What are the treatment options for myelodysplastic syndrome?

Treatment Options for Myelodysplastic Syndrome

Treatment for MDS is determined by risk stratification using IPSS or IPSS-R scoring systems, which divide patients into lower-risk and higher-risk categories, with fundamentally different therapeutic goals and approaches for each group. 1, 2

Risk Stratification Framework

Risk assessment must be performed before initiating therapy to guide treatment selection 1:

• IPSS categories: Low, Intermediate-1 (INT-1), Intermediate-2 (INT-2), and High 1
• IPSS-R categories: Very low, low, intermediate, high, and very high 1, 2
• Lower-risk MDS: IPSS Low/INT-1 or IPSS-R very low/low/intermediate 1
• Higher-risk MDS: IPSS INT-2/High or IPSS-R high/very high 1

Patient age, performance status, comorbidities, and donor availability are critical determinants of treatment tolerance and eligibility for intensive therapies 1.

Lower-Risk MDS Treatment

For Anemia Management

Erythropoiesis-stimulating agents (ESAs) are first-line therapy for anemic patients with serum erythropoietin <500 mU/mL and transfusion requirement <2 units per month 1, 2:

• Epoetin alfa or beta: 30,000-60,000 IU per week subcutaneously 1, 2
• Darbepoetin alfa: 150-300 μg per week (equipotent alternative) 1, 2
• Add G-CSF 300 mg/week in 2-3 divided doses if no response after 8 weeks of ESA monotherapy 1
• Response rates: 36-40% with ESA monotherapy 1

For MDS with del(5q)

Lenalidomide is the preferred first-line treatment for lower-risk MDS with del(5q) deletion, achieving 60-65% transfusion independence rates 1, 2:

• Median duration of transfusion independence: 2-2.5 years 2
• Also effective in 25-30% of lower-risk MDS without del(5q) resistant to ESA 1
• Combination of lenalidomide plus ESA yields higher response rates than lenalidomide alone in ESA-resistant patients 1

For Thrombocytopenia

TPO receptor agonists (romiplostim, eltrombopag) should be used only in patients with severe thrombocytopenia and <5% marrow blasts 2:

• Romiplostim at high doses (500-1,500 μg/week) yields 55% platelet responses 1
• Risk of transient marrow blast increase (~15%), reversible after discontinuation 1
• Significantly reduces severe bleeding and platelet transfusion requirements 1

Alternative Lower-Risk Therapies

• Antithymocyte globulin (ATG): Consider in patients with HLA-DR15 genotype, thrombocytopenia with anemia, small PNH clone, or marrow hypocellularity 1
• Hypomethylating agents: Yield RBC transfusion independence in 30-40% of lower-risk patients, approved in several countries including the United States 1

Higher-Risk MDS Treatment

First-Line Therapy

Azacitidine 75 mg/m² subcutaneously for 7 consecutive days every 28 days is the preferred first-line treatment for higher-risk MDS patients not immediately eligible for transplantation 1:

• At least 6 cycles are required, as most patients only respond after several courses 1
• Alternative "5-2-2" regimens (5 days on, 2 days off, 2 days on) are acceptable and easier to administer 1
• Azacitidine is preferred over decitabine because it has demonstrated survival benefit in phase III randomized trials, while decitabine has not 1
• Median overall survival with azacitidine: improves compared to supportive care 1

Decitabine is an alternative hypomethylating agent 3:

• FDA-approved for all MDS subtypes including intermediate-1, intermediate-2, and high-risk IPSS groups 3
• Two dosing regimens: 15 mg/m² IV over 3 hours every 8 hours for 3 days (repeat every 6 weeks) OR 20 mg/m² IV over 1 hour daily for 5 days (repeat every 4 weeks) 3
• Achieves 13% complete response, 6% partial response, 15% hematologic improvement 1
• Progression-free survival longer than supportive care, but overall survival benefit not statistically significant (10.1 vs 8.5 months) 1

Allogeneic Stem Cell Transplantation

Allogeneic SCT is the only potentially curative treatment and should be offered to all fit patients ≤70 years with higher-risk MDS who have a donor 1, 2:

• Can be preceded by chemotherapy or hypomethylating agents to reduce blast percentage 1
• Both standard and reduced-intensity preparative approaches are acceptable 1
• Matched sibling or matched unrelated donors are appropriate 1
• Use of 2-6 cycles of azacitidine before transplant is common to reduce marrow blasts or allow time for donor identification 1

High-Intensity Chemotherapy

AML-like intensive chemotherapy has limited indication and should be reserved for fit patients <70 years without unfavorable cytogenetics (especially normal karyotype) and >10% marrow blasts, preferably as a bridge to allogeneic SCT 1:

• Suggested regimens: cytarabine with idarubicin OR cytarabine with fludarabine 1
• Patients with unfavorable karyotype show few complete responses and shorter CR duration 1
• Direct comparison suggests hypomethylating agents may have survival advantage over intensive chemotherapy, though data are limited 1

Supportive Care (All Risk Categories)

Transfusion Support

RBC transfusions (leukocyte-reduced) should be given for symptomatic anemia, generally maintaining hemoglobin ≥8 g/dL 1, 2, 4:

• Higher thresholds (9-10 g/dL) for patients with cardiovascular comorbidities 1, 4
• CMV-negative blood products recommended for CMV-negative transplant candidates 1
• Irradiated products suggested for transplant candidates 1
• Platelet transfusions for thrombocytopenic bleeding 1

Iron Chelation Therapy

Iron chelation is recommended after 20-30 RBC transfusions or when serum ferritin exceeds 1000-2500 ng/mL 1, 2:

• Deferoxamine: Daily subcutaneous administration 1
• Deferasirox: Oral daily administration 1
• Particularly important for lower-risk patients and potential transplant candidates 1, 2
• Goal: decrease ferritin levels to <1000 ng/mL 1

Growth Factor Support

• G-CSF or GM-CSF: Not recommended for routine infection prophylaxis 1
• Consider use if recurrent or resistant infections in neutropenic patients 1
• Can improve neutropenia in 60-75% of cases during active infection 1, 4

Antifibrinolytic Agents

• Aminocaproic acid may be considered for bleeding refractory to platelet transfusions or profound thrombocytopenia 1

Common Pitfalls and Caveats

Do not use azacitidine for fewer than 6 cycles unless there is clear disease progression, as responses are often delayed 1. Avoid TPO receptor agonists in patients with ≥5% marrow blasts due to risk of blast increase 1, 2. Do not delay allogeneic SCT evaluation in younger higher-risk patients, as this is the only curative option 1, 2. Patients with higher-risk MDS who fail hypomethylating agents have very poor survival (median <6 months) and should be considered for clinical trials 1.