Baricitinib in Combination with High-Dose Dexamethasone As First-Line Treatment for Newly Diagnosed Immune Thrombocytopenia: A Prospective, Multicenter, Randomized Trial

Abstract

Introduction: High-dose dexamethasone is among the standard initial therapeutic options for patients with newly diagnosed immune thrombocytopenia (ITP). Although most patients achieve initial remission, optimal first-line therapy remains a challenge due to the low rates of sustained response and the high incidence of corticosteroid-dependency. Antiplatelet autoantibodies and splenic macrophages play central roles in the pathogenesis of ITP. Baricitinib, a Janus-associated kinase 1/2 (JAK1/2) inhibitor, can inhibit antigen presentation by innate immune cells and subsequent T-cell activation while also alleviating B-cell abnormalities and antibody production. The results of our single-arm pilot study suggested that baricitinib might increase the rate of durable response in patients with steroid-resistant or relapsed ITP (NCT05446831, presented at EHA2023, P1594). Accordingly, we further conducted a randomized, controlled trial to evaluate the efficacy and safety of baricitinib plus high-dose dexamethasone as first-line therapy for adulthood ITP. Methods: This multicenter, open-label, randomized, controlled, phase 2 trial was conducted in 10 different tertiary medical centers in China. Adult patients with newly diagnosed, treatment-naïve, confirmed primary ITP who had a platelet count <30×10⁹/L, or a platelet count <50×10⁹/L with clinically significant bleeding, were eligible for this study. Patients were randomly assigned at a 1:1 ratio to receive baricitinib (2 mg daily for 6 consecutive months) plus high-dose dexamethasone (40 mg daily for 4 consecutive days, repeated in the case of lack of response by Day 10) or high-dose dexamethasone alone. The primary endpoint was durable response at the 6-month follow-up. Efficacy endpoints were analyzed in the intention-to-treat population. Safety profiles were analyzed in all patients receiving at least one dose of study medications. The study protocol was approved by the ethics committee or institutional review board of each participating center and was registered with ClinicalTrials.gov (NCT 05932524). Results: A total of 172 patients were screened, of which 132 patients were eligible for this study. Patients were randomly assigned to receive baricitinib plus high-dose dexamethasone (n=66) or high-dose dexamethasone monotherapy (n=66). Four patients did not receive allocated treatment, leaving 128 patients in the safety analysis set. At the 6-month follow-up, a significantly higher proportion of participants in the baricitinib plus high-dose dexamethasone group (42/66, 63.6%) than in the high-dose dexamethasone monotherapy group (25/66, 37.9%) achieved durable response (OR 2.870, 95% CI 1.416-5.816; p=0.003). Initial response was achieved by 52 (78.8%) patients in the combination group and 47 (71.2%) patients in the monotherapy group. No significant difference was observed in the median time from initial treatment to response between the two groups. Complete response (at any time during the treatment) was achieved by 40 (60.6%) patients in the combination group and 35 (53.0%) patients in the monotherapy group. Patients responding to treatment in the combination group showed significantly longer durations of response than responders in the monotherapy group. Patients in both groups reported significantly improved health-related quality of life. The most common adverse events were infections (15/64, 23.4%) and insomnia (12/64, 18.8%) in the combination group, and insomnia (10/64, 15.6%) and anxiety or mood disorders (9/64, 14.1%) in the monotherapy group. No grade 4 or worse adverse events or treatment-related deaths were reported in either group. No thrombotic events, major adverse cardiovascular events (MACE), treatment-related bleeding or anemia were observed. Treatment discontinuation due to an adverse event was reported in 2 (3.1%) patients in the combination group and 3 (4.7%) patients in the monotherapy group. Conclusions: This is the first study reporting JAK inhibition as a first-line therapy for ITP. Baricitinib at 2 mg daily plus high-dose dexamethasone was well tolerated in patients with newly diagnosed ITP and might contribute to achieving a higher rate of durable response.