Cyclosporine in Severe Aplastic Anemia: Immunosuppressive Mechanism
Cyclosporine is used in severe aplastic anemia because it suppresses the T-cell-mediated autoimmune destruction of bone marrow stem and progenitor cells, which is the underlying pathophysiology of this disease. 1
Mechanism of Action
Cyclosporine works by specifically and reversibly inhibiting immunocompetent T-lymphocytes, particularly T-helper cells, which are the primary mediators of bone marrow destruction in aplastic anemia 1. The drug:
- Inhibits cell-mediated immune reactions including allograft rejection and graft-versus-host disease, making it effective against the immune-mediated marrow failure seen in aplastic anemia 1
- Blocks lymphokine production and release, including interleukin-2 (T-cell growth factor), thereby preventing T-cell activation and proliferation 1
- Does not cause bone marrow suppression, which is critical since these patients already have profound cytopenias 1
Standard Treatment Protocol
The combination of antithymocyte globulin (ATG) plus cyclosporine is the standard immunosuppressive therapy for severe aplastic anemia patients without an HLA-matched sibling donor 2, 3, 4:
- Horse ATG at 40 mg/kg/day for 4 days combined with cyclosporine at 5 mg/kg/day divided into two doses is the recommended regimen 3
- This combination achieves response rates of 65-70% in severe aplastic anemia 5
- Horse ATG is superior to rabbit ATG, with a 68% response rate versus 37% for rabbit ATG at 6 months (P<0.001) 4
Patient Selection Criteria
Cyclosporine-based immunosuppression is specifically indicated for 2:
- Patients ≤60 years with ≤5% marrow blasts 2
- Hypocellular bone marrow (<25% cellularity) 2
- HLA-DR15 positivity 2
- Presence of PNH clone 2
- STAT-3 mutant cytotoxic T-cell clones 2
These features indicate an immune-mediated pathophysiology most likely to respond to immunosuppression.
Clinical Efficacy
The evidence strongly supports cyclosporine's role:
- Response occurs rapidly (median 60 days with cyclosporine versus 82 days without; P=0.019) 5
- Failure-free survival is superior with cyclosporine (39% versus 24% without; P=0.04) 5
- Overall survival at 3 years reaches 96% with horse ATG plus cyclosporine 4
- Pre-treatment neutrophil counts >0.3 × 10⁹/L predict better response to immunosuppressive therapy (P=0.02) 6
Monitoring Requirements
Critical monitoring parameters include 3:
- Blood pressure at each visit (cyclosporine causes hypertension) 3
- Serum creatinine, CBC, liver function tests, potassium, and lipid levels 3
- Dose reduction of 25-50% if creatinine increases >30% above baseline 3
- Blood concentration monitoring to maintain therapeutic levels (100-200 ng/mL by HPLC for whole blood trough concentrations) 1
Common Pitfalls
Relapse and cyclosporine dependence are significant concerns: 26% of responders become cyclosporine-dependent, and the projected relapse rate is 38% at 11 years 5. Additionally, clonal or malignant diseases develop in 25% of patients over long-term follow-up 5.
The key distinction from transplantation is that most patients are not cured with immunosuppression—remissions are often unstable and require prolonged therapy 5.