In the literature there are numerous options for the treatment of ITP.54,55 Most of these studies are anecdotal, enrolled small number of patients, and sometimes included patients with mild thrombocytopenia, but these therapeutic options can be tried in patients who are refractory to standard therapies and have bleeding. The agents with the greatest amount of supporting data are danazol, vincristine, azathioprine, cyclophosphamide, and fostamatinib.
Danazol 200 mg 4 times daily is thought to downregulate the macrophage Fc receptor. The onset of action may be delayed and a therapeutic trial of up to 4 to 6 months is advised. Danazol is very effective in patients with antiphospholipid antibody syndrome who develop ITP and may be more effective in premenopausal women.56 Once a response is seen, danazol should be continued for 6 months and then an attempt to wean the patient off the agent should be made. A partial response can be seen in 70% to 90% of patients, but a complete response is rare.54
Vincristine 1.4 mg/m2 weekly has a low response rate, but if a response is going to occur, it will occur rapidly within 2 weeks. Thus, a prolonged trial of vincristine is not needed; if no platelet rise is seen in several weeks, the drug should be stopped. Again, partial responses are more common than complete response—50% to 63% versus 0% to 6%.54Azathioprine 150 mg orally daily, like danazol, demonstrates a delayed response and requires several months to assess for response. However, 19% to 25% of patients may have a complete response.54 It has been reported that the related agent mycophenolate 1000 mg twice daily is also effective in ITP.57
Cyclophosphamide 1 g/m2 intravenously repeated every 28 days has been reported to have a response rate of up to 40%.58 Although considered more aggressive, this is a standard immunosuppressive dose and should be considered in patients with very low platelet counts. Patients who have not responded to single-agent cyclophosphamide may respond to multi-agent chemotherapy with agents such as etoposide and vincristine plus cyclophosphamide.59
Fostamatinib, a spleen tyrosine kinase (SYK) inhibitor, is currently under investigation for the treatment of ITP.60 This agent prevents phagocytosis of antibody-coated platelets by macrophages. In early studies fostamatinib has been well tolerated at a dose of 150 mg twice daily, with 75% of patients showing a response. Large phase 3 trials are underway, and if the earlier promising results hold up fostamatinib may be a novel option for refractory patients.
A Practical Approach to Refractory ITP
One approach is to divide patients into bleeders, or those with either very low platelet counts (< 5 × 103/µL) or who have had significant bleeding in the past, and nonbleeders, or those with platelet counts above 5 × 103/µL and no history of severe bleeding. Bleeders who do not respond adequately to splenectomy should first start with rituximab since it is not cytotoxic and is the only other “curative” therapy (Table 2).
Patients who do not respond to rituximab should then be tried on TPO-RAs. Patients who are unresponsive to these agents and still have severe disease with bleeding should receive aggressive therapy with immunosuppression. One approach to consider is bolus cyclophosphamide. If this is unsuccessful, then using a combination of azathioprine plus danazol can be considered. Since this combination may take 4 to 6 months to work, these patients may need frequent IVIG infusions to maintain a safe platelet count.
Nonbleeders should be tried on danazol and other relatively safe agents. If this fails, rituximab or TPO-RAs can be considered. Before one considers cytotoxic therapy, the risk of the therapy must be weighed against the risk posed by the thrombocytopenia. The mortality from ITP is fairly low (5%) and is restricted to patients with severe disease. Patients with only moderate thrombocytopenia and no bleeding are better served with conservative management. There is little justification for the use of continuous steroid therapy in this group of patients given the long-term risks of this therapy.
Special Situations
Surgery
Patients with ITP who need surgery either for splenectomy or for other reasons should have their platelet counts raised to a level greater than 20 to 30 × 103/µL before surgery. Most patients with ITP have increased platelet function and will not have excessive bleeding with these platelet counts. For patients with platelet counts below this level, an infusion of immune globulin or anti-D may rapidly increase the platelet counts. If the surgery is elective, short-term use of TPO-RAs to raise the counts can also be considered.
