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Abstract：
Tirabrutinib is a second-generation Bruton\'s tyrosine kinase inhibitor with greater selectivity than ibrutinib. Here, we conducted a multicenter, phase II study of tirabrutinib in patients with treatment-naïve (Cohort A) or with relapsed/refractory (Cohort B) Waldenström\'s macroglobulinemia (WM). Patients were treated with tirabrutinib 480 mg once daily. The primary endpoint was major response rate (MRR; ≥ partial response). Secondary endpoints included overall response rate (ORR; ≥ minor response), time to major response (TTMR), progression-free survival (PFS), overall survival (OS), and safety. In total, 27 patients (18 in Cohort A; 9 in Cohort B) were enrolled. The median age was 71 y, and the median serum immunoglobulin M level was 3600 mg/dL. Among the patients, 96.2% had the MYD88L265P mutation. MRR and ORR were 88.9% and 96.3%, respectively (Cohort A: MRR, 88.9%; ORR, 94.4%; Cohort B: MRR, 88.9%; ORR, 100%). Median TTMR was 1.87 mo. PFS and OS were not reached with a median follow-up of 6.5 and 8.3 mo for Cohorts A and B, respectively. The most common adverse events (AEs) were rash (44.4%), neutropenia (25.9%), and leukopenia (22.2%), with most AEs classified as grade 1 or 2. Grade ≥ 3 AEs included neutropenia (11.1%), lymphopenia (11.1%), and leukopenia (7.4%). No grade 5 AEs were noted. All bleeding events were grade 1; none were associated with drug-related atrial fibrillation or hypertension. Although the follow-up duration was relatively short, the study met the primary endpoint. Therefore, tirabrutinib monotherapy is considered to be highly effective for both untreated and relapsed/refractory WM with a manageable safety profile. (JapicCTI-173646).
摘要：
Tirabrutinib是第二代Bruton的酪氨酸激酶抑制剂，具有比ibrutinib更大的选择性。这里,我们进行了一个多中心，替拉鲁替尼治疗初治(队列A)或复发/难治性(队列B)瓦尔登斯特伦巨球蛋白血症(WM)患者的II期研究。患者每天一次用替拉鲁替尼480mg治疗。主要终点是主要反应率（MRR；≥部分反应）。次要终点包括总反应率（ORR；≥轻微反应），主要响应时间（TTMR），无进展生存期（PFS），总生存期（OS），和安全。总的来说,纳入27例患者(队列A中18例;队列B中9例)。平均年龄为71岁，中位血清免疫球蛋白M水平为3600mg/dL。在患者中,96.2%有MYD88L265P突变。MRR和ORR分别为88.9%和96.3%,分别(队列A：MRR，88.9%；ORR，94.4%；队列B：MRR，88.9%；ORR，100%）。TTMR中位数为1.87个月。队列A和B的中位随访时间为6.5和8.3mo，未达到PFS和OS，分别。最常见的不良事件（AE）是皮疹（44.4%），中性粒细胞减少症（25.9%），和白细胞减少症（22.2%），大多数AE被归类为1级或2级。≥3级不良事件包括中性粒细胞减少症（11.1%），淋巴细胞减少（11.1％），和白细胞减少(7.4%)。没有发现5级AE。所有出血事件均为1级，无一例与药物相关的房颤或高血压相关。虽然随访时间相对较短,该研究达到了主要终点.因此,替拉鲁替尼单药治疗被认为对未治疗和复发/难治性WM非常有效,且安全性可控.（JapicCTI-173646）。
