When are immunosuppressants (e.g. azathioprine or cyclosporine) used in the treatment of immune thrombocytopenic purpura (ITP)?

When to Use Immunosuppressants in ITP

Immunosuppressants such as azathioprine and cyclosporine are used as second-line therapy in ITP patients who have failed or are intolerant to corticosteroids, typically after deferring splenectomy for at least 6 months or in patients who have failed splenectomy. 1

Treatment Algorithm for Immunosuppressant Use

First-Line Therapy Failure

• Immunosuppressants are considered after patients fail initial corticosteroid therapy (prednisone 1-2 mg/kg/day or high-dose dexamethasone) or IVIg 1
• The decision to use immunosuppressants typically occurs when platelet counts remain persistently below 30 × 10⁹/L with bleeding risk, or when corticosteroid side effects become unacceptable after 6-8 weeks of treatment 1

Timing Relative to Splenectomy

• Splenectomy is generally deferred for at least 6 months after diagnosis due to the possibility of spontaneous remission, patient preference, or active comorbidities 1
• Immunosuppressants serve as a bridge therapy during this deferral period or as an alternative when splenectomy is contraindicated 1
• For patients who fail splenectomy, immunosuppressants remain a viable option alongside thrombopoietin receptor agonists and rituximab 1

Specific Immunosuppressant Selection

Azathioprine

• Dose: 150 mg/day (or 1-2 mg/kg/day), with response expected after 3-6 months of continuous therapy 1, 2, 3
• Achieves complete response in approximately 45% of patients, with many requiring continued therapy at reduced doses 1, 2
• Particularly valuable in resource-limited settings due to cost-effectiveness 2
• Critical monitoring requirement: Screen for thiopurine methyltransferase deficiency if cytopenias develop (0.25% of population lacks this enzyme) 2
• Favorable safety profile with no reported leukemia cases in ITP patients, unlike cyclophosphamide 1, 2

Cyclosporine A

• Dose: 2.5-3 mg/kg/day, effective as monotherapy or combined with prednisone 1
• Clinical improvement observed in over 80% of patients resistant to first-line therapy, with 42% achieving complete response 1
• Remissions can be durable (mean 29 months) even after discontinuation 1
• Contraindications: Unsuitable for elderly patients and those with renal insufficiency 1
• Monitor for: Fatigue, renal insufficiency, hypertension, and neuropathy (usually moderate and transient) 1

Cyclophosphamide

• Reserved for highly refractory cases due to serious toxicity concerns 1
• Oral dosing: 1-2 mg/kg daily for at least 16 weeks; IV dosing: 0.3-1 g/m² for 1-3 doses every 2-4 weeks 1
• Response rates vary widely (24-85%) 1
• Major safety concern: Reports of acute myeloid leukemia development in ITP and SLE patients; sterility risk inadequately addressed 1

Alternative Second-Line Options to Consider

Thrombopoietin Receptor Agonists

• Recommended by ASH for patients at bleeding risk who relapse after splenectomy or have splenectomy contraindications (Grade 1B recommendation) 1
• Romiplostim: 1-10 mcg/kg subcutaneously weekly; Eltrombopag: 25-75 mg orally daily 1, 4
• Response rates of 70-80%, but most patients require continued therapy 5, 4

Rituximab

• May be considered for bleeding-risk patients who failed one line of therapy (Grade 2C recommendation) 1
• Standard dosing: 375 mg/m² weekly for 4 doses 5, 6
• Overall response rate approximately 44-60%, with 18-40% complete response 5, 6

Critical Clinical Pitfalls

Timing Errors

• Do not rush to immunosuppressants before 6 months: Spontaneous remission can occur even years after diagnosis 1
• Do not continue ineffective therapy: Azathioprine requires 3-6 months to assess efficacy; if no response by then, discontinue 2, 3

Monitoring Failures

• For azathioprine: Check for thiopurine methyltransferase deficiency and monitor for transaminase elevations 2
• For cyclosporine: Regular renal function and blood pressure monitoring essential 1
• Avoid cyclophosphamide in young patients due to sterility risk and leukemia potential 1

Combination Therapy Consideration

• In particularly severe refractory cases (failed median of 6 prior treatments), combination immunosuppression (azathioprine + mycophenolate mofetil + cyclosporine) achieved 73.7% response rate with acceptable toxicity 7
• This approach should be reserved for truly refractory patients under specialist supervision 7