What medications are used to treat aplastic anemia?

Medications for Aplastic Anemia

First-Line Immunosuppressive Therapy

For patients with severe aplastic anemia who are not candidates for allogeneic hematopoietic stem cell transplantation, the standard first-line treatment is horse anti-thymocyte globulin (ATG) at 40 mg/kg/day for 4 days combined with cyclosporine at 5 mg/kg/day divided into two doses. 1

ATG Dosing Protocols

• Horse ATG (ATGAM or biosimilar thymogam) should be administered at 40 mg/kg/day for 4 consecutive days, providing a total dose of 160 mg/kg 1, 2
• Lower-dose protocols (15-25 mg/kg/day for 4-5 days) have shown comparable response rates and survival outcomes in real-world settings, though this is not the standard recommendation 3, 4
• Equine ATG has demonstrated superior efficacy compared to rabbit-derived ATG in aplastic anemia, though rabbit ATG is approved only for renal transplant rejection 5

Cyclosporine Dosing and Monitoring

• Initial cyclosporine dose: 5 mg/kg/day divided into two equal doses, adjusted to maintain blood trough levels of 200-400 μg/L 1, 6
• Duration: Continue for at least 6 months, with gradual tapering based on response 2, 6
• Monitoring requirements include blood pressure at each visit, along with serum creatinine, complete blood count, liver function tests, potassium, and lipid levels 1
• Dose adjustments: Reduce cyclosporine by 25-50% if serum creatinine increases >30% above baseline 1
• For hypertension, decrease cyclosporine dose and consider calcium channel blockers 1

Expected Response and Outcomes

• Response rates: Approximately 60% at 3 months, 61% at 6 months, and 58% at 1 year after ATG/cyclosporine therapy 2
• Survival: Overall actuarial survival at 7 years is 55%, with 86% survival at 5 years for responders versus 40% for non-responders 2
• Predictors of response: Reticulocyte count or platelet count >50 × 10³/μL at 3 months predicts 90% survival at 5 years 2
• Relapse is common but severe pancytopenia usually does not recur, and relapse does not significantly influence survival 2

Second-Line and Adjunctive Therapies

Eltrombopag

Eltrombopag is FDA-approved for adult patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy. 7

• Initial dose: 36 mg orally once daily for most patients, with dose reductions needed for hepatic impairment and patients of East/Southeast Asian ancestry 7
• Maximum dose: Do not exceed 108 mg per day 7
• Administration: Take without a meal or with a meal low in calcium (≤50 mg), at least 2 hours before or 4 hours after medications containing polyvalent cations 7
• Monitoring: Hepatic function must be monitored before and during therapy due to risk of hepatotoxicity 7

Eltrombopag as First-Line Therapy (ATG-Free Regimen)

• A recent phase 2 trial (SOAR) demonstrated that eltrombopag 150 mg (100 mg in Asian patients) combined with cyclosporine 10 mg/kg/day achieved a 46% overall response rate at 6 months as first-line treatment 6
• This ATG-free approach may be beneficial where horse-ATG is unavailable or not tolerated 6
• Most common adverse events include increased serum bilirubin (41%), nausea (30%), increased ALT (22%), and diarrhea (22%) 6

Conditioning Regimens for Transplantation

For patients proceeding to allogeneic hematopoietic stem cell transplantation:

• HLA-matched sibling transplantation: Cyclophosphamide 200 mg/kg total dose plus ATG 11.25-15 mg/kg (Cy-ATG regimen) 5, 1
• Unrelated donor transplantation: Fludarabine 120 mg/m², cyclophosphamide 120 mg/kg, and ATG 11.25-15 mg/kg (FluCy-ATG regimen) 5, 1
• Haploidentical transplantation: Busulfan 6.4 mg/kg IV, fludarabine 120 mg/m², cyclophosphamide 200 mg/kg, and ATG 10 mg/kg or ATG-F 20 mg/kg (mBuCyFluATG regimen) 5, 1

Critical Safety Considerations

ATG-Related Toxicities

• Infusion reactions: Monitor for pulmonary edema and systemic inflammatory response syndrome during drug infusion 5
• Hematologic toxicity: Daily CBC monitoring during initiation, with subsequent intervals based on clinical response 5
• Serum sickness: May occur due to equine immunoglobulin, potentially causing acute renal dysfunction in approximately 10% of patients 5
• Major adverse reactions: Anaphylaxis, dyspnea, hemolysis, leukopenia, thrombocytopenia (in roughly one-third of patients), and sepsis 5
• Infection prophylaxis: Consider prophylaxis for Pneumocystis pneumonia in all patients receiving ATG 5

Cyclosporine-Related Toxicities

• Nephrotoxicity: Occurs in approximately 10% of patients; requires dose reduction if creatinine increases significantly 5, 1
• Hypertension: Common during administration; may require antihypertensive therapy 5, 1
• Other effects: Hirsutism, gum hypertrophy, and increased risk of malignancies (non-Hodgkin's lymphoma, cervical/vaginal/vulvar carcinomas in females) 5

Long-Term Complications

• Clonal evolution: Approximately 13% of patients show evolution to other hematologic diseases, including monosomy 7 and acute myeloid leukemia 2
• Relapse: Common but usually does not result in severe pancytopenia recurrence 2
• No deaths among responders occurred more than 3 years after treatment in long-term follow-up 2