Immune thrombocytopenia purpura (ITP) is an acquired autoimmune condition characterized both by peripheral platelet destruction and reduced platelet production. In adulthood, ITP is typically a relapsing and remitting condition, with only 20 to 45 percent of adults achieving complete remission by six months with current therapies.1 Only approximately 20 percent of patients receiving glucocorticoids alone will achieve a durable remission.2 Patients frequently require multiple phases of therapy during their disease course. Consequently, efforts to improve ITP therapy must address both initial therapies and second- or third-line therapies.
The ASH 2019 Guidelines for ITP make recommendations regarding treatment for both newly diagnosed and relapsed ITP.3 For front-line therapy of ITP (newly diagnosed ITP with platelets < 30 × 109/L), the ASH panel suggests that corticosteroids be used as the initial therapeutic agent. The course of steroids should be limited to six weeks or less, and either prednisone 0.5 to 2.0 mg/kg/day or dexamethasone 40 mg daily for four days may be used. Corticosteroids should be used alone rather than in combination with rituximab.4 Meanwhile, for patients who require second-line therapy for chronic ITP, the panel suggests the use of splenectomy, thrombopoietin receptor agonist (TPO-RA), or rituximab. There is a suggestion that splenectomy be delayed by at least one year after diagnosis due to the potential for spontaneous remission within the first year.
Within the past 18 months, there have been emerging data that have implications for both front-line and second-line ITP therapy. Regarding front-line therapy, the FLIGHT study was recently published comparing the addition of mycophenolate mofetil (MMF) to corticosteroids versus corticosteroids alone.5 In this multicenter, open-label randomized trial in the United Kingdom, 120 patients with newly diagnosed ITP were randomized to MMF plus corticosteroids (prednisone or dexamethasone) versus corticosteroids alone. MMF was started at 500 mg twice daily and titrated up to 1,000 mg twice daily for at least six months before the dose was reduced by 250 mg each month to achieve the lowest dose to maintain platelets of greater than 30 × 109/L. The primary outcome was treatment failure, defined as platelet count less than 30 × 109/L and initiation of a second-line therapy, and patients were observed for at least 12 months.
The investigators found that the addition of mycophenolate led to significantly fewer treatment failures (22% vs. 44%; HR, 0.41; 95% CI, 0.21-0.80; p=0.008), and a greater complete response rate (patients achieving platelets > 100 × 109/L; 91% vs. 64%; p<0.001). There was no difference in bleeding, rescue hemostatic therapy, or infection. However, patients receiving MMF reported significantly lower physical function and greater fatigue on validated scales including SF-36, ICECAP-A, and FACTI-F.
Meanwhile, regarding second-line therapy, fostamatinib was recently studied (2019) with additional post-hoc data published this year.6 Fostamatinib is a spleen tyrosine kinase (syk) inhibitor that has been approved for the treatment of chronic ITP in patients. It was approved based on data pooled from two industry-sponsored phase III randomized trials in which a total of 150 patients were randomized (2:1) to fostamatinib or placebo.7,8 These patients were mostly heavily pretreated, with a median duration of 8.5 years since ITP diagnosis, and most patients received three or more lines of prior therapy. In this study, 44 percent of patients had an overall response (OR; any platelet counts greater than 50 × 109/L within 12 weeks) but only 18 percent had a stable response (platelets greater than 50 × 109/L for at least 4-6 weeks). However, median duration of response in stable responders was greater than 28 months. A post-hoc analysis completed in 2020 demonstrated that fostamatinib was more likely to be effective when used as second-line therapy (after steroids and/or intravenous immunoglobulin, 78% OR rate) compared with when it was used as third- or fourth-line therapy (48% OR).9
How should these data influence practice? The front-line data regarding MMF are compelling, with MMF being a steroid-sparing agent that appears to improve OR and reduce the development of refractory or relapsed ITP necessitating subsequent lines of therapy by about half. However, this needs to be balanced by the somewhat surprising finding of a reduction in patient-reported quality-of-life measures in those receiving MMF, even without differences in common MMF-related adverse effects (infection, diarrhea). The authors posited that this may have been due to the psychological burden of adding an additional therapy. In my own practice, I will not yet be adding MMF routinely to front-line therapy for ITP until seeing additional real-world experiences with this regimen, particularly with respect to its effect on quality of life and longer-term data on relapse rates beyond 12 to 24 months. However, I eagerly await additional data.
Similarly, for second-line treatment, the fostamatinib response rates are not sufficiently compelling at this stage, and I will continue to look to rituximab, TPO-RAs, and splenectomy as second-line therapies as per the current ASH guidelines. However, this novel agent does hold promise as an option for those patients who have had refractory ITP despite multiple lines of therapy, as almost half of such patients did respond to fostamatinib, and those who responded had quite a durable remission.
In summary, in the past 18 months there have been emerging data regarding front-line therapy using an old drug (MMF), and second-line therapy with a new drug (fostamatinib). While neither are sufficiently compelling at this moment to routinely change clinical practice or guidelines, more real-world data would be valued because there are likely to be specific scenarios in which they could be helpful. I congratulate the authors for completing these important studies.
Dr. Tseng indicated no relevant conflicts of interest.