Management of Severe Aplastic Anemia
For patients with newly diagnosed severe aplastic anemia, allogeneic hematopoietic stem cell transplantation (HSCT) should be considered as first-line therapy, with immunosuppressive therapy (IST) using antithymocyte globulin (ATG) plus cyclosporine as the alternative when transplantation is not feasible.
Initial Assessment and Diagnosis
Confirm diagnosis through:
- Complete blood count showing pancytopenia
- Bone marrow biopsy demonstrating hypocellularity
- Exclusion of other causes of bone marrow failure
Determine disease severity based on:
- Neutrophil count <0.5 × 10³/μL
- Platelet count <20 × 10³/μL
- Reticulocyte count <20 × 10³/μL
- Bone marrow cellularity <25%
Treatment Algorithm
Step 1: Immediate HLA Typing
- Perform HLA typing of patient and family members at diagnosis
- Simultaneously search unrelated donor registries
Step 2: Determine First-Line Treatment Based on Donor Availability
For Patients with Available Donors:
- Priority order for bone marrow transplantation:
- HLA-identical sibling donor
- HLA-matched unrelated donor
- HLA-haploidentical donor (if matched unrelated donor not rapidly available)
Conditioning Regimens for HSCT 1:
For HLA-matched sibling transplantation:
- Cy-ATG regimen: Cyclophosphamide 200 mg/kg (days -5 to -2) + ATG 11.25-15.00 mg/kg (days -5 to -2)
For unrelated donor transplantation:
- FluCy-ATG regimen: Fludarabine 120 mg/m² (days -5 to -2) + Cyclophosphamide 120 mg/kg (days -5, -2) + ATG 11.25-15.00 mg/kg (days -5 to -2)
For haploidentical transplantation:
- FluCy-ATG regimen: Fludarabine 120 mg/m² (days -5 to -2) + Cyclophosphamide 90 mg/kg (days -3, -2) + ATG 10 mg/kg (days -5 to -2)
For Patients Without Available Donors or Ineligible for Transplantation:
- Immunosuppressive therapy (IST) 2, 3, 4:
- ATG 40 mg/kg/day for 4 days
- Cyclosporine 10-12 mg/kg/day for 6 months (adjusted for blood levels)
- Short course of corticosteroids (methylprednisolone 1 mg/day for about 2 weeks)
Supportive Care During Treatment
Transfusion support:
- Platelet transfusions for counts <10 × 10³/μL or bleeding
- Red blood cell transfusions for symptomatic anemia
- Consider irradiated blood products to prevent transfusion-associated graft-versus-host disease
Infection prevention and management:
- Antimicrobial prophylaxis for neutropenic patients
- Prompt evaluation and treatment of febrile episodes
- G-CSF may be considered for severe neutropenia with infection
Monitoring Response to Treatment
- Evaluate hematologic response at 3,6, and 12 months
- Response criteria: No longer meeting severity criteria and transfusion independence
- Early response (by 3 months) is associated with better long-term survival 4
- Good prognostic indicators: Reticulocyte count or platelet count >50 × 10³/μL at 3 months
Management of Treatment Failure or Relapse
For non-responders to IST by 6 months:
- Consider second course of ATG (different preparation)
- Evaluate for alternative donor HSCT
- Consider clinical trials with novel agents
For relapse after IST:
- Additional courses of immunosuppression are often effective 2
- Consider HSCT if suitable donor available
Long-term Follow-up
- Monitor for:
- Disease relapse (common but usually less severe than initial presentation)
- Evolution to myelodysplastic syndrome or acute leukemia (rare but serious)
- Development of paroxysmal nocturnal hemoglobinuria (more common)
Clinical Considerations
- HSCT offers higher cure rates and lower risk of disease recurrence compared to IST 5
- The risk of graft-versus-host disease with HSCT must be weighed against the persistent risk of relapse and secondary malignancies with IST
- Approximately 60-78% of patients respond to initial ATG+cyclosporine therapy 2, 4
- Overall survival with IST is approximately 55-72% at 5-7 years 2, 4
- Recent evidence suggests that HSCT from well-matched donors may be preferable to IST even for patients traditionally treated with immunosuppression 5