What are the clinical scenarios and dosing recommendations for the use of Anti-Thymocyte Globulin (ATG) in patients requiring immunosuppression?

Use of Anti-Thymocyte Globulin (ATG)

ATG should be used primarily in three clinical scenarios: aplastic anemia (horse ATG preferred at 40 mg/kg/day for 4 days with cyclosporine), renal transplant rejection (10-15 mg/kg/day for 14 days), and steroid-refractory acute graft-versus-host disease, always with mandatory infection prophylaxis and close monitoring for anaphylaxis during infusion. 1, 2

FDA-Approved Indications and Dosing

Aplastic Anemia

• Horse ATG (equine) is superior to rabbit ATG for aplastic anemia and should be the preferred formulation 1, 3
• Standard dosing: 40 mg/kg/day IV for 4 days (total 160 mg/kg) combined with cyclosporine 5 mg/kg/day divided into two doses 1
• FDA-approved dosing range: 10-20 mg/kg/day for 8-14 days, with additional alternate-day therapy up to 21 total doses if needed 2
• Lower dose regimens (25 mg/kg/day × 4 days) have shown similar efficacy in resource-constrained settings with 77% overall response rate at 6 months 4
• Younger age, shorter duration of aplasia, and higher baseline granulocyte counts correlate with better response and survival 5

Renal Transplant Rejection

• Equine ATG: 10-15 mg/kg/day IV for 14 days for rejection treatment; additional alternate-day therapy up to 21 total doses may be given 2
• Rabbit ATG: FDA-approved only for renal transplant rejection treatment (not prophylaxis), though equine ATG is approved for both treatment and prophylaxis 6

Steroid-Refractory Acute GVHD

• Rabbit ATG (thymoglobulin): 2.5 mg/kg/day for 4-6 consecutive days or on days 1,3,5, and 7 6
• Overall response rate 54-59% with complete response 20-38% 6
• Skin GVHD responds best (96-100%), followed by GI (46-83%), with liver GVHD responding poorly (25-36%) 6
• One-year survival only 32-55% even in responders, with high infectious mortality 6

Critical Administration Requirements

Infusion Protocol

• Must infuse over at least 4 hours through high-flow central vein or arteriovenous fistula 2
• Mandatory in-line filter with 0.2-1.0 micron pore size to prevent administration of insoluble material 2
• Dilute to maximum concentration of 4 mg/mL in 0.9% saline or dextrose/saline combinations 2
• Never dilute in pure dextrose solution as low salt concentrations cause precipitation 2
• Use diluted solution within 24 hours including infusion time 2

Anaphylaxis Monitoring

• Monitor continuously during infusion and for at least 24 hours post-infusion for anaphylaxis 2
• Chest pain or back pain may indicate onset of anaphylaxis or hemolysis 6
• ATG is contraindicated in patients with prior anaphylaxis to equine products 2

Mandatory Monitoring and Prophylaxis

Laboratory Monitoring

• Daily CBC during initiation, then adjust frequency based on clinical response 6, 7
• Monitor for target CD3 counts <20/mL and CD2 counts <50/mL, or sheep erythrocyte rosette levels <10% 6, 7
• Daily hepatic and renal function tests during initiation 7
• For cyclosporine combination: monitor blood pressure, serum creatinine, CBC, liver function, potassium, and lipids at each visit 1

Infection Prophylaxis

• Pneumocystis pneumonia prophylaxis is mandatory in all patients 6, 1
• Close monitoring for CMV, fungal, and atypical bacterial infections required 6, 7
• Infectious complications are common with 37% bacterial, 26% viral, and 32% fungal infections reported 6, 7

Major Toxicities and Management

Equine ATG-Specific Toxicities

• Anaphylaxis, dyspnea, pulmonary edema, hemolysis, and serum sickness (10% acute renal dysfunction) 6
• Thrombocytopenia in approximately one-third of patients 6
• Leukopenia, sepsis, tachycardia, hypertension, peripheral edema 6
• Increased malignancy risk: non-Hodgkin's lymphoma in males; lymphoma and cervical/vaginal/vulvar carcinomas in females 6

Rabbit ATG-Specific Toxicities

• Fever, hyperkalemia, hypertension, CMV infection, leukopenia, thrombocytopenia, tachyarrhythmia 6, 7
• Nausea and abdominal pain in one-third of patients; dyspnea in 25% 6
• Antibodies develop in virtually all patients, potentially limiting efficacy with repeated use 6
• Lower incidence of nephrotoxicity and serum sickness compared to equine ATG 6

Cyclosporine Dose Adjustments (When Used in Combination)

• Reduce dose by 25-50% if serum creatinine increases >30% above baseline 1
• For hypertension, decrease cyclosporine and consider calcium channel blockers 1

Off-Label Uses with Evidence Support

Lung Transplant Rejection

• Used for both treatment and prophylaxis with favorable outcomes, though not FDA-approved 6

Myelodysplastic Syndrome (Low-Risk)

• ATG plus cyclosporine for 180 days in patients <60 years with <5% marrow blasts, normal cytogenetics, and transfusion dependency 6
• Highly recommended in presence of hypoplastic bone marrow 6
• Response rate significantly higher with ATG/CSA versus supportive care, but higher serious adverse events including hemorrhage, cardiac events, serum sickness, thrombosis, and severe infection 6

Critical Drug Interactions and Contraindications

• ATG reduces effectiveness of live virus vaccines 6
• Additive immunosuppression when combined with other agents, particularly lymphocyte-depleting therapies 6, 7
• May cause unreliable blood cross-match and panel-reactive antibody assays 6
• Rabbit antibody-based serum immunoassays unreliable during rabbit ATG therapy 6
• Pregnancy Category C; breastfeeding not recommended 6, 7