What is the treatment approach for refractory anemia?

Treatment Approach for Refractory Anemia

For patients with refractory anemia, immunosuppressive therapy with antithymocyte globulin (ATG) plus cyclosporine A is the preferred first-line treatment for those who are not transplant candidates, particularly younger patients (<60 years) with hypoplastic bone marrow, while allogeneic stem cell transplantation remains the only curative option for eligible patients. 1, 2

Initial Risk Stratification

• Use the International Prognostic Scoring System (IPSS) or revised IPSS to stratify all patients, as most refractory anemia cases fall into lower-risk categories 1
• Assess transfusion dependency status, as this is associated with shorter survival and increased risk of conversion to acute myeloid leukemia, even in low-risk patients 1
• Exclude hypocellular myelodysplastic syndrome and constitutional bone marrow failure syndromes that may masquerade as idiopathic refractory anemia 3

Treatment Algorithm by Clinical Scenario

Younger Patients (<60 Years) with Lower-Risk Disease

First-line therapy should be immunosuppressive treatment with ATG plus cyclosporine A for patients who are not candidates for allogeneic stem cell transplantation. 1, 2

• The response rate to immunosuppressive therapy is approximately 30% in appropriately selected patients 1, 2
• Response typically occurs within 3-6 months of treatment initiation 1, 2
• 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 2
• Immunosuppressive therapy is highly recommended when hypoplastic bone marrow is present 1
• The protocol consists of horse ATG administered for 5 consecutive days and oral cyclosporine A for 180 days (6 months) 2

Patients with Symptomatic Anemia

Consider erythropoiesis-stimulating agents (ESAs) for symptomatic anemia, particularly if serum erythropoietin levels are ≤500 mU/mL. 1, 2

• The response rate to ESAs increases to approximately 60% with the addition of G-CSF, especially in patients with refractory anemia with ringed sideroblasts (RARS) 1, 2
• ESAs should be used at the lowest dose sufficient to reduce the need for RBC transfusions 4
• Critical caveat: ESAs carry risks of death, myocardial infarction, stroke, and venous thromboembolism when targeting hemoglobin levels >11 g/dL 4
• Monitor hemoglobin weekly after initiation and after each dose adjustment until stable 4
• Evaluate iron status before and during treatment; administer supplemental iron when serum ferritin is <100 mcg/L or transferrin saturation is <20% 4

Transfusion-Dependent Patients

Administer red blood cell transfusions based on clinical evaluation of anemia-related symptoms and comorbidities, with the goal of preserving quality of life. 1

• Maintain hemoglobin ≥8 g/dL using leukocyte-reduced products 2
• Iron chelation therapy should be initiated when serum ferritin exceeds 1,000 ng/mL with evidence of ongoing transfusion dependence to preserve organ function and possibly improve survival 1, 2, 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
• Iron overload typically develops after receiving approximately 100 ml/kg of blood, with ferritin levels plateauing below 3,000 ng/ml in over half of chronically transfused patients 5

Patients Failing First-Line Immunosuppressive Therapy

For patients refractory to initial immunosuppressive therapy, consider hypomethylating agents (azacitidine or decitabine) as the next treatment option. 1, 2

• Azacitidine shows survival benefit in randomized trials, particularly for patients with chromosome 7 alterations 1, 2
• A second course of ATG plus cyclosporine may be considered, although response rates in the refractory setting are only 30-35% 3
• Alemtuzumab or the thrombopoietin mimetic eltrombopag may also produce responses in refractory disease 3
• Imetelstat is a newer option for patients who are refractory/resistant or ineligible for erythropoiesis-stimulating agent treatment, achieving RBC transfusion independence for ≥8 weeks in 40% of patients compared with 15% on placebo 6

Transplant-Eligible Patients

Allogeneic stem cell transplantation should be considered early in eligible patients, as it remains the only curative option. 1, 2

• Candidates include those with age <65-70 years, acceptable performance status, and favorable comorbidity profile 2
• Donors should be HLA-identical siblings or matched unrelated donors 2
• Use myeloablative conditioning for patients <55 years without comorbidities and reduced-intensity conditioning for older patients 2
• Important caveat: 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
• Patients lacking a fully matched donor should be considered for alternate donor (cord or haploidentical) transplantation 3

Essential Supportive Care Measures

• Initiate broad-spectrum antibiotics immediately for any fever or infection symptoms in neutropenic patients 1
• Consider G-CSF for neutropenic patients with recurrent infections 2
• Administer platelet transfusions for severe thrombocytopenia or bleeding 2
• Monitor organ function regularly, particularly cardiac and hepatic function in transfusion-dependent patients 5
• For patients undergoing surgery with ESA treatment, DVT prophylaxis is recommended due to increased risk of deep venous thrombosis 4

Common Pitfalls to Avoid

• Do not target hemoglobin levels >11 g/dL with ESAs, as this increases risks of death, cardiovascular events, and stroke 4
• Do not delay iron chelation in transfusion-dependent patients once ferritin exceeds 1,000 ng/mL, as iron overload significantly impacts survival 1, 5
• Do not use ESAs in patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure 4
• Do not use modified TBI approaches with lung and liver shielding, as this is associated with unacceptably high relapse rates (34% vs 2% with conventional approaches) 7