Abstract：
BACKGROUND: Patients with newly diagnosed high-risk Burkitt lymphoma are treated with high-intensity immune-chemotherapy regimens such as R-CODOX-M/R-IVAC or with lower-intensity regimens such as DA-EPOCH-R. The aim of this study was to make a formal comparison between these regimens.
METHODS: This multicentre, phase 3, open-label, randomised study was done in 26 clinical centres in the Netherlands, Belgium, and Switzerland. Eligible patients were aged 18-75 years with newly diagnosed high-risk Burkitt lymphoma without CNS involvement. Patients were randomly assigned to two cycles of R-CODOX-M/R-IVAC (R-CODOX-M: rituximab 375 mg/m2 on day 1 and 9, cyclophosphamide 800 mg/m2 on day 1, cyclophosphamide 200 mg/m2 on days 2-5, vincristine 1·5 mg/m2 on days 1 and 8, doxorubicin 40 mg/m2 on day 1, and methotrexate 3000 mg/m2 on day 10; R-IVAC: rituximab 375 mg/m2 on days 3 and 7, iphosphamide 1500 mg/m2 on days 1-5, etoposide 60 mg/m2 on days 1-5, and cytarabin 2000 mg/m2 on day 1 and 2) or six cycles of DA-EPOCH-R (dose-adjusted etoposide 50-124 mg/m2 on days 1-4, prednisolone 120 mg/m2 on days 1-5, vincristine 0·4 mg/m2 on days 1-4, dose-adjusted cyclophosphamide 480-1866 mg/m2 on day 5, dose-adjusted doxorubicin 10-24·8 mg/m2 on days 1-4, rituximab 375 mg/m2 on days 1 and 5). Patients older than 65 years received a dose modified R-CODOX-M/R-IVAC. All drugs were intravenous except for prednisolone, which was oral. Patients also received four intrathecal CNS administrations with cytarabin (70 mg) and four with methotrexate (15 mg). Patients were stratified by centre, leukemic disease, and HIV-positivity. The primary endpoint was progression-fee survival. All analyses were done by modified intention-to-treat, excluding randomly assigned patients who were subsequently found to have CNS involvement or diagnosis other than Burkitt lymphoma at study entry. This study is registered with the European Clinical Trial Register, EudraCT2013-004394-27.
RESULTS: Due to a slow accrual, the study was closed prematurely on Nov 15, 2021. Between Aug 4, 2014, and Sept 17, 2021, 89 patients were enrolled and randomly assigned to receive R-CODOX-M/R-IVAC (n=46) or DA-EPOCH-R (n=43). Five patients were excluded after random assignment (three in the R-CODOX-M/R-IVAC group [one diagnosis other than Burkitt lymphoma at study entry according to local pathology and two CNS involvement] and two in the DA-EPOCH-R group [one diagnosis other than Burkitt lymphoma at study entry according to local pathology and one CNS involvement]. 84 remaining patients were included in the modified intention-to-treat analysis. 73 (87%) of 84 patients were male, 76 (90%) presented with stage III or IV disease, and nine (11%) had HIV-positive Burkitt lymphoma. Median patient age was 52 years (IQR 37-64). With a median follow-up of 28·5 months (IQR 13·2-43·7), 2-year progression-free survival was 76% (95% CI 60-86%) in the R-CODOX-M/R-IVAC group and 70% (54-82%) in the DA-EPOCH-R group (hazard ratio 1·42, 95% CI 0·63-3·18; p=0·40). There were two deaths in the R-CODOX-M/R-IVAC group (one infection [treatment related] and one due to disease progression [not treatment related]) and one death in the DA-EPOCH-R group (COVID-19 infection [treatment related]). In the R-CODOX-M/R-IVAC group, four patients went off-protocol because of toxic effects, versus none in the DA-EPOCH-R group. Patients treated with R-CODOX-M/R-IVAC had more infectious adverse events (24 [56%] of 43 patients had at least one grade 3-5 infection vs 14 [34%] of 41 patients in the DA-EPOCH-R group).
CONCLUSIONS: The trial stopped early, but the available data suggest that while DA-EPOCH-R did not result in superior progression-free survival compared with R-CODOX-M/R-IVAC, it was associated with fewer toxic effects and need for supportive care. DA-EPOCH-R appears to be an additional valid therapeutic option for patients with high-risk Burkitt lymphoma without CNS involvement.
BACKGROUND: The Dutch Cancer Society and the Schumacher-Kramer Foundation.
METHODS: This multicentre, phase 3, open-label, randomised study was done in 26 clinical centres in the Netherlands, Belgium, and Switzerland. Eligible patients were aged 18-75 years with newly diagnosed high-risk Burkitt lymphoma without CNS involvement. Patients were randomly assigned to two cycles of R-CODOX-M/R-IVAC (R-CODOX-M: rituximab 375 mg/m2 on day 1 and 9, cyclophosphamide 800 mg/m2 on day 1, cyclophosphamide 200 mg/m2 on days 2-5, vincristine 1·5 mg/m2 on days 1 and 8, doxorubicin 40 mg/m2 on day 1, and methotrexate 3000 mg/m2 on day 10; R-IVAC: rituximab 375 mg/m2 on days 3 and 7, iphosphamide 1500 mg/m2 on days 1-5, etoposide 60 mg/m2 on days 1-5, and cytarabin 2000 mg/m2 on day 1 and 2) or six cycles of DA-EPOCH-R (dose-adjusted etoposide 50-124 mg/m2 on days 1-4, prednisolone 120 mg/m2 on days 1-5, vincristine 0·4 mg/m2 on days 1-4, dose-adjusted cyclophosphamide 480-1866 mg/m2 on day 5, dose-adjusted doxorubicin 10-24·8 mg/m2 on days 1-4, rituximab 375 mg/m2 on days 1 and 5). Patients older than 65 years received a dose modified R-CODOX-M/R-IVAC. All drugs were intravenous except for prednisolone, which was oral. Patients also received four intrathecal CNS administrations with cytarabin (70 mg) and four with methotrexate (15 mg). Patients were stratified by centre, leukemic disease, and HIV-positivity. The primary endpoint was progression-fee survival. All analyses were done by modified intention-to-treat, excluding randomly assigned patients who were subsequently found to have CNS involvement or diagnosis other than Burkitt lymphoma at study entry. This study is registered with the European Clinical Trial Register, EudraCT2013-004394-27.
RESULTS: Due to a slow accrual, the study was closed prematurely on Nov 15, 2021. Between Aug 4, 2014, and Sept 17, 2021, 89 patients were enrolled and randomly assigned to receive R-CODOX-M/R-IVAC (n=46) or DA-EPOCH-R (n=43). Five patients were excluded after random assignment (three in the R-CODOX-M/R-IVAC group [one diagnosis other than Burkitt lymphoma at study entry according to local pathology and two CNS involvement] and two in the DA-EPOCH-R group [one diagnosis other than Burkitt lymphoma at study entry according to local pathology and one CNS involvement]. 84 remaining patients were included in the modified intention-to-treat analysis. 73 (87%) of 84 patients were male, 76 (90%) presented with stage III or IV disease, and nine (11%) had HIV-positive Burkitt lymphoma. Median patient age was 52 years (IQR 37-64). With a median follow-up of 28·5 months (IQR 13·2-43·7), 2-year progression-free survival was 76% (95% CI 60-86%) in the R-CODOX-M/R-IVAC group and 70% (54-82%) in the DA-EPOCH-R group (hazard ratio 1·42, 95% CI 0·63-3·18; p=0·40). There were two deaths in the R-CODOX-M/R-IVAC group (one infection [treatment related] and one due to disease progression [not treatment related]) and one death in the DA-EPOCH-R group (COVID-19 infection [treatment related]). In the R-CODOX-M/R-IVAC group, four patients went off-protocol because of toxic effects, versus none in the DA-EPOCH-R group. Patients treated with R-CODOX-M/R-IVAC had more infectious adverse events (24 [56%] of 43 patients had at least one grade 3-5 infection vs 14 [34%] of 41 patients in the DA-EPOCH-R group).
CONCLUSIONS: The trial stopped early, but the available data suggest that while DA-EPOCH-R did not result in superior progression-free survival compared with R-CODOX-M/R-IVAC, it was associated with fewer toxic effects and need for supportive care. DA-EPOCH-R appears to be an additional valid therapeutic option for patients with high-risk Burkitt lymphoma without CNS involvement.
BACKGROUND: The Dutch Cancer Society and the Schumacher-Kramer Foundation.
摘要：
背景：新诊断的高风险伯基特淋巴瘤患者接受高强度免疫化疗方案如R-CODOX-M/R-IVAC或低强度方案如DA-EPOCH-R。这项研究的目的是对这些方案进行正式比较。
方法：这个多中心，阶段3，开放标签，随机研究在荷兰的26个临床中心进行，比利时,和瑞士。符合条件的患者年龄为18-75岁，患有新诊断的高风险Burkitt淋巴瘤，无中枢神经系统受累。患者被随机分配到两个周期的R-CODOX-M/R-IVAC（R-CODOX-M：第1天和第9天的利妥昔单抗375mg/m2，第1天的环磷酰胺800mg/m2，第2-5天的环磷酰胺200mg/m2，第1天和第8天的长春新碱，第1天的多柔阿多柔霉素40mg/m2，第65岁以上的患者接受了剂量修改的R-CODOX-M/R-IVAC。除了泼尼松龙，所有药物都是静脉注射的，这是口头的。患者还接受了四次鞘内中枢神经系统给予阿糖胞苷（70mg）和四次甲氨蝶呤（15mg）。患者按中心分层，白血病,和艾滋病毒阳性。主要终点是进展费用生存期。所有分析均通过改良的意向治疗进行，排除随机分配的患者,这些患者随后在进入研究时被发现有中枢神经系统受累或诊断为Burkitt淋巴瘤以外的其他疾病.这项研究在欧洲临床试验注册中心注册，EudraCT2013-004394-27.
结果：由于应计速度缓慢，该研究于2021年11月15日提前结束。在2014年8月4日至2021年9月17日之间，89名患者被纳入并随机分配接受R-CODOX-M/R-IVAC（n=46）或DA-EPOCH-R（n=43）。随机分配后排除5例患者（R-CODOX-M/R-IVAC组3例[根据局部病理和2例中枢神经系统受累于研究入组时诊断为Burkitt淋巴瘤以外的一种诊断]，DA-EPOCH-R组2例[根据局部病理和1例中枢神经系统受累于研究入组时诊断为Burkitt淋巴瘤以外的一种诊断]。其余84例患者被纳入改良的意向治疗分析。84例患者中73例（87%）为男性，76（90％）患有III或IV期疾病，9例（11%）患有HIV阳性伯基特淋巴瘤。患者年龄中位数为52岁（IQR37-64）。中位随访时间为28·5个月（IQR13·2-43·7），R-CODOX-M/R-IVAC组的2年无进展生存率为76％（95％CI60-86％），DA-EPOCH-R组为70％（54-82％）（风险比1·42，95％CI0·63-3·18；p=0·40）。R-CODOX-M/R-IVAC组有2例死亡(1例感染[治疗相关]，1例由于疾病进展[非治疗相关])，DA-EPOCH-R组有1例死亡(COVID-19感染[治疗相关])。在R-CODOX-M/R-IVAC组中,四名患者因为毒性作用而退出协议，而在DA-EPOCH-R组中没有。接受R-CODOX-M/R-IVAC治疗的患者有更多的感染性不良事件（43例患者中有24例[56％]至少有一种3-5级感染，而DA-EPOCH-R组中41例患者中有14例[34％]）。
结论：试验提前停止，但现有数据表明，虽然与R-CODOX-M/R-IVAC相比，DA-EPOCH-R并没有获得更好的无进展生存期，它与较少的毒性作用和需要支持治疗相关.对于没有中枢神经系统受累的高风险伯基特淋巴瘤患者，DA-EPOCH-R似乎是另一种有效的治疗选择。
背景：荷兰癌症协会和舒马赫-克莱默基金会。
方法：这个多中心，阶段3，开放标签，随机研究在荷兰的26个临床中心进行，比利时,和瑞士。符合条件的患者年龄为18-75岁，患有新诊断的高风险Burkitt淋巴瘤，无中枢神经系统受累。患者被随机分配到两个周期的R-CODOX-M/R-IVAC（R-CODOX-M：第1天和第9天的利妥昔单抗375mg/m2，第1天的环磷酰胺800mg/m2，第2-5天的环磷酰胺200mg/m2，第1天和第8天的长春新碱，第1天的多柔阿多柔霉素40mg/m2，第65岁以上的患者接受了剂量修改的R-CODOX-M/R-IVAC。除了泼尼松龙，所有药物都是静脉注射的，这是口头的。患者还接受了四次鞘内中枢神经系统给予阿糖胞苷（70mg）和四次甲氨蝶呤（15mg）。患者按中心分层，白血病,和艾滋病毒阳性。主要终点是进展费用生存期。所有分析均通过改良的意向治疗进行，排除随机分配的患者,这些患者随后在进入研究时被发现有中枢神经系统受累或诊断为Burkitt淋巴瘤以外的其他疾病.这项研究在欧洲临床试验注册中心注册，EudraCT2013-004394-27.
结果：由于应计速度缓慢，该研究于2021年11月15日提前结束。在2014年8月4日至2021年9月17日之间，89名患者被纳入并随机分配接受R-CODOX-M/R-IVAC（n=46）或DA-EPOCH-R（n=43）。随机分配后排除5例患者（R-CODOX-M/R-IVAC组3例[根据局部病理和2例中枢神经系统受累于研究入组时诊断为Burkitt淋巴瘤以外的一种诊断]，DA-EPOCH-R组2例[根据局部病理和1例中枢神经系统受累于研究入组时诊断为Burkitt淋巴瘤以外的一种诊断]。其余84例患者被纳入改良的意向治疗分析。84例患者中73例（87%）为男性，76（90％）患有III或IV期疾病，9例（11%）患有HIV阳性伯基特淋巴瘤。患者年龄中位数为52岁（IQR37-64）。中位随访时间为28·5个月（IQR13·2-43·7），R-CODOX-M/R-IVAC组的2年无进展生存率为76％（95％CI60-86％），DA-EPOCH-R组为70％（54-82％）（风险比1·42，95％CI0·63-3·18；p=0·40）。R-CODOX-M/R-IVAC组有2例死亡(1例感染[治疗相关]，1例由于疾病进展[非治疗相关])，DA-EPOCH-R组有1例死亡(COVID-19感染[治疗相关])。在R-CODOX-M/R-IVAC组中,四名患者因为毒性作用而退出协议，而在DA-EPOCH-R组中没有。接受R-CODOX-M/R-IVAC治疗的患者有更多的感染性不良事件（43例患者中有24例[56％]至少有一种3-5级感染，而DA-EPOCH-R组中41例患者中有14例[34％]）。
结论：试验提前停止，但现有数据表明，虽然与R-CODOX-M/R-IVAC相比，DA-EPOCH-R并没有获得更好的无进展生存期，它与较少的毒性作用和需要支持治疗相关.对于没有中枢神经系统受累的高风险伯基特淋巴瘤患者，DA-EPOCH-R似乎是另一种有效的治疗选择。
背景：荷兰癌症协会和舒马赫-克莱默基金会。
