Venetoclax plus dose-adjusted R-EPOCH for Richter syndrome
Venetoclax plus dose-adjusted R-EPOCH for Richter syndrome
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DOI：
10.1182/blood.2021011386
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发表时间：
2022-02-03
期刊：
影响因子：
20.3
通讯作者：
Brown, Jennifer R.
中科院分区：
文献类型：
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作者：
Davids, Matthew S.;Rogers, Kerry A.;Brown, Jennifer R.
慢性淋巴细胞白血病（CLL）的Richter综合征（RS）是典型的化疗耐药，预后差。我们假设口服Bcl-2抑制剂venetoclax可以使RS对化学免疫治疗敏感并改善预后。我们进行了一项单组、制药商申办的2期试验，研究维奈托克加剂量调整的利妥昔单抗、依托泊苷、泼尼松、长春新碱、环磷酰胺和多柔比星（VR-EPOCH），以确定完全缓解（CR）率。患者接受R-EPOCH治疗1个周期，然后在计数恢复后，每日加速递增至400 mg，然后再接受VR-EPOCH治疗5个21天周期。应答者在研究结束后接受维奈托克维持治疗或细胞治疗。26例患者接受了治疗，其中13例（50%）达到CR，11例达到CLL的不可检测的骨髓微小残留病。另外3名患者获得部分缓解（总缓解率为62%）。中位无进展生存期为10.1个月，中位总生存期为19.6个月。血液学毒性包括≥ 3级中性粒细胞减少（65%）和血小板减少（50%），发热性中性粒细胞减少（38%）。每日递增维奈托克剂量时，无患者发生肿瘤溶解综合征。VR-EPOCH在RS中有效，比历史方案具有更深、更持久的反应。观察强化免疫化疗和维奈托克的毒副反应。我们的数据表明，研究比较venetoclax与化学免疫治疗单独化疗是必要的。
Richter syndrome (RS) of chronic lymphocytic leukemia (CLL) is typically chemoresistant, with a poor prognosis. We hypothesized that the oral Bcl-2 inhibitor venetoclax could sensitize RS to chemoimmunotherapy and improve outcomes. We conducted a single-arm, investigator-sponsored, phase 2 trial of venetoclax plus dose-adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (VR-EPOCH) to determine the rate of complete response (CR). Patients received R-EPOCH for 1 cycle, then after count recovery, accelerated daily venetoclax ramp-up to 400 mg, then VR-EPOCH for up to 5 more 21-day cycles. Responders received venetoclax maintenance or cellular therapy off-study. Twenty-six patients were treated, and 13 of 26 (50%) achieved CR, with 11 achieving undetectable bone marrow minimal residual disease for CLL. Three additional patients achieved partial response (overall response rate, 62%). Median progression-free survival was 10.1 months, and median overall survival was 19.6 months. Hematologic toxicity included grade >= 3 neutropenia (65%) and thrombocytopenia (50%), with febrile neutropenia in 38%. No patients experienced tumor lysis syndrome with daily venetoclax ramp-up. VR-EPOCH is active in RS, with deeper, more durable responses than historical regimens. Toxicities from intensive chemoimmunotherapy and venetoclax were observed. Our data suggest that studies comparing venetoclax with chemoimmunotherapy to chemoimmunotherapy alone are warranted.