TP53-mutant mantle cell lymphoma (MCL) is associated with poor survival outcomes with standard chemoimmunotherapy. Dual Bruton tyrosine kinase and BCL2-inhibition with or without anti-CD20 monoclonal antibody therapy has shown promising activity in TP53-mutant MCL. We conducted a multicenter, phase 2 study of zanubrutinib, obinutuzumab, and venetoclax (BOVen) in untreated patients with MCL with a TP53 mutation. Patients initially received 160 mg zanubrutinib twice daily and obinutuzumab. Obinutuzumab at a dose of 1000 mg was given on cycle 1 day 1, 8, and 15, and on day 1 of cycles 2 to 8. After 2 cycles, venetoclax was added with weekly dose ramp-up to 400 mg daily. After 24 cycles, if patients were in complete remission with undetectable minimal residual disease (MRD) using an immunosequencing assay, treatment was discontinued. The primary end point was met if ≥11 patients were progression free at 2 years. The study included 25 patients with untreated MCL with a TP53 mutation. The best overall response rate was 96% (24/25) and the complete response rate was 88% (22/25). Frequency of undetectable MRD (uMRD) at a sensitivity level of 1 × 10–5 and uMRD at a sensitivity level of 1 × 10–6 at cycle 13 was 95% (18/19) and 84% (16/19), respectively. With a median follow-up period of 28.2 months, the primary end point was met with a 2-year progression-free survival of 72%, and the 2-year disease-specific and overall survival were 91% and 76%, respectively. Common side effects were generally low grade and included diarrhea (64%), neutropenia (32%), and infusion-related reactions (24%). BOVen was well tolerated and met its primary efficacy end point in TP53-mutant MCL. These data support its use and further evaluation of the BOVen regimen in this high-risk population. This trial was registered at www.ClinicalTrials.gov as #NCT03824483.

中文翻译：

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Zanubrutinib、obinutuzumab 和 venetoclax 用于 TP53 突变套细胞淋巴瘤的一线治疗


TP53 突变套细胞淋巴瘤 （MCL） 与标准化学免疫疗法的不良生存结果相关。双重布鲁顿酪氨酸激酶和 BCL2 抑制联合或不联合抗 CD20 单克隆抗体治疗在 TP53 突变型 MCL 中显示出有希望的活性。我们在 TP53 突变的未经治疗的 MCL 患者中进行了 zanubrutinib 、 obinutuzumab 和 venetoclax （BOVen） 的多中心 2 期研究。患者最初接受 160 mg zanubrutinib 每日 2 次和 obinutuzumab。剂量为 1000 mg 的 Obinutuzumab 在第 1 周期的第 1 天、第 8 天和第 15 天以及第 2 至 8 周期的第 1 天给药。2 个周期后，加入维奈托克，每周剂量增加至每天 400 毫克。24 个周期后，如果患者完全缓解且使用免疫测序测定检测不到微小残留病 （MRD），则停止治疗。如果 ≥11 例患者在 2 年时无进展，则达到主要终点。该研究包括 25 名未经治疗的 TP53 突变 MCL 患者。最佳总缓解率为 96% （24/25），完全缓解率为 88% （22/25）。在第 13 周期，灵敏度水平为 1 × 10-5 的检测不到的 MRD （uMRD） 的频率和灵敏度水平为 1 × 10-6 的 uMRD 的频率分别为 95% （18/19） 和 84% （16/19）。中位随访期为 28.2 个月，达到主要终点的 2 年无进展生存率为 72%，2 年疾病特异性生存率和总生存率分别为 91% 和 76%。常见的副作用通常是低度的，包括腹泻 （64%） 、中性粒细胞减少 （32%） 和输液相关反应 （24%）。BOVen 耐受性良好，并在 TP53 突变 MCL 中达到其主要疗效终点。这些数据支持其在该高危人群中使用和进一步评估 BOVen 方案。 该试验在 www.ClinicalTrials.gov 注册为 #NCT03824483。