S299: orelabrutinib, an irreversible inhibitor of bruton’s tyrosine kinase, for treatment of primary immune thrombocytopenia: results of a randomized, open-label phase ii study

Topic: 33. Bleeding disorders (congenital and acquired) Background: Orelabrutinib is an oral, highly-selective, irreversible inhibitor of Bruton’s Tyrosine Kinase (BTK). Orelabrutinib has been approved for the treatment of B cell malignancies in China. Preclinical study showed that orelabrutinib suppressed the activation and differentiation of B cells, and increased the platelet count in active Immune Thrombocytopenia (ITP) murine models. Aims: This ongoing randomized, open-label phase II study is aiming to evaluate the efficacy, safety and tolerability of orelabrutinib in patients with persistent or chronic primary ITP. Methods: Eligible patients who did not respond to or relapsed after or could not tolerate first-line therapy including glucocorticoids (GC) or intravenous immunoglobulin (IVIG) were randomized 1:1 to receive oral orelabrutinib 50mg or 30mg once daily for 24 weeks. If the platelet count was lower than 50×109/L without safety issue at Week 4, intra-patient daily dose escalation from 30mg to 50mg was allowed. The primary endpoint was the percentage of patients who achieved at least two consecutive platelet counts ≥50x109/L without rescue medication in the 4 weeks before the elevated platelet count. Results: As of cut-off date on 6 Feb 2023, 33 patients were randomized to 50mg arm (n=15) and 30mg arm (n=18), respectively with median treatment time of 13.7 weeks (range, 2.9-50.1). Among the 30mg arm, 12 patients were transferred from 30mg to 50mg after Week 4 due to no primary response. At baseline, the mean age was 41.9 years and 63.6% were female. The mean platelet count was 13.4±10.54x109/L and patients had received a median of 5 different prior ITP therapies (range, 1-12) with mean disease duration of 8.2 years. Overall 36.4% (12/33) patients met the primary endpoint, 40% (6/15) at the 50mg arm, 22.2% (4/18) at the 30mg arm, and 2 patients reached primary endpoint after transferring to 50mg. Total 27.3% (9/33) patients achieved durable response defined as the percentage of patients with platelet count ≥50x109/L for at least 4 of the 6 visits between 14-24 weeks without rescue medication within 4 weeks before the elevated platelet count. The data from 22 patients with previous response to GC or IVIG were analyzed as a sub-group: 75.0% (6/8) at the 50mg arm and 28.6% (4/14) at the 30mg arm achieved the primary endpoint. The durable response rate was 50% (4/8) at the 50mg arm and 21.4% (3/14) at the 30mg arm, respectively. Among 12 patients with primary endpoint response, 81.8% (9/11) patients achieved durable response and 1 patient who received only 8 weeks treatment by cutoff but had 8 consecutive platelet counts≥50x109/L. The median time to the first platelet count of ≥50x109/L was 9.0 days (range, 7-156) with initial 50mg dose, and 43.0 days (range, 7-128) with initial 30mg dose. A total of 28.1% of patients experienced at least one treatment related adverts events (TRAE), all of which were grade 1 or 2. There was no treatment-related bleeding or thrombotic events. No grade 3 or higher TRAE, serious TRAE and death were reported. There was no TRAE leading to drug discontinuation. Summary/Conclusion: Both 50mg QD and 30mg QD of orelabrutinib were safe in the treatment of patients with ITP. Generally, orelabrutinib 50mg QD responded rapidly with better efficacy, especially in those who had responded to previous GC/IVIG therapies. Figure:Keywords: B cell, Platelet count, Immune thrombocytopenia (ITP), Treatment