Background
Prospective randomized trial at a single NIH facility. 120 patients with severe acquired aplastic anemia randomized to horse ATG (Atgam) versus rabbit ATG (Thymoglobulin), each with cyclosporine, G-CSF, and methylprednisolone. Horse ATG had been established first-line therapy; rabbit ATG was hypothesized superior given greater lymphocyte-depleting potency. The trial was stopped early after interim analysis demonstrated unexpected inferiority of rabbit ATG.
Interventions and follow up
Arm A: Horse ATG (Atgam) 40 mg/kg/day × 4 days + cyclosporine + G-CSF + methylprednisolone
Arm B: Rabbit ATG (Thymoglobulin) 3.5 mg/kg/day × 5 days + cyclosporine + G-CSF + methylprednisolone
Primary endpoint: Hematologic response at 6 months
Median follow up: 3 years
Arm B: Rabbit ATG (Thymoglobulin) 3.5 mg/kg/day × 5 days + cyclosporine + G-CSF + methylprednisolone
Primary endpoint: Hematologic response at 6 months
Median follow up: 3 years
Results
Hematologic response at 6 months: 68% (horse ATG) vs 37% (rabbit ATG), P<.001
Overall survival at 3 years (censored at SCT): 96% vs 76%, P=.04
Overall survival at 3 years (including SCT events): 94% vs 70%, P=.008
Relapse rate: similar between groups in responders
Overall survival at 3 years (censored at SCT): 96% vs 76%, P=.04
Overall survival at 3 years (including SCT events): 94% vs 70%, P=.008
Relapse rate: similar between groups in responders
Adverse events
Infusion/immune: serum sickness in both groups; fever, rash, arthralgias from ATG common and expected
Infections: related to prolonged immunosuppression, similar in both arms
Hematologic: thrombocytopenia and neutropenia as expected manifestations of aplastic anemia; no unexpected safety signals
Infections: related to prolonged immunosuppression, similar in both arms
Hematologic: thrombocytopenia and neutropenia as expected manifestations of aplastic anemia; no unexpected safety signals
Conclusions
Rabbit ATG was unexpectedly inferior to horse ATG as first-line immunosuppressive therapy for severe aplastic anemia, with significantly lower response rates and worse survival, confirming horse ATG + cyclosporine as the standard of care.
Key Limitations
Population: single-center NIH trial; patient selection may differ from community practice
Conduct: stopped early after interim analysis showing rabbit ATG inferiority, limiting characterization of long-term outcomes
Generalizability: specific rabbit ATG product/dosing and protocol-driven cyclosporine management may not apply to all formulations or real-world practice
Conduct: stopped early after interim analysis showing rabbit ATG inferiority, limiting characterization of long-term outcomes
Generalizability: specific rabbit ATG product/dosing and protocol-driven cyclosporine management may not apply to all formulations or real-world practice
Clinical Context
This trial definitively established horse ATG (not rabbit ATG) as the correct ATG formulation for first-line IST in severe aplastic anemia. Current standard of care is horse ATG + cyclosporine + eltrombopag (Townsley 2017; RACE trial), achieving ~>80% response in non-transplant candidates. Matched-sibling allogeneic transplant is preferred for younger patients with a suitable donor. Rabbit ATG remains appropriate within transplant conditioning regimens but should not be used as first-line IST. ESMO guidelines reflect this standard.