What are the treatment options for a patient with refractory Immune Thrombocytopenic Purpura (ITP) who has failed first-line therapies such as corticosteroids?

Treatment of Refractory ITP

For adults with refractory ITP who have failed corticosteroids, thrombopoietin receptor agonists (TPO-RAs) should be the preferred second-line therapy, with either eltrombopag or romiplostim as first choice, followed by rituximab or splenectomy based on patient-specific factors. 1

Definition of Refractory ITP

• Refractory ITP is defined as failure to respond to corticosteroids after 6-8 weeks of treatment, or requiring continuous corticosteroid therapy to maintain safe platelet counts 1
• Patients requiring on-demand corticosteroid administration after completing first-line induction should be considered non-responders and switched promptly to alternative therapy 1
• Initial corticosteroid treatment should never exceed 6-8 weeks due to severe adverse events including osteoporosis, diabetes, hypertension, and infections 1, 2

Second-Line Treatment Algorithm

First Choice: TPO-RAs (Eltrombopag or Romiplostim)

The American Society of Hematology suggests TPO-RAs over both rituximab and splenectomy for patients who are corticosteroid-dependent or unresponsive 1

• Eltrombopag: Oral daily medication achieving platelet responses in 70-80% of patients 3, 4

  • Starting dose: 50 mg once daily (25 mg for East/Southeast Asian patients) 4
  • Can be titrated up to 75 mg daily based on response 4
  • Allows 53-62% of patients to reduce or discontinue concomitant corticosteroids 4

• Romiplostim: Weekly subcutaneous injection with similar efficacy to eltrombopag 1, 5

  • Indicated for adults with insufficient response to corticosteroids, immunoglobulins, or splenectomy 5
  • Choice between eltrombopag and romiplostim depends on patient preference for oral daily vs. weekly subcutaneous administration 1

• Key advantages of TPO-RAs: Maintenance therapy with sustained response while on treatment, safer profile than prolonged corticosteroids, allows reduction of other ITP medications 1, 6

Second Choice: Rituximab

Rituximab should be considered for patients who wish to avoid long-term medication or surgery 1

• Achieves short-term responses in 50-60% of patients, with long-term responses in 20-30% 1
• Given as limited course (not maintenance therapy), but half of responders lose response within 1-2 years and require retreatment 6
• Critical safety concerns: Risk of hepatitis B reactivation, multifocal leukoencephalopathy, hypogammaglobulinemia, and reduced vaccine efficacy 1
• Particularly effective in young women with short ITP history 1

Third Choice: Splenectomy

Splenectomy should be delayed for at least 12 months from diagnosis to allow for spontaneous remission or medical therapy response 1, 3

• Initial response rate of 80-85% with sustained long-term responses in 60-66% of patients 1, 3
• Up to 30% of initial responders relapse, typically within first 2 years 1, 3
• Mandatory pre-operative requirements: Pneumococcal, meningococcal C, and Haemophilus influenzae b vaccines at least 4 weeks before surgery 3
• Lifelong risks: 3-fold increased risk of septicemia, 4.5-fold increased risk of pulmonary embolism, 2.7-fold increased risk of venous thromboembolism persisting >10 years 3
• Requires lifelong prophylactic antibiotics and immediate emergency evaluation for any fever >38°C 3

Treatment Selection Framework

The 2019 ASH guidelines provide conditional recommendations suggesting: 1

1. TPO-RAs over rituximab (for sustained response while on therapy)
2. Rituximab over splenectomy (to avoid irreversible surgery)
3. TPO-RAs or splenectomy as equivalent options (based on patient values)

Decision factors favoring each option:

• Choose TPO-RAs if: Patient requires ongoing medication management, wishes to avoid surgery, needs sustained platelet response, or has failed rituximab 1, 6

• Choose rituximab if: Patient values avoiding long-term daily medication, accepts risk of retreatment, or wishes to delay/avoid splenectomy 1, 6

• Choose splenectomy if: Patient values achieving durable response without long-term medication, has failed medical therapies, or has severe refractory disease requiring definitive treatment 1, 3

Common Pitfalls to Avoid

• Excessive corticosteroid duration: Never continue corticosteroids beyond 6-8 weeks as first-line therapy due to cumulative toxicity including weight gain, diabetes, osteoporosis, and infections 1
• Premature splenectomy: Avoid splenectomy before 12 months unless severe bleeding unresponsive to medical therapies, as spontaneous remissions can occur 1, 3
• Underuse of TPO-RAs: These agents should be considered early rather than exhausting multiple other therapies first, given their superior efficacy and safety profile 1, 6

Alternative Third-Line Options

For patients failing TPO-RAs, rituximab, and splenectomy, consider: 1, 7

• Fostamatinib (maintenance therapy with different mechanism) 6
• Mycophenolate mofetil, azathioprine, danazol, or cyclosporine (lower response rates, greater toxicity, reserved for limited-resource settings) 1