in patients with unfavorable cytogenetics. 1 This approach is now less commonly used since hypomethylating agents became available. 1

Lower-Risk MDS Treatment Algorithm

The primary goal is treating cytopenias and improving quality of life, not modifying disease course. 2, 5

For Anemia (Most Common)

First-line: Erythropoiesis-stimulating agents (ESAs) such as recombinant erythropoietin or darbepoetin alfa for patients with serum EPO <500 U/L requiring <2 RBC units/month. 1, 2, 5

ESAs improve anemia in 15-40% of patients for a median duration of 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. 1, 2

Common pitfall: Grade 3-4 neutropenia and thrombocytopenia occur in approximately 60% of patients during the first weeks of lenalidomide treatment, requiring close blood count monitoring with dose reduction and/or G-CSF addition if needed. 1

In the EU, lenalidomide is approved only after ESA failure or ineligibility in del(5q) patients. 1

For MDS with ring sideroblasts (MDS-RS) or SF3B1 mutation refractory to ESA: Luspatercept achieves erythroid response in 63% and RBC transfusion independence in 38% of patients. 1, 2, 6, 4

This was demonstrated in a phase III placebo-controlled randomized study and is now FDA and EMA approved. 1

For Neutropenia

G-CSF improves neutropenia in 60-75% of cases and can be added to anti-infective drugs, though prolonged use has not demonstrated survival impact. 1

For Thrombocytopenia

Thrombopoietin receptor agonists may be considered if marrow blasts are <5%, though data are limited. 1

Supportive Care (All Risk Categories)

RBC transfusions should maintain hemoglobin ≥8 g/dL, or 9-10 g/dL in patients with comorbidities worsened by anemia or poor functional tolerance. 2

Transfuse sufficient RBC concentrates to increase hemoglobin >10 g/dL to limit chronic anemia effects on quality of life. 2

Iron chelation is indicated in patients with chronic transfusion dependence. 7

Psychosocial support and patient support group contacts should be systematically offered to all patients. 2

Special Considerations

IPSS-R Intermediate Risk

Whether these patients receive lower-risk or higher-risk MDS treatment depends on age, comorbidities, severity of cytopenias, somatic mutations (particularly TP53), and response to first-line treatment. 1, 2

TP53 Mutations in del(5q) MDS

Resistance to lenalidomide in del(5q) MDS with TP53 mutations is associated with particularly poor prognosis, and these patients are candidates for hypomethylating agents and allogeneic stem cell transplantation whenever possible. 1, 2

Pediatric MDS

Allogeneic hematopoietic stem cell transplantation from an HLA-identical donor is the treatment of choice for most children with MDS. 7

Genetic evaluation for germline predisposition syndromes is critical for optimal classification and management in pediatric patients. 7