What is the recommended treatment for severe aplastic anemia?

Treatment of Severe Aplastic Anemia

For patients under 50 years with severe aplastic anemia and an HLA-matched sibling donor, allogeneic hematopoietic stem cell transplantation (allo-HSCT) should be offered as first-line therapy; for those without a matched donor or over 50 years, immunosuppressive therapy with horse antithymocyte globulin (ATG) plus cyclosporine is the standard first-line treatment. 1

First-Line Treatment Algorithm by Age and Donor Availability

Patients <50 Years Old with Matched Sibling Donor

• Proceed directly to allo-HSCT as first-line therapy for severe or very severe aplastic anemia (SAA/vSAA) 1
• Conditioning regimen: Cyclophosphamide-ATG (Cy-ATG) for HLA-matched sibling transplantation 1
  • Cyclophosphamide 200 mg/kg total dose (days -5 to -2)
  • ATG 11.25-15.00 mg/kg total dose (days -5 to -3 or -2) 1

Pediatric Patients with ≥9/10 Matched Unrelated Donor

• May choose allo-HSCT as first-line therapy 1
• Use FluCy-ATG conditioning regimen for unrelated donor transplants 1

Patients Without Matched Donor or Age 50-60 Years

• Initiate combination immunosuppressive therapy with horse ATG plus cyclosporine 1, 2, 3
• Horse ATG: 40 mg/kg/day for 4 days 2, 3, 4
• Cyclosporine: 10-12 mg/kg/day for 6 months, adjusted to blood trough levels of 200-400 μg/L 3, 5
• Add short course of methylprednisolone (1 mg/day for approximately 2 weeks) 3

Critical timing consideration: Response to ATG-cyclosporine typically occurs within 1-3 months, with 60% responding by 3 months and up to 78% by 1 year 2, 3. Early hematologic response (reticulocyte or platelet count >50 × 10³/μL at 3 months) predicts excellent 5-year survival of 90% versus 42% in those with less robust recovery 3.

Alternative First-Line Approach When ATG Unavailable

Eltrombopag Plus Cyclosporine (ATG-Free Regimen)

• Consider when horse ATG is not available or not tolerated 5
• Eltrombopag: 150 mg daily (100 mg in Asian patients) for 6 months 5
• Cyclosporine: 10 mg/kg/day adjusted to trough 200-400 μg/L for 6 months 5
• Overall response rate: 46% by 6 months 5
• Important limitation: This is less effective than standard ATG-cyclosporine and should only be used when ATG is truly unavailable 5

Second-Line Treatment for Refractory or Relapsed Disease

Patients <50 Years Who Failed Immunosuppression

• Proceed to allo-HSCT with haploidentical donor (HID), matched unrelated donor (MUD), or cord blood transplant (CBT) 1
• Modified conditioning regimens for haploidentical transplant include:
  • mBuCyFluATG: Busulfan 6.4 mg/kg IV (days -7 to -6), Fludarabine 120 mg/m² (days -10 to -7), Cyclophosphamide 200 mg/kg (days -6 to -3), ATG-F 20 mg/kg (days -4 to -1) 1

Patients 50-60 Years with ECOG ≤2 Who Failed Immunosuppression

• Recommend MSD or MUD transplantation 1

Relapse After Initial Immunosuppression

• Relapse is common (36% actuarial risk at 2 years) but does not significantly impact survival 2
• Most relapsed patients respond to additional courses of immunosuppression 2
• Severe pancytopenia usually does not recur with relapse 3

Eltrombopag as Salvage Therapy

FDA-Approved Indication

• Eltrombopag is approved for severe aplastic anemia patients who have had insufficient response to immunosuppressive therapy 6
• This is a third-line option, not first-line treatment 6

Dosing for Severe Aplastic Anemia

• Initiate at 36 mg orally once daily 6
• For East/Southeast Asian ancestry: reduce to 18 mg once daily 6
• For hepatic impairment (Child-Pugh A, B, or C): reduce to 18 mg once daily 6
• Maximum dose: 54 mg daily 6

Critical safety monitoring: Monitor hepatic function regularly as eltrombopag carries risk of severe hepatotoxicity 6. Obtain complete blood counts weekly until stable platelet count achieved, then monthly 6.

Monitoring and Response Assessment

Early Response Indicators (3 Months)

• Reticulocyte count >50 × 10³/μL predicts 90% 5-year survival 3
• Platelet count >50 × 10³/μL predicts 90% 5-year survival 3
• Transfusion independence 3

Long-Term Outcomes

• Responders to ATG-cyclosporine have 86% actuarial survival at 5 years 3
• No deaths among responders beyond 3 years after treatment 3
• Evolution to myelodysplastic syndrome or acute leukemia is rare (approximately 2%) 2
• Paroxysmal nocturnal hemoglobinuria develops in approximately 10% of patients 2

Critical Pitfalls to Avoid

Do not use eltrombopag as first-line monotherapy: It is only approved after immunosuppression failure and should not replace standard ATG-cyclosporine 6, 5.

Do not delay transplant in young patients with matched donors: Allo-HSCT offers superior long-term outcomes and should be pursued immediately in appropriate candidates 1.

Do not use eltrombopag in myelodysplastic syndromes: It is contraindicated in MDS patients 6.

Do not overlook donor availability early: Young patients without matched sibling donors should have haploidentical transplant considered as first-line therapy rather than waiting for immunosuppression failure 1.