化疗延迟对儿童伯基特淋巴瘤预后影响的多中心研究

A multicenter study on effect of delayed chemotherapy on prognosis of Burkitt lymphoma in children

目的分析儿童伯基特淋巴瘤(BL)化疗延迟的影响因素及其对预后的影响。方法回顾性队列研究。收集中国儿童淋巴瘤协作组(CNCL)2017年5月至2022年12月收治的591例年龄≤18岁BL患儿临床资料,治疗均采用CNCL-BL-2017方案。依据临床特征,治疗方案分为A组、B组、C组。根据化疗总时间是否延迟分为化疗延迟组和非化疗延迟组。治疗方案C组患儿根据化疗总延迟时间分为非延迟组、1~7 d化疗延迟组和>7 d化疗延迟组。分析化疗延迟与性别、年龄、化疗前合并肿瘤溶解综合征、骨髓受累、治疗分组、血清乳酸脱氢酶(LDH)>正常4倍、化疗后合并Ⅲ~Ⅳ级骨髓抑制、中期评估有残留、重症感染(包括重症肺炎、败血症、脑膜炎、水痘等)等因素的关系。应用Logistic回归分析影响化疗延迟的因素,采用Kaplan-Meier及Log-Rank检验绘制生存曲线并组间比较。结果591例患儿中男504例、女87例,随访时间34.8(18.6,50.1)个月,3年总生存率(OS)为(92.5±1.1)%,3年无事件生存率(EFS)为(90.5±1.2)%。化疗延迟组73例(12.4%),非化疗延迟组518例(87.6%)。化疗延迟的原因包含重症感染72例(98.6%)、骨髓抑制65例(89.0%)、脏器功能损伤35例(47.9%)、肿瘤溶解综合征22例(30.1%)等。治疗方案B组7例化疗延迟中COPADM(长春新碱+环磷酰胺+泼尼松+柔红霉素+甲氨蝶呤+鞘内注射)阶段4例,CYM(甲氨蝶呤+阿糖胞苷+鞘内注射)阶段3例,治疗方案C组66例化疗延迟常见于COPADM(28例)和CYVE1(小剂量阿糖胞苷+大剂量阿糖胞苷+依托泊苷+甲氨蝶呤,12例)两阶段。多因素Logistic回归分析显示年龄>10岁(OR=0.54,95%CI 0.30~0.93)、化疗前合并肿瘤溶解综合征(OR=0.48,95%CI 0.27~0.84)、化疗后合并Ⅲ~Ⅳ级骨髓抑制(OR=0.55,95%CI 0.33~0.91)为化疗延迟的独立危险因素。化疗延迟组患儿3年OS、EFS均低于非化疗延迟组[(79.4±4.9)%比(94.2±1.1)%,(80.2±4.8)%比(92.0±1.2)%,均P<0.05]。治疗方案C组患儿>7 d化疗延迟组(42例)的3年OS低于1~7 d化疗延迟组(22例)、非化疗延迟组(399例)[(76.7±6.9)%比(81.8±8.2)%比(92.7±1.3)%,P=0.002]。治疗方案C组患儿中COP(长春新碱+环磷酰胺+泼尼松)阶段化疗延迟组(9例)3年OS低于非化疗延迟组(454例)[(66.7±15.7)%比(91.3±1.4)%,P=0.005]。COPADM1阶段化疗延迟组(11例)3年OS低于非化疗延迟组(452例)[(63.6±14.5)%比(91.5±1.3)%,P=0.001]。结论儿童BL诊治过程中,化疗延迟与年龄>10岁、化疗前合并肿瘤溶解综合征、化疗后合并Ⅲ~Ⅳ级骨髓抑制有关,一旦发生化疗延迟,影响疾病预后。

ObjectiveTo analyze the factors affecting delayed chemotherapy in children with Burkitt lymphoma(BL)and their influence on prognosis.MethodsRetrospective cohort study.Clinical data of 591 children aged≤18 years with BL from May 2017 to December 2022 in China Net Childhood Lymphoma(CNCL)was collected.The patients were treated according to the protocol CNCL-BL-2017.According to the clinical characteristics,therapeutic regimen was divided into group A,group B and group C.Based on whether the total chemotherapy time was delayed,patients were divided into two groups:the delayed chemotherapy group and the non-delayed chemotherapy group.Based on the total delayed time of chemotherapy,patients in group C were divided into non-delayed chemotherapy group,1-7 days delayed group and more than 7 days delayed group.Relationships between delayed chemotherapy and gender,age,tumor lysis syndrome before chemotherapy,bone marrow involvement,disease group(B/C group),serum lactate dehydrogenase(LDH)>4 times than normal,gradeⅢ-Ⅳmyelosuppression after chemotherapy,minimal residual disease in the interim assessment,and severe infection(including severe pneumonia,sepsis,meningitis,chickenpox,etc.)were analyzed.Logistic analysis was used to identify the relevant factors.Kaplan-Meier method was used to analyze the patients'survival information.Log-Rank was used for comparison between groups.ResultsAmong 591 patients,504 were males and 87 were females,the follow-up time was 34.8(18.6,50.1)months.The 3-year overall survival(OS)rate was(92.5±1.1)%,and the 3-year event-free survival(EFS)rate was(90.5±1.2)%.Seventy-three(12.4%)patients were in delayed chemotherapy group and 518(87.6%)patients were in non-delayed chemotherapy group.The reasons for chemotherapy delay included 72 cases(98.6%)of severe infection,65 cases(89.0%)of bone marrow suppression,35 cases(47.9%)of organ dysfunction,22 cases(30.1%)of tumor lysis syndrome,etc.There were 7 cases of chemotherapy delay in group B,which were seen in COPADM(vincristine+cyclophosphamide+prednisone+daunorubicin+methotrexate+intrathecal injection,4 cases)and CYM(methotrexate+cytarabine+intrathecal injection,3 cases)stages.There were 66 cases of chemotherapy delay in group C,which were common in COPADM(28 cases)and CYVE 1(low dose cytarabine+high dose cytarabine+etoposide+methotrexate,12 cases)stages.Multinomial Logistic regression analysis showed that the age over 10 years old(OR=0.54,95%CI 0.30-0.93),tumor lysis syndrome before chemotherapy(OR=0.48,95%CI 0.27-0.84)and gradeⅢ-Ⅳmyelosuppression after chemotherapy(OR=0.55,95%CI 0.33-0.91)were independent risk factors for chemotherapy delay.The 3-year OS rate and the 3-year EFS rate of children with Burkitt lymphoma in the delayed chemotherapy group were lower than those in the non-delayed chemotherapy group((79.4±4.9)%vs.(94.2±1.1)%,(80.2±4.8)%vs.(92.0±1.2)%,both P<0.05).The 3-year OS rate of the group C with chemotherapy delay>7 days(42 cases)was lower than that of the group with chemotherapy delay of 1-7 days(22 cases)and the non-delay group(399 cases)((76.7±6.9)%vs.(81.8±8.2)%vs.(92.7±1.3)%,P=0.002).The 3-year OS rate of the chemotherapy delay group(9 cases)in the COP(vincristine+cyclophosphamide+prednisone)phase was lower than that of the non-chemotherapy delay group(454 cases)((66.7±15.7)%vs.(91.3±1.4)%,P=0.005).Similarly,the 3-year OS rate of the chemotherapy delay group(11 cases)in the COPADM1 phase was lower than that of the non-chemotherapy delay group(452 cases)((63.6±14.5)%vs.(91.5±1.3)%,P=0.001).ConclusionsThe delayed chemotherapy was related to the age over 10 years old,tumor lysis syndrome before chemotherapy and gradeⅢ-Ⅳmyelosuppression after chemotherapy in pediatric BL.There is a significant relationship between delayed chemotherapy and prognosis of BL in children.