What are the treatment options for a patient with refractory Immune Thrombocytopenic Purpura (ITP)?

Treatment of Refractory ITP

Thrombopoietin receptor agonists (TPO-RAs) are the preferred treatment for refractory ITP, offering sustained platelet responses with favorable long-term safety profiles and the potential for remission in up to 30% of patients after discontinuation. 1, 2

Defining Refractory ITP

Refractory ITP refers to patients who have failed first-line corticosteroid therapy and require ongoing treatment to maintain hemostatic platelet counts (typically >30-50 × 10⁹/L). 2, 3 These patients have typically failed multiple prior treatments, often including splenectomy. 4

First-Choice Treatment: TPO-RAs

TPO-RAs (romiplostim and eltrombopag) should be the initial second-line therapy for refractory ITP. 2, 3

Efficacy Profile

• Overall platelet response rates of 88% in non-splenectomized patients and 79% in splenectomized patients 2
• Sustained responses documented for up to 4 years with continuous administration 2
• Up to 30% of patients achieve long-term remission after tapering and discontinuation 1, 2
• Patients who fail one TPO-RA may still respond to the alternate agent 2

Key Advantages Over Other Options

• Only therapy specifically developed to treat ITP 1
• Stably increase platelet counts, reduce bleeding, reduce need for rescue therapy, and improve quality of life 1
• Well-tolerated for long-term management with favorable safety profiles 1
• No increased risk of infections, thromboembolism, or malignancy compared to splenectomy 1

Practical Management

• Avoid abrupt interruptions or excessive dose adjustments, which can cause platelet fluctuations, especially in splenectomized patients or those on romiplostim 2
• For patients achieving stable platelet counts at the lowest dose, consider holding therapy to monitor for potential remission 2
• Monitor for potential thrombotic complications if platelet counts become excessively elevated 5

Alternative Second-Line Options

Splenectomy

While historically the gold standard, splenectomy should now be considered after TPO-RAs given the availability of effective medical therapy. 2, 3

Efficacy:

• Initial response rate of 80-85% 1, 3
• Long-term durable response in 60-70% of patients 2, 3
• Up to 30% of initial responders relapse within 10 years, typically within 2 years 1

Significant Risks:

• 10% surgical complication rate within 30 days, even with laparoscopic approaches 1
• 3- to 4-fold increased risk of death from septicemia (3.02-fold), pulmonary embolism (4.53-fold), and non-Hodgkin lymphoma (4.69-fold) that persists for >10 years 1
• Lifelong increased infection risk 1

When to Consider: For patients who prefer to minimize medication and monitoring needs, or when TPO-RAs are unavailable due to cost constraints. 1, 6

Rituximab

An alternative second-line option with more limited long-term efficacy. 2, 3

Efficacy:

• Initial response rates of 60% with complete responses in 40% 2
• Long-term sustained responses in only 20-30% of cases 2, 3
• Response typically occurs within 1-8 weeks 2

Important Limitations:

• Lack of significant benefit with long-term use should limit its routine use 1
• Effects of age, sex, and ITP duration on efficacy should restrict use in male patients and those with ITP >1 year 1

Third-Line Options for Truly Refractory Cases

When patients fail TPO-RAs, splenectomy, and rituximab, consider the following immunosuppressive agents:

Combination Immunosuppressive Therapy

The most effective approach for truly refractory cases. 4

• Azathioprine + mycophenolate mofetil + cyclosporine achieved 73.7% response rate in patients who failed a median of 6 prior treatments 4
• Responses lasted a median of 24 months 4
• 14.3% remained in remission after stopping all medications 4
• No severe adverse events occurred 4

Individual Immunosuppressive Agents

Azathioprine (1-2 mg/kg daily):

• Response rates up to 45-67% 2, 6
• Requires 3-6 months for effect 2, 6
• Relatively favorable safety profile with mild side effects 6
• Safe in pregnancy 6
• Cost-effective option in resource-limited settings 6

Cyclosporin A (5 mg/kg/day initially, then 2.5-3 mg/kg/day):

• Response rates of 50-80% 2
• Onset within 3-4 weeks 2

Mycophenolate mofetil (1000 mg twice daily):

• Response rates up to 75% within 4-6 weeks 2
• However, as single-agent therapy, only 7 of 18 patients (39%) achieved sustained response >50 × 10⁹/L 7
• May be more effective in patients with shorter ITP duration 7

Cyclophosphamide (1-2 mg/kg orally daily or 0.3-1 g/m² IV every 2-4 weeks):

• Response rates of 24-85% 2
• Associated with rare risk of leukemia 6

Danazol (200 mg 2-4 times daily):

• Response rates up to 67% 2
• Requires 3-6 months of treatment 2

Dapsone (75-100 mg daily):

• Response rates up to 50% within 3 weeks 2

Critical Pitfalls to Avoid

Prolonged corticosteroid use (>6-8 weeks) must be avoided. 2, 3 Patients requiring on-demand corticosteroid administration after completing first-line treatment should be considered non-responders and promptly switched to second-line therapy. 2 The risks of prolonged corticosteroid use—including weight gain, osteoporosis, cataracts, infections, and increased bleeding risk—often exceed the risks of the disease itself. 1, 3

Do not delay TPO-RA initiation in favor of splenectomy based on outdated treatment paradigms. 2, 3 The historical preference for splenectomy was established before TPO-RAs were available and should be reconsidered given current evidence. 1

Treatment decisions should be based on bleeding symptoms and bleeding risk, not platelet count alone. 2, 3 The goal is maintaining hemostatic platelet counts (30-50 × 10⁹/L), not normalizing counts. 2, 3