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

Role of Azathioprine in Refractory ITP

Azathioprine should be considered as a second-line therapy option for refractory ITP patients who have failed first-line treatments (corticosteroids) or splenectomy, with an expected complete response rate of approximately 45% when administered at 150 mg/day for a median of 18 months. 1

Positioning in Treatment Algorithm

Azathioprine is classified as a second-line therapy alongside rituximab, splenectomy, and thrombopoietin receptor agonists. 1 However, the 2010 international consensus guidelines from Blood notably position azathioprine primarily as part of combination chemotherapy regimens rather than as monotherapy for third-line treatment in patients failing both first- and second-line approaches. 2

When to Use Azathioprine

• Consider azathioprine after failure of corticosteroids or when splenectomy has failed or is contraindicated. 1, 3
• Azathioprine represents a particularly valuable option in resource-limited settings where TPO receptor agonists (eltrombopag, romiplostim) are cost-prohibitive. 1
• The drug is one of the few ITP medications considered relatively safe in pregnancy with no increased fetal malformation rate, and is safe during lactation. 1

Dosing and Administration

Standard dosing is 1-2 mg/kg daily (maximum 150 mg/day). 1 In clinical practice:

• Start with 150 mg/day orally, which can be adjusted based on response and tolerability. 3
• Some protocols begin at 1 mg/kg/day (50-100 mg) and titrate up to 2 mg/kg/day depending on response. 4
• Screen for thiopurine methyltransferase (TPMT) deficiency if cytopenias develop, as approximately 0.25% of the population lacks this enzyme. 1

Expected Response and Timeline

Response Rates

• Complete response (platelet count >100,000/μL) occurs in approximately 45% of patients. 1, 3
• Overall response rates (including partial responses) range from 38-64% across studies. 4, 3
• Up to two-thirds of patients may show some response to therapy. 1

Time to Response

Response to azathioprine is characteristically slow, requiring 3-6 months of continuous administration before determining efficacy. 1 Specific timelines include:

• Median time to response is approximately 4 months (range 3-6 months). 3
• In one study, median time to response was 95 days with cumulative overall response rate of 38.1% at day 90. 4
• A minimum 4-month trial is required before concluding treatment failure. 3

Duration of Response

• Of patients achieving complete remission, responses can persist for 7-182 months. 3
• Approximately 40% of responders maintain response for 1 year or more, and 32% for 2 years or more. 3
• The cumulative relapse rate at 5 years is approximately 21.2%. 4
• Some patients (approximately 10 of 24 complete responders in one series) maintain remission even after azathioprine discontinuation. 3

Maintenance Therapy

Although continued therapy is generally required to maintain response, often a reduced dose suffices. 1 In practice:

• Median treatment duration is 18 months (range 3-84 months). 3
• Patients who achieve response may continue azathioprine for a median of approximately 1067 days (range 236-2465 days) before attempting discontinuation. 4
• Seven of 24 complete responders relapsed after azathioprine was stopped or dose reduced, suggesting need for prolonged therapy in many patients. 3

Safety Profile

Azathioprine has a relatively favorable safety profile with generally mild side effects, particularly compared to other immunosuppressive options. 1

Common Adverse Effects

• Leucopenia is the most frequent adverse event, followed by anemia. 4
• Hepatobiliary laboratory abnormalities (transaminase elevations up to 3x normal) occur in some patients. 1, 3
• Weakness and sweating are reported constitutional symptoms. 1
• Overall, 41% of patients report one or more adverse events. 4

Serious Adverse Events

• Serious adverse events (grade ≥3) occur in approximately 4.7% of patients. 4
• Unlike cyclophosphamide, leukemia has only rarely been associated with azathioprine in other disorders and has not been described in ITP patients. 1
• No opportunistic infections were observed in one large series of 53 patients. 3
• Mortality from bleeding while on treatment has been reported (5 of 53 patients in one series), though this reflects disease severity rather than drug toxicity. 3

Combination Therapy Approach

For patients failing both first- and second-line monotherapies, azathioprine can be incorporated into combination chemotherapy regimens. 2 The international consensus guidelines describe:

• Combination of cyclophosphamide (100-200 mg/day IV) on days 1-5 or 7, prednisone (0.5-1.0 mg/kg orally daily) on days 1-7, vincristine (1-2 mg IV) on day 1, and azathioprine (100 mg orally daily) on days 1-5 or 7. 2
• This combination achieved 68% overall response rate including 42% complete response in 31 patients, with therapy being well tolerated. 2
• Triple immunosuppression with azathioprine, mycophenolate mofetil, and cyclosporine achieved 73.7% response rate in highly refractory patients who had failed a median of 6 prior treatments. 5

Critical Pitfalls to Avoid

• Do not discontinue azathioprine before 4 months of therapy, as responses are characteristically delayed. 3
• Do not use azathioprine as first-line monotherapy when TPO receptor agonists are available and accessible, as these have superior response rates (70-88%) and faster time to response (1-4 weeks). 2
• Monitor complete blood counts regularly for leucopenia and liver function tests for hepatotoxicity. 4, 3
• Consider TPMT testing before initiation or if unexpected cytopenias develop. 1

Comparison to Other Third-Line Options

When azathioprine is considered in the context of other refractory ITP treatments:

• TPO receptor agonists (eltrombopag, romiplostim) have superior response rates (70-88%) and faster response times (1-4 weeks) but require continuous administration and are significantly more expensive. 2
• Campath-1H achieves 67% initial response but all but one patient relapsed within 24 months, and it carries risk of severe immunosuppression. 2
• Combination chemotherapy achieves similar response rates (68%) but carries risk of secondary malignancies. 2
• Azathioprine monotherapy offers a more favorable safety profile than these alternatives, making it particularly suitable for patients requiring long-term therapy. 1, 3