What are the treatment options for a patient diagnosed with myelodysplastic syndrome (MDS), considering their age, overall health, and medical history?

Treatment of Myelodysplastic Syndrome (MDS)

Treatment selection for MDS depends fundamentally on risk stratification using the International Prognostic Scoring System-Revised (IPSS-R), which divides patients into lower-risk and higher-risk categories with distinct therapeutic goals and approaches. 1

Risk Stratification Framework

The IPSS-R score is the critical first step that determines all subsequent treatment decisions, incorporating peripheral blood cytopenias severity, bone marrow blast percentage, and cytogenetic abnormalities. 2 This classification separates patients into fundamentally different treatment pathways with different survival expectations and therapeutic objectives. 1

Lower-Risk MDS Treatment Algorithm

Primary Treatment Goals

The primary objective in lower-risk MDS is treating cytopenias (particularly anemia), improving quality of life, and reducing transfusion burden, as approximately half of elderly lower-risk patients die from causes unrelated to MDS or AML progression. 1, 2

First-Line Treatment for Anemia

Erythropoiesis-stimulating agents (ESAs) such as recombinant erythropoietin or darbepoetin are the first-choice treatment for anemia in most lower-risk MDS patients without del(5q). 1, 2 ESAs achieve 40-60% erythroid response rates when baseline erythropoietin level is <200-500 U/L and transfusion requirements are low or absent. 2, 3 Weekly doses of 30,000-80,000 units of EPO or 150-300 μg of darbepoetin alfa are recommended. 1

For patients with SF3B1 mutation and transfusion dependence, luspatercept is the optimal first-line systemic treatment, with 77% of SF3B1-positive patients achieving hematologic improvement compared to only 40% in SF3B1-negative patients. 3

Special Populations

For patients with trisomy 8 (classified as intermediate-risk cytogenetics), antithymocyte globulin (ATG) is most effective in relatively young patients (<65 years) with low-risk MDS, transfusion history <2 years, no excess blasts, and possibly those with thrombocytopenia in addition to anemia. 2

Supportive Care Requirements

Iron chelation therapy should be initiated when patients become transfusion-dependent, as iron overload increases infection-related mortality and decreases cardiac function. 1, 2, 3 Monitor serum ferritin levels with a goal <1000 mcg/L. 2

Chronic RBC transfusions maintain hemoglobin ≥8 g/dL, or 9-10 g/dL if cardiovascular comorbidities are present. 3

Higher-Risk MDS Treatment Algorithm

Primary Treatment Goals

In higher-risk MDS, treatment goals shift to altering the natural history of disease by delaying AML progression and prolonging overall survival. 2, 4

First-Line Treatment

Hypomethylating agents (HMAs), specifically azacitidine at 75 mg/m² subcutaneously for 7 consecutive days every 28 days, are the first-line reference treatment for higher-risk MDS. 1, 2 Azacitidine extends survival by up to 74% despite modest complete response rates. 2

At least six cycles of azacitidine are required before assessing response, as most patients only respond after several courses. 2 The median time to response is approximately 93 days (range 55-272 days). 5

Decitabine is an alternative HMA with similar efficacy, achieving an overall response rate (CR+PR) of 17% in the ITT population, with a median duration of response of 288 days. 5

Role of Intensive Chemotherapy

AML-like intensive chemotherapy has limited indication in higher-risk MDS and should be reserved for fit patients (generally <70 years of age) without unfavorable cytogenetics (especially patients with normal karyotype) and >10% marrow blasts, preferably as a bridge to allogeneic stem cell transplantation. 1

MDS patients with unfavorable karyotype show few complete responses and shorter CR duration with intensive chemotherapy. 1 Suggested regimens include combinations of cytarabine with idarubicin or fludarabine. 1

Low-dose cytarabine (20 mg/m²/day, 14-21 days every 4 weeks) was found to be significantly inferior to azacitidine in terms of response and survival, especially in patients with unfavorable cytogenetics, and should only be considered when HMAs are not available. 1

Allogeneic Stem Cell Transplantation

Allogeneic stem cell transplantation (allo-SCT) remains the only potentially curative treatment for higher-risk MDS patients and should be evaluated at diagnosis for all patients up to age 70 years (although particularly fit patients >70 years can sometimes be considered). 1, 2

HLA-identical (or single antigen mismatched) siblings or matched unrelated individuals should be considered as suitable donors. 1 Haploidentical donors and cord blood are now widely used as alternative donors with comparable outcomes. 1

For patients aged <55 years without comorbidities, myeloablative conditioning should be offered, as relapse risk appears higher with reduced-intensity conditioning (RIC). 1

Treatment aimed at reducing blast count before allo-SCT is generally considered when marrow blasts are >10%, especially for non-myeloablative allo-SCT. 1

Iron chelation should be provided to eligible patients at least until the onset of conditioning treatment, as systemic iron overload contributes to negative outcomes after allo-HSCT, with elevated labile plasma iron levels predicting increased infection-related non-relapse mortality. 1

Second-Line Treatment After HMA Failure

IPSS higher-risk MDS patients who fail to respond to HMAs have extremely poor survival (median <6 months) unless they are potentially eligible for allo-SCT. 1

The recommended approach is to enroll these patients in a clinical trial with investigational agents. 1 Retreatment with AML-like chemotherapy or low-dose cytarabine yields dismal results. 1

IDH1 inhibitor (ivosidenib) and IDH2 inhibitor (enasidenib) are being tested in clinical trials in MDS, which carries IDH1/2 mutations in around 15% of cases. 1 The bcl2 inhibitor venetoclax is being tested in higher-risk MDS, especially in combination with azacitidine. 1

Key Predictors of Post-Transplant Outcome

Comorbidity, age, IPSS-R score, cytogenetics, mutations including TP53 mutation, conditioning regimen, and donor selection are predictors of post-transplant outcome and should be considered during the decision process. 1

Common Pitfalls to Avoid

• Do not assess HMA response before at least 6 cycles, as premature discontinuation may miss delayed responders. 2
• Do not use intensive chemotherapy in patients with unfavorable cytogenetics, as they show few complete responses and shorter CR duration. 1
• Do not delay allo-SCT evaluation in higher-risk patients, as this is the only curative option and should be assessed at diagnosis. 1, 2
• Do not ignore iron overload in transfusion-dependent patients, as it significantly impacts transplant outcomes and overall mortality. 1, 2, 3