What are the recommended dosages and treatment durations for anti‑thymocyte globulin (ATG), cyclosporine, and eltrombopag in an adult with severe aplastic anemia who is not a candidate for immediate allogeneic stem‑cell transplantation?

Dosing and Duration of Immunosuppressive Therapy for Severe Aplastic Anemia

For adults with severe aplastic anemia not eligible for immediate transplantation, administer horse ATG at 40 mg/kg/day for 4 consecutive days combined with cyclosporine at 5 mg/kg/day (divided into two doses) starting on day 1, continuing cyclosporine for at least 6 months with gradual tapering thereafter. 1

Anti-Thymocyte Globulin (ATG) Dosing

Standard Horse ATG Protocol

• Dose: 40 mg/kg/day intravenously for 4 consecutive days (total cumulative dose: 160 mg/kg) 1
• Timing: Initiate as soon as diagnosis is confirmed and patient is medically stable 2
• Preparation requirements: All blood products must be irradiated and filtered before transfusion 2, 3

Alternative Lower-Dose Regimens

While the standard dose is preferred, lower-dose protocols have shown comparable efficacy in resource-limited settings:

• 25 mg/kg/day for 4 days demonstrated similar overall response rates (77% at 6 months) compared to standard dosing 4
• 15 mg/kg/day for 5 days produced equivalent response rates (71%) and survival outcomes 5

These lower-dose regimens may be considered when standard-dose ATG is unavailable or cost-prohibitive, though they represent off-label modifications 4, 5.

Rabbit ATG Considerations

• Not recommended as first-line therapy - rabbit ATG shows inferior early complete response rates compared to horse ATG (1.9% vs 13.0% at 6 months) 6
• If horse ATG is unavailable, rabbit ATG may be used but expect delayed time to complete response due to more profound and protracted lymphocyte depletion 6
• Rabbit ATG is only FDA-approved for renal transplant rejection, not aplastic anemia 1

Critical Monitoring During ATG Infusion

• Daily complete blood counts during the 4-day infusion period 1
• Monitor for pulmonary edema and systemic inflammatory response syndrome 1
• Watch for serum sickness (occurs in ~10% of patients, may cause acute renal dysfunction) 1
• Screen for anaphylaxis, dyspnea, hemolysis, and sepsis 1
• Pneumocystis pneumonia prophylaxis should be initiated in all patients receiving ATG 1

Cyclosporine Dosing and Duration

Initial Dosing

• Starting dose: 5 mg/kg/day divided into two equal doses (e.g., 2.5 mg/kg twice daily) 1
• Target trough level: 200-400 μg/L 7
• Begin on day 1 simultaneously with ATG 1

Treatment Duration

• Minimum duration: 6 months of full-dose therapy 3, 7
• Tapering strategy: After 6 months, if response is achieved, gradually taper cyclosporine over subsequent months 1
• Continue monitoring during taper as rebound cytopenias can occur 3

Dose Adjustments for Toxicity

For nephrotoxicity:

• Reduce dose by 25-50% if serum creatinine increases >30% above baseline 1
• Monitor serum creatinine at each visit 1

For hypertension:

• Decrease cyclosporine dose and consider adding calcium channel blockers 1
• Measure blood pressure at every visit 1

Routine Monitoring Requirements

• At each visit: Blood pressure, serum creatinine, complete blood count, liver function tests, potassium, and lipid levels 1
• Cyclosporine trough levels: Adjust dose to maintain therapeutic range of 200-400 μg/L 7

Common Side Effects to Anticipate

• Hypertension, nephrotoxicity, hirsutism, and gum hypertrophy are expected 1
• These are dose-dependent and often improve with dose reduction 1

Eltrombopag: Dosing and Clinical Context

First-Line Combination Therapy (Preferred Approach)

For treatment-naïve severe aplastic anemia, combine eltrombopag with horse ATG plus cyclosporine starting from day 1 and continuing for 6 months, yielding complete response rates of 58% and overall response rates of 94% at 6 months. 3

• Dose: 150 mg daily (100 mg daily in patients of Asian ethnicity) 7
• Duration: 6 months when combined with ATG and cyclosporine 3, 7
• Initiation timing: Start on day 1 simultaneously with ATG and cyclosporine 3

Refractory Disease Setting

• Add eltrombopag to supportive care for patients who fail initial immunosuppressive therapy 3
• Response rates of 40-48% in refractory patients 3
• This represents salvage therapy after ATG failure 2, 3

ATG-Free Regimen (When ATG Unavailable)

Recent evidence supports eltrombopag plus cyclosporine without ATG:

• Overall response rate: 46% at 6 months 7
• Dosing: Eltrombopag 150 mg daily (100 mg in Asian patients) plus cyclosporine 10 mg/kg/day for 6 months 7
• This approach is reasonable where horse ATG is unavailable or not tolerated, though response rates are lower than triple therapy 7

Discontinuation Strategy

Unlike immune thrombocytopenia where gradual tapering is recommended, in aplastic anemia the literature describes abrupt discontinuation in robust responders. 3

Critical Safety Monitoring for Eltrombopag

• Liver function tests regularly: Increased transaminases occur in 13% of patients and represent the only dose-limiting toxicity 3
• Monitor for thrombosis: Thromboembolism is a serious adverse event requiring vigilance 3
• Watch for rebound thrombocytopenia upon discontinuation 3
• Avoid combination with azacitidine due to increased progression to AML risk 3

Treatment Algorithm Summary

Step 1: Confirm severe aplastic anemia diagnosis with bone marrow biopsy showing hypocellularity <25% and peripheral cytopenias 2

Step 2: Initiate triple therapy on day 1:

• Horse ATG 40 mg/kg/day IV × 4 days 1
• Cyclosporine 5 mg/kg/day PO (divided twice daily) 1
• Eltrombopag 150 mg daily (100 mg if Asian) 3, 7

Step 3: Continue cyclosporine and eltrombopag for 6 months 3, 7

Step 4: At 6 months, assess response:

• If complete or partial response: Discontinue eltrombopag abruptly, begin cyclosporine taper 3
• If no response: Consider repeat immunosuppression with rabbit ATG or proceed to allogeneic transplantation 2

Common Pitfalls to Avoid

• Do not delay ATG administration for minor infections if they are under control; infectious complications should be "under suitable control" but need not be completely resolved 2
• Do not use rabbit ATG as first-line unless horse ATG is truly unavailable - it produces slower and less robust responses 6
• Do not forget Pneumocystis prophylaxis - all patients receiving ATG require this 1
• Do not use non-irradiated blood products - transfusion-associated GVHD is preventable with irradiation 2, 3
• Do not continue full-dose cyclosporine indefinitely - taper after 6 months in responders to minimize long-term toxicity 1

Patient Selection Considerations

Immunosuppressive therapy is particularly effective in:

• Younger patients with hypoplastic bone marrow and trisomy 8 3
• HLA-DR15 positive patients, especially those over 50 years with long-duration transfusion dependency 3
• Patients with hypocellular bone marrow remain significant predictors of achieving red blood cell transfusion independence 3

These factors strengthen the indication for immunosuppressive therapy over immediate transplantation consideration 3.