What is the treatment approach for refractory anemia?

Treatment Approach for Refractory Anemia

For patients with refractory anemia (RA), a subtype of myelodysplastic syndrome, the treatment strategy depends on risk stratification, transfusion dependence, and transplant eligibility, with immunosuppressive therapy being the preferred first-line approach for younger, lower-risk patients who are not transplant candidates. 1

Initial Assessment and Risk Stratification

• Confirm the diagnosis of refractory anemia and exclude hypocellular myelodysplastic syndrome or constitutional bone marrow failure syndromes before initiating treatment 2
• Use the International Prognostic Scoring System (IPSS) or revised IPSS to stratify patients, as most RA cases fall into lower-risk categories 3
• Evaluate iron status before and during treatment; administer supplemental iron therapy when serum ferritin is less than 100 mcg/L or when serum transferrin saturation is less than 20% 4
• Assess for transfusion dependency, as this is associated with shorter survival and increased risk of conversion to acute myeloid leukemia, particularly in low-risk RA patients 1

Treatment Algorithm by Patient Category

For Younger Patients (<60 years) with Lower-Risk Disease

Immunosuppressive therapy with antithymocyte globulin (ATG) plus cyclosporine A (CSA) should be the preferred first-line treatment for patients who are not candidates for allogeneic stem cell transplantation 3

• Best candidates include: age <60 years, IPSS low or intermediate-1 risk, HLA-DR15 positive phenotype, short duration of transfusion requirement, and presence of PNH-positive clone 3
• Administer horse ATG for 5 consecutive days and oral cyclosporine A for 180 days (6 months) 3
• Response typically occurs within 3-6 months of treatment initiation, with approximately 30% response rates in appropriately selected patients 3
• Immunosuppressive therapy is highly recommended in the presence of hypoplastic bone marrow 1

For Patients with Symptomatic Anemia

Erythropoiesis-stimulating agents (ESAs) should be considered for symptomatic anemia, particularly if serum erythropoietin levels are ≤500 mU/mL 1, 3

• Administer epoetin alfa 150 IU/kg subcutaneously three times weekly, increasing to 300 IU/kg if needed 1, 4
• Alternative dosing: 40,000-60,000 IU once weekly 1
• Response rates increase to approximately 60% with the addition of G-CSF, especially in patients with refractory anemia with ringed sideroblasts (RARS) 1, 3
• Selected patients with RARS, symptomatic RA, erythropoietin levels <500 U/L, and transfusion requirements <2 units/month obtain the highest benefit 1
• Use the lowest dose sufficient to reduce the need for RBC transfusions; do not target hemoglobin >11 g/dL due to increased cardiovascular risks 4

For Transfusion-Dependent Patients

Red blood cell transfusions should be administered based on clinical evaluation of anemia-related symptoms and comorbidities, with the goal of preserving quality of life 1

• Maintain hemoglobin ≥8 g/dL in stable patients, or 9-10 g/dL in those with cardiovascular comorbidities 5
• Use leukocyte-reduced RBC products to minimize alloimmunization 5
• Iron chelation therapy should be considered for patients with serum ferritin >1,000 ng/mL and ongoing transfusion dependence to preserve organ function and possibly improve survival 1, 6
• Secondary iron overload significantly worsens survival, with a 30% increase in hazard for every 500 ng/mL increase in serum ferritin above 1,000 ng/mL 1

For Patients Failing First-Line Therapy

For patients refractory to immunosuppressive therapy, hypomethylating agents (azacitidine or decitabine) should be considered next 3

• Azacitidine shows survival benefit in randomized trials, particularly for patients with chromosome 7 alterations 3
• A second course of ATG plus cyclosporine may be attempted, though response rates are only 30-35% in the refractory setting 2
• Novel agents such as luspatercept and imetelstat are emerging options; imetelstat achieved RBC transfusion independence for ≥8 weeks in 40% of patients versus 15% with placebo in the phase III IMerge trial 7

For Transplant-Eligible Patients

Allogeneic stem cell transplantation remains the only curative option and should be considered early in eligible patients 3

• Candidates include those with age <65-70 years, acceptable performance status, and favorable comorbidity profile 3
• Use HLA-identical siblings or matched unrelated donors 3
• Myeloablative conditioning for patients <55 years without comorbidities; reduced-intensity conditioning for older patients 3
• Elevated pretransplantation serum ferritin is associated with lower overall and disease-free survival, with increased treatment-related mortality and risk of veno-occlusive disease 1

Critical Pitfalls to Avoid

• Do not use ESAs in patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure 4
• Avoid targeting hemoglobin levels >11 g/dL with ESAs, as this increases risks of death, myocardial infarction, stroke, and thromboembolism 4
• Do not use shielded total body irradiation approaches in transplant conditioning, as this is associated with unacceptably high relapse rates (34% versus 2% with conventional regimens) 8
• Recognize that transfusion dependency itself is a negative prognostic factor, with effects most noticeable in low-risk RA patients due to their longer survival and subsequent increased transfusion burden 1

Supportive Care Essentials

• Administer G-CSF or GM-CSF for neutropenic patients with recurrent or resistant bacterial infections 5
• Provide platelet transfusions for severe thrombocytopenia or active bleeding 5
• Monitor serum ferritin levels regularly in chronically transfused patients, as iron overload contributes to increased mortality through cardiac disease, liver disease, and endocrine dysfunction 1, 5
• Initiate broad-spectrum antibiotics immediately for any fever or infection symptoms in neutropenic patients 5