What is the role of azathioprine in the treatment of Immune Thrombocytopenic Purpura (ITP)?

Role of Azathioprine in Immune Thrombocytopenic Purpura (ITP)

Azathioprine is an effective second-line immunosuppressive agent for ITP patients who are refractory to first-line therapies, with complete response rates of approximately 45% when administered at 150 mg/day, though continued therapy is generally required to maintain response. 1

Positioning in ITP Treatment Algorithm

• Azathioprine is classified as a second-line therapy option for ITP, alongside other agents such as rituximab, splenectomy, and thrombopoietin receptor agonists 1
• It should be considered after failure of first-line therapies (corticosteroids, IVIg, anti-D) or when patients have contraindications to these treatments 1
• The main goal when using azathioprine is to attain a sustained increase in platelet count that provides hemostasis for the individual patient 1

Dosing and Administration

• Standard dosing is 1-2 mg/kg daily (maximum: 150 mg/day) 1
• Patients should be monitored for thiopurine methyltransferase deficiency if cytopenias develop, as approximately 0.25% of the population lacks this enzyme 1
• Response to azathioprine is typically slow, requiring continued administration for 3-6 months before determining efficacy 1, 2

Efficacy

• Complete response rates of approximately 45% have been reported in patients treated with azathioprine (150 mg/day) for a median of 18 months 1
• Up to two-thirds of patients may show some response to therapy 1, 2
• In a study of 53 patients (40 post-splenectomy), 64% responded to azathioprine, with 45% achieving complete remission 2
• More recent data from 2021 showed a cumulative overall response rate (complete and partial) of 38.1% at day 90 3
• Median time to response is approximately 4 months, highlighting the need for patience when initiating this therapy 2, 4

Duration of Treatment and Maintenance

• Although continued therapy is generally required to maintain response, often a reduced dose suffices 1
• Some patients may maintain durable responses after discontinuation of therapy 2
• In one study, 10 of 24 complete responders maintained remission after discontinuation of azathioprine 2
• For patients who respond, the optimal duration of treatment remains to be established 2

Safety Profile

• Azathioprine has a relatively favorable safety profile with generally mild side effects 1
• Common adverse effects include:
  • Weakness and sweating 1
  • Transaminase elevations 1, 3
  • Leukopenia (most frequent adverse event in recent studies) 3
  • Anemia and hepatobiliary laboratory abnormalities 3
• Serious adverse events (grade ≥3) occur in approximately 4.7% of patients 3
• Unlike cyclophosphamide, leukemia has only rarely been associated with azathioprine in other disorders and has not been described in ITP patients 1
• Azathioprine is one of the few ITP medications considered relatively safe in pregnancy, with no increased rate of fetal malformation, and is safe during lactation 1

Patient Selection Considerations

• Azathioprine may be particularly valuable in:
  • Patients who have failed or have contraindications to splenectomy 2, 5
  • Settings where access to newer therapies like TPO receptor agonists is limited due to cost constraints 1, 4
  • Patients requiring long-term immunosuppression who cannot tolerate other agents 1
• In developing countries with limited resources, azathioprine represents a cost-effective second-line option 4

Practical Considerations

• Monitor complete blood counts regularly to detect cytopenias 3
• Check liver function tests periodically 1, 3
• Patients should be counseled that response may take several months to develop 2, 4
• A trial of at least 4 months is recommended before determining treatment failure 2
• Consider testing for thiopurine methyltransferase deficiency in patients who develop significant cytopenias 1

Azathioprine remains a valuable option in the ITP treatment armamentarium, particularly in resource-limited settings or for patients who cannot access or tolerate newer therapies, though its slow onset of action must be considered when selecting treatment for patients requiring more rapid platelet count increases 1, 4.