What is the initial treatment approach for myelodysplastic syndrome (MDS)?

Initial Treatment Approach for Myelodysplastic Syndrome

The initial treatment approach for MDS is fundamentally determined by risk stratification using IPSS-R, which divides patients into lower-risk and higher-risk categories, with each requiring distinctly different therapeutic strategies focused on either improving cytopenias and quality of life versus prolonging survival. 1, 2

Risk Stratification First

• All newly diagnosed MDS patients must be risk-stratified using the International Prognostic Scoring System-Revised (IPSS-R) before initiating therapy, as this determines the entire treatment algorithm 1, 2
• The IPSS-R incorporates bone marrow blast percentage, cytogenetic abnormalities, and depth of cytopenias to categorize patients into lower-risk (very low, low, intermediate) versus higher-risk (intermediate, high, very high) groups 2
• Additional prognostic factors including somatic mutations (particularly TP53), transfusion requirements, age, performance status, and comorbidities should be assessed as they influence treatment selection 1, 2

Treatment Algorithm for Lower-Risk MDS

In lower-risk MDS, the primary goal is treating cytopenias (especially anemia) and improving quality of life, as approximately half of elderly patients die from causes unrelated to MDS progression. 1

For Anemia WITHOUT del(5q):

• Erythropoiesis-stimulating agents (ESAs) are the first-line treatment, using recombinant EPO at 30,000-80,000 units weekly or darbepoetin 150-300 μg weekly 1, 2
• ESAs achieve 40-60% erythroid response rates when baseline EPO levels are low (<200-500 U/L) and transfusion requirements are absent or minimal 1
• Adding G-CSF to ESAs improves efficacy in patients with suboptimal response 1
• Median response duration is approximately 2 years, and receiving ESAs is an independent favorable prognostic factor for survival 1
• Response assessment should occur within 8-12 weeks of treatment initiation 1

For Anemia WITH del(5q):

• Lenalidomide is the first-line treatment for lower-risk MDS with del(5q) deletion, achieving 60-65% response rates with median transfusion independence of 2-2.5 years 1, 2
• The recommended dose is 10 mg daily for 3 weeks out of every 4 weeks 1
• Cytogenetic responses occur in 50-75% of patients, including 30-45% complete cytogenetic responses 1
• Critical caveat: TP53 mutations (present in ~20% of del(5q) MDS) confer resistance to lenalidomide and higher AML progression risk, requiring consideration of more aggressive therapy 1
• Grade 3-4 neutropenia and thrombocytopenia occur in ~60% during the first weeks, necessitating close blood count monitoring with dose reduction and/or G-CSF addition as needed 1

For Thrombocytopenia:

• TPO receptor agonists (romiplostim, eltrombopag) are recommended for severe thrombocytopenia, but ONLY in patients with bone marrow blasts <5% 2

Supportive Care in Lower-Risk MDS:

• RBC transfusions should be given for symptomatic anemia, generally at hemoglobin thresholds of at least 8 g/dL (higher thresholds for patients with cardiovascular comorbidities) 2
• Iron chelation therapy is recommended for patients with iron overload, particularly those who are transplant candidates, have received 20-60 RBC units, or have serum ferritin >1000-2500 U/L 2

Treatment Algorithm for Higher-Risk MDS

For higher-risk MDS, the treatment goal shifts to prolonging survival, with allogeneic stem cell transplantation being the only potentially curative option. 1, 2

Transplant-Eligible Patients:

• All higher-risk MDS patients up to age 70 years (and particularly fit patients >70 years) should be evaluated for allogeneic stem cell transplantation (allo-SCT) eligibility at diagnosis 1, 2
• Allo-SCT remains the only potentially curative treatment for higher-risk MDS 1, 2
• HLA-identical or single antigen mismatched siblings or matched unrelated donors are preferred, though haploidentical donors and cord blood are now acceptable alternatives with comparable outcomes 1
• Patients aged <55 years without comorbidities should receive myeloablative conditioning rather than reduced-intensity conditioning due to higher relapse risk with RIC 1
• Cytoreductive therapy to reduce blast count is generally considered when marrow blasts are >10%, especially before non-myeloablative allo-SCT 1
• Iron chelation should be administered to eligible patients with iron overload until conditioning treatment begins, as elevated labile plasma iron predicts increased infection-related mortality and decreased overall survival post-transplant 1

Non-Transplant Candidates:

• Azacitidine 75 mg/m² daily for 7 days every 4-6 weeks is the first-line therapy for higher-risk MDS patients not immediately eligible for allo-SCT 2, 3
• Azacitidine is FDA-approved for all FAB MDS subtypes including refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS) with cytopenias or transfusion requirements, refractory anemia with excess blasts (RAEB), RAEB in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL) 3
• Treatment should continue as long as the patient continues to benefit, as responses may take multiple cycles to manifest 3
• Premedication for nausea and vomiting is required 3
• Decitabine is an alternative hypomethylating agent, though azacitidine is more commonly recommended as first-line 4

Monitoring and Dose Modifications:

• Complete blood counts must be monitored at baseline, prior to each cycle, and as needed to assess response and toxicity 3, 4
• Myelosuppression (anemia, neutropenia, thrombocytopenia) is the most frequent cause of dose reduction, delay, and discontinuation with hypomethylating agents 4
• Dose delays, reductions, growth factors, and anti-infective therapies should be used to manage toxicity 4
• Important caveat: Myelosuppression and worsening neutropenia may occur more frequently in the first or second treatment cycles and do not necessarily indicate MDS progression 4

Special Considerations Across All Risk Categories

• Patients with intermediate IPSS-R scores may benefit from treatments typically applied to higher-risk MDS if they demonstrate poor prognostic features such as adverse somatic mutations or resistance to first-line therapy 1
• Tumor lysis syndrome can occur in MDS patients treated with azacitidine; baseline risk assessment and monitoring are essential 3
• Both azacitidine and decitabine cause embryo-fetal toxicity; women of childbearing potential must use effective contraception during treatment and for 6 months after the last dose, while men should avoid fathering children during treatment and for 3 months after 3, 4