Sirolimus Combined Dexamethasone As the First-Line Therapy for Newly Diagnosed Adult Primary Immune Thrombocytopenia: A Multicenter, Open-Label, Prospective, Randomized Controlled Clinical Trial
Authors: Feng Yimei , Zeng Hanqing , Liao Yi , Yang Yi , Yu Wenzheng , Yuan Changyong , Li Guojun , Liu Zhanshu , Shu Huae , Zhang Guoxiang , Feng Yaqing , Peng Chunfang , Chen Xiaoli , Liu Jia , Yao Han , Hou Ming , Zhang Xi 
Published: December 2024

Background and purpose ：
Immune thrombocytopenia (ITP) is an acquired platelet disorder characterized by immune-mediated platelet destruction and impaired platelet production. The first-line treatment recommended for ITP is steroids, but their numerous side effects and high relapse rate are serious drawbacks. Approximately half of newly diagnosed ITP patients experience a relapse within 6 months of steroid treatment, highlighting the need for further exploration on reducing relapse rates. Sirolimus (SRL) is a mammalian target of rapamycin inhibitor (mTORi) that has been shown to induce apoptosis of both activated and irregular lymphocytes to promote tolerance. Recently, increasing reports highlight the use of mTORi for immune hematological diseases, including ITP. Here, we present the preliminary results of the first prospective, multicenter, randomized, controlled trial comparing the efficacy and safety of steroids (high-dose dexamethasone, HD-DXM) versus sirolimus combined HD-DXM as first-line treatment in adults with newly diagnosed primary ITP.
Methods:
This multicenter, randomized, open-label, clinical trial was done in 13 medical hospitals in China. Eligible patients were aged 18 years or older with newly diagnosed, treatment-naive primary immune thrombocytopenia. Participants were randomly assigned (1:1) to receive either dexamethasone (orally at 40 mg per day for 4 days) plus sirolimus (orally at 2 mg once a day for 3 months, targeted a plasma concentration of 5-15 ng/ml in circulation) (called experimental group) or dexamethasone monotherapy (orally at 40 mg a day for 4 days) (called control group). Patients who did not respond to treatment (platelet counts remained &lt;30 × 10⁹/L) were given an additional cycle of dexamethasone for 4 days in each group. The coprimary endpoints were 14-day initial overall response, 3-month and 6-month overall response. Complete response was defined as a platelet count at or above 100 × 10⁹ /L. Partial response was defined as a platelet count at or above 30 × 10⁹/L-100 × 10⁹ /L and at least a doubling of the baseline platelet count and an absence of bleeding. A response lasting for at least 6 months without any additional primary immune thrombocytopenia specific intervention was defined as sustained response. This study is registered with Chinese Clinical Trial Registry (Number ChiCTR1900020657).
Results:
30 patients in the HD-DXM plus sirolimus arm and 30 patients in the HD-DXM monotherapy arm were included in the full analysis set. At the second week after treatment, HD-DXM plus sirolimus resulted in a higher incidence of initial response (66.7% vs 51.7%, P=0.243) and complete response (CR, 40.0% vs 20.7%, P=0.107) compared with corticosteroids monotherapy, but without statistical differences. At 3 months, the response rate was significantly higher in the HD-DXM combined sirolimus group compared to the HD-DXM monotherapy group (ORR: 57.1% Vs 24.1%, P=0.011; CR 35.7% Vs 10.3%, P=0.022). The response rate at 6 months was also higher in the HD-DXM combined sirolimus group compared to the HD-DXM monotherapy group (46.4% vs 17.2%, P=0.018; sustained CR: 28.6% vs 10.3%, P=0.081).
The study drugs were generally well tolerated. The top three adverse reactions of the sirolimus group are abnormal blood lipids (26.7%), oral ulcers (10%), and upper respiratory tract infections (6.7%), while the top three adverse reactions of the hormone group are palpitations (23.3%), gastrointestinal discomfort (23.3%), and insomnia (13.3%). It can be seen that the treatment responses of the two groups decrease with the prolonging of drug withdrawal time (including ORR and CR rates), indicating that some ITP patients may require continuous drug therapy. For example, choosing a safe drug with few side effects, such as sirolimus, may achieve long-term sustained response. This needs further clinical research to confirm.
Conclusions: Sirolimus combined corticosteroids significantly improved the initial response and yielded favorable sustained response in newly diagnosed ITP patients, thus could be further validated as a frontline treatment for ITP.