What is the dosage and administration of Anti-Thymocyte Globulin (ATG) for immunosuppression?

ATG Dosing and Administration for Immunosuppression

Primary Dosing Regimens by Indication

For aplastic anemia, the standard ATG dose is 20 mg/kg/day for 10 days (equine ATG) or 2 mg/kg IV daily for 3 consecutive days (rabbit ATG), always combined with cyclosporine. 1, 2

Aplastic Anemia (First-Line Immunosuppression)

• Equine ATG (Atgam): 40 mg/kg/day IV for 4 days is the standard dose, though lower doses of 25 mg/kg/day × 4 days have shown equivalent efficacy in resource-constrained settings 3
• Rabbit ATG (Thymoglobulin): 2 mg/kg IV daily for 3 consecutive days, administered over approximately 12 hours starting at 0.125 mL/kg/hr for 1 hour, then 0.25 mL/kg/hr × 1 hour, then 0.35 mg/kg/hr for remainder of infusion 2
• Combination therapy: ATG must be combined with cyclosporine A at 12.5 mg/kg/day orally for 6 months to achieve optimal response rates of 58-77% 1, 4, 5

Myelodysplastic Syndromes (MDS)

• Horse ATG: Administered for 5 days combined with oral cyclosporine for 180 days 4
• Patient selection: Recommended for patients <60 years with <5% marrow blasts, normal cytogenetics, transfusion dependency, and hypoplastic bone marrow 4
• Response predictors: Better outcomes occur with age <60 years, low IPSS risk, hypocellularity, short transfusion duration, and HLA-DR15 phenotype 4

Hematopoietic Stem Cell Transplantation Conditioning

For transplant conditioning, ATG dosing varies by donor type: 10 mg/kg total for matched unrelated/haploidentical donors (Thymoglobulin) or 40 mg/kg total for ATG-F (Grafalon). 4

Myeloablative Conditioning

• Thymoglobulin: 10 mg/kg total dose given over days -5 to -2 for unrelated donor, cord blood, or haploidentical transplants 4
• ATG-F (Grafalon): 40 mg/kg total dose given over days -5 to -2 for same donor types 4
• Schedule: Typically divided as 2.5 mg/kg/day × 4 days (Thymoglobulin) or 10 mg/kg/day × 4 days (ATG-F) 4

Reduced-Intensity Conditioning

• Thymoglobulin: 10 mg/kg total over days -5 to -2 4
• ATG-F: 40 mg/kg total over days -5 to -2 4
• Used in patients >55 years or those with HSCT-CI ≥3 regardless of age 4

Cardiac Transplant Rejection (Antibody-Mediated)

• Rabbit ATG (rATG): Used in severe hemodynamic compromise, though specific dosing not detailed in cardiac protocols 4
• Thymoglobulin: 1.5 mg/kg IV daily for 5-7 days in pediatric protocols, with first dose over ≥6 hours and subsequent doses over 4 hours through central line 4
• Stanford protocol: 1.5 mg/kg/day for 3 consecutive days with plasmapheresis in severe cases 4

Administration Guidelines

Premedications (Required)

• Methylprednisolone: 1-2 mg/kg IV given 30 minutes to 4 hours before ATG 2
• Acetaminophen: 10 mg/kg IV 2
• Diphenhydramine: 0.5 mg/kg IV 2

Infusion Technique

• Central line access: Strongly preferred for rabbit ATG to minimize thrombophlebitis 2
• Infusion rate: Start at 0.125 mL/kg/hr for 1 hour, increase to 0.25 mL/kg/hr for 1 hour, then 0.35 mg/kg/hr for remainder 2
• Duration: First dose over ≥6 hours; subsequent doses may be given over 4 hours if tolerated 4, 2

Critical Monitoring Parameters

Hematologic Monitoring

• Complete blood counts: Monitor daily during administration and frequently thereafter 6
• Lymphocyte depletion: Rabbit ATG causes more profound and protracted lymphocyte depletion than horse ATG 7
• Target suppression: CD3+ counts <20/mL and CD2+ counts <50/mL, or sheep erythrocyte rosette levels <10% 4

Infection Prophylaxis (Mandatory)

• Pneumocystis pneumonia prophylaxis: Required in all patients receiving ATG 4
• CMV monitoring: Particularly important with rabbit ATG 4
• EBV surveillance: Epstein-Barr virus reactivation substantially increased with ATG (20% vs 2% without ATG), requiring prospective monitoring and rituximab if needed 8

Important Clinical Considerations

Comparative Efficacy: Horse vs Rabbit ATG

• Overall response rates: Similar between horse and rabbit ATG at 6,12, and 18 months (approximately 45-50%) 7
• Complete response timing: Horse ATG achieves CR faster at 6 months (13.0% vs 1.9%), but rates equalize by 12-18 months 7
• Survival: No significant difference in overall or failure-free survival between formulations 7

Common Pitfalls to Avoid

• Never use ATG without cyclosporine in aplastic anemia—combination therapy is essential for optimal response 4, 1, 5
• Do not delay treatment: Shorter interval from symptom onset to therapy initiation trends toward better outcomes 3
• Avoid inadequate premedication: Failure to premedicate increases risk of severe infusion reactions including anaphylaxis, hemolysis, and serum sickness 4, 2
• Monitor renal function closely: Cyclosporine initiation may need delay to preserve renal function; adjust based on trough levels 2

Serious Adverse Events

• Immediate reactions: Anaphylaxis, dyspnea, pulmonary edema, chest/back pain (indicating hemolysis or anaphylaxis) 4
• Hematologic: Leukopenia (common), thrombocytopenia (33% of patients), hemolysis 4
• Infectious: Increased risk of bacterial, fungal (including Pneumocystis), and viral infections (CMV, EBV) 4, 8
• Cardiovascular: Tachycardia, hypertension, peripheral edema commonly observed 4
• Late complications: Post-transplant lymphoproliferative disorder, increased malignancy risk 4, 6