What are the treatment options for a patient with Myelodysplastic Syndromes (MDS)?

Treatment Options for Myelodysplastic Syndromes (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 requiring completely different therapeutic approaches. 1, 2

Risk Stratification First

Before initiating any therapy, IPSS-R scoring is mandatory, incorporating cytogenetic risk, bone marrow blast percentage, hemoglobin, platelet count, and absolute neutrophil count to stratify patients into five risk groups (very low, low, intermediate, high, very high) with distinct survival outcomes ranging from 8.8 years to 0.8 years median overall survival. 3, 1, 2

Higher-Risk MDS Treatment

Allogeneic Stem Cell Transplantation (Allo-SCT)

Allo-SCT is the only potentially curative treatment for higher-risk MDS and should be evaluated at diagnosis for all patients aged <65-70 years without major comorbidities. 3, 4 HLA-identical siblings or matched unrelated donors are preferred. 3, 2 Patients aged <55 years without comorbidities should receive myeloablative conditioning rather than reduced-intensity conditioning due to higher relapse rates with the latter. 3

Hypomethylating Agents (HMAs) - First-Line for Non-Transplant Candidates

For higher-risk MDS patients (IPSS INT-2 or high risk) without major comorbidities who are not immediately eligible for allo-SCT, azacitidine is the first-line reference treatment. 3, 1, 5

• Dosing regimen: Azacitidine 75 mg/m²/day subcutaneously for 7 consecutive days every 28 days. 3, 1, 2
• Duration before assessment: At least 6 cycles are mandatory before evaluating efficacy, as most patients only respond after several courses. 3, 1, 2
• Evidence basis: Azacitidine demonstrated superior survival compared to conventional care regimens (supportive care, low-dose cytarabine, and AML-like chemotherapy) in randomized trials. 3
• Response criteria: Beyond complete remission (CR) and partial remission (PR), hematologic improvement in cytopenias (particularly anemia and thrombocytopenia) should be considered indicative of response, as it associates with prolonged survival. 3

AML-Like Intensive Chemotherapy - Limited Role

AML-like intensive chemotherapy has limited indication in higher-risk MDS, particularly because patients with unfavorable karyotype show few complete responses and shorter CR duration. 3 This treatment can be considered for younger patients (generally <60-65 years) with favorable cytogenetics and marrow blasts >10%, preferably as a bridge to allo-SCT. 3 Suggested regimens include cytarabine combinations with idarubicin, fludarabine, or topotecan. 3

Low-Dose Cytarabine - Inferior Option

Low-dose cytarabine (20 mg/m²/day, 14-21 days every 4 weeks) was found significantly inferior to azacitidine in terms of response and survival in randomized trials, especially in patients with unfavorable cytogenetics. 3 It may be considered only in higher-risk MDS patients with normal karyotype who are not candidates for intensive chemotherapy or allo-SCT when azacitidine is not available. 3

Second-Line Treatment After HMA Failure

Patients who fail azacitidine or are primary refractory to HMAs have extremely poor survival (median <6 months) except for those eligible for allo-SCT. 3 The recommended approach is enrollment in clinical trials with investigational agents, and if the patient becomes eligible for allo-SCT, proceed to transplant. 3

Lower-Risk MDS Treatment

In lower-risk MDS, the primary goal is treating cytopenias (mainly anemia) and improving quality of life, as approximately half of elderly lower-risk patients die from causes unrelated to MDS or AML. 3, 2, 4

For Patients WITHOUT del(5q)

Erythropoiesis-Stimulating Agents (ESAs) - First-Line

ESAs (recombinant EPO or darbepoetin) are the first-choice treatment for anemia in lower-risk MDS without del(5q), particularly when baseline EPO level is <500 U/L and transfusion requirement is <2 RBC units/month. 3, 1, 2

• Dosing: Weekly doses of 30,000-80,000 units of EPO or 150-300 μg darbepoetin alfa achieve approximately 60% erythroid response rates. 3
• Response timing: Responses occur within 8-12 weeks of treatment. 3
• Duration: Median duration of response is approximately 2 years, with longer responses in patients with major response, IPSS low or intermediate-1, marrow blasts <5%, and no multi-lineage dysplasia. 3
• Enhancement: Efficacy can be improved by adding G-CSF. 3
• Survival benefit: Receiving ESAs was an independent favorable prognostic factor for survival in lower-risk MDS with anemia, with no impact on AML progression. 3

For Patients WITH del(5q)

Lenalidomide - Treatment of Choice

Lenalidomide is the treatment of choice for lower-risk MDS with del(5q) and transfusion-dependent anemia, achieving RBC transfusion independence in 60-65% of patients with median duration of 2-2.5 years. 1 Anemia in lower-risk MDS with del(5q) shows lower response rates and significantly shorter responses to ESA compared to other lower-risk MDS. 3

Luspatercept - For ESA-Refractory Patients

Luspatercept is approved for RBC transfusion-dependent, lower-risk MDS with ring sideroblasts (MDS-RS) or SF3B1 mutation who are refractory to ESA, achieving erythroid response in 63% and RBC transfusion independence in 38% of patients. 1

Supportive Care - Universal Across All Risk Categories

Red Blood Cell Transfusions

RBC transfusions should maintain hemoglobin ≥8 g/dL, or 9-10 g/dL in patients with comorbidities worsened by anemia or poor functional tolerance, with sufficient RBC concentrates to increase hemoglobin >10 g/dL to limit chronic anemia effects on quality of life. 1

Iron Chelation Therapy

Iron chelation therapy should be considered for transfusion-dependent patients, as iron overload increases infection-related mortality. 2 Monitor serum ferritin levels with goal <1000 mcg/L. 2

Psychosocial Support

Psychosocial support and patient support group contacts should be systematically offered to all patients. 1

Common Pitfalls to Avoid

• Do not assess azacitidine efficacy before 6 cycles - most patients only respond after several courses, and premature discontinuation denies potential responders the benefit. 3, 1
• Do not use alternative azacitidine schedules (5-day regimens) in higher-risk MDS - while they may give similar response rates in lower-risk MDS, they have not demonstrated survival advantage in higher-risk disease. 3
• Do not overlook allo-SCT evaluation at diagnosis - this is the only curative option and should be assessed early in all eligible higher-risk patients. 3, 2, 4
• Do not use ESAs as first-line in del(5q) MDS - these patients respond poorly to ESAs and should receive lenalidomide. 3, 1