What is the dosing and administration of Antithymocyte Globulin (ATG) in patients with severe aplastic anemia?

Dosing and Administration of Antithymocyte Globulin (ATG) in Severe Aplastic Anemia

For patients with severe aplastic anemia, the recommended ATG dosing regimen is horse ATG (ATGAM) 40 mg/kg/day for 4 days or rabbit ATG 10-15 mg/kg total dose administered over 5 days, combined with cyclosporine. 1

Standard Dosing Regimens

Horse ATG (ATGAM or Thymogam)

• Standard dose: 40 mg/kg/day for 4 days 1
• Alternative lower dose: 25 mg/kg/day for 4 days (shown to have comparable efficacy with fewer adverse events) 2, 3
• Administration schedule: Days -5 to -2 relative to planned treatment timeline 1
• Must be combined with cyclosporine for optimal outcomes 1

Rabbit ATG (ATG-F)

• Standard dose: 10-15 mg/kg total, typically divided over 5 days 1
• Alternative optimized protocol: 1.97 mg/kg/day for 9 days (shown to have better response rates and survival compared to higher doses over shorter duration) 4
• Administration schedule: Days -5 to -2 or -4 to -1 depending on protocol 1

Conditioning Regimens for Different Transplant Types

HLA-Matched Sibling Transplantation

• Cy-ATG regimen: Cyclophosphamide 200 mg/kg total + ATG 11.25-15 mg/kg 1

HLA-Matched Unrelated HSCT

• FluCy-ATG regimen:
  • Fludarabine: 120 mg/m² (days -5 to -2)
  • Cyclophosphamide: 120 mg/kg (days -5, -2)
  • ATG: 11.25-15 mg/kg (days -5 to -2) 1

Haploidentical HSCT

• mBuCyFluATG regimen:
  • 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: 10 mg/kg or ATG-F: 20 mg/kg (days -4 to -1) 1

Monitoring During ATG Administration

• Pre-treatment evaluation:

  • Complete blood count with differential and reticulocyte count 1
  • Peripheral blood smear examination 1
  • Bone marrow evaluation if diagnosis is uncertain 1
  • Screening for infections (bacterial, fungal, viral - especially CMV and HIV) 1

• During administration:

  • Monitor for infusion reactions (pulmonary edema, SIRS) 1
  • Daily CBC and hepatic/renal function during initiation of therapy 1
  • Monitor for serum sickness (fever, rash, arthralgia) 1, 5

• Dose adjustment monitoring:

  • Maintain CD3 counts <20/mL and CD2 counts <50/mL 1
  • Alternative approach: suppress sheep erythrocyte rosette levels to <10% 1

Response Assessment

• Evaluate response at 3 months (expected response rate: 36-50%) 2, 4
• Evaluate response at 6 months (expected response rate: 56-77%) 2, 4
• Complete response: transfusion independence with normal blood counts 5
• Partial response: transfusion independence with improved but not normal counts 5

Factors Affecting Treatment Outcomes

• Favorable response predictors:

  • Age <60 years 1
  • HLA-DR15 phenotype 1
  • Hypocellular bone marrow 1
  • Shorter interval between diagnosis and treatment (<23 days) 4
  • Lower IPSS risk score (for MDS patients) 1

• Common adverse events to monitor:

  • Serum sickness (fever, rash, arthralgia) 1, 5
  • Infections (bacterial, fungal, viral) 1
  • Thrombocytopenia (occurs in approximately one-third of patients) 1
  • Nephrotoxicity (occurs in about 10% of patients) 1

Important Considerations

• Early initiation of therapy (<23 days from diagnosis) significantly improves overall survival 4
• Lower-dose protocols (25 mg/kg/day × 4 days) show comparable efficacy with fewer adverse events and are suitable for resource-constrained settings 2, 3
• Optimized rabbit ATG protocol (lower dose over longer duration) shows better survival than standard higher-dose shorter duration 4
• Combination with cyclosporine is essential for optimal response 1, 4