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)。