[Report of Chinese Children's Cancer Group acute lymphoblastic leukemia 2015 multicenter study].

Objective: To evaluate the outcomes and identify the prognostic factors of childhood acute lymphoblastic leukemia (ALL) treated with Chinese Children's Cancer Group study ALL-2015 (CCCG-ALL-2015) protocol. Methods: There were two randomization studies in CCCG-ALL-2015 study. A total of 7 640 newly diagnosed ALL patients in 20 hospitals of multi-institutional study group between January 2015 and December 2019 were treated with unified protocol. CCCG-ALL-2015 protocol featured risk-directed therapy based on morphology, immunophenotype, and genetic features, and adjusted according to minimal residual disease (MRD) assay on day 19 and day 46 of induction, which totally omitted prophylactic cranial irradiation. Two randomized controlled trails were designed. Children with Philadelphia chromosome-positive ALL (Ph+ALL) were randomly treated with dasatinib (Ph-D group) or imatinib (Ph-I group). During the latter half of continuation therapy, children were randomly treated with seven pulses of vincristine plus dexamethasone (group A) or not (group B). The survival rates of different groups were compared. Event-free survival (EFS) and overall survival (OS) curves were estimated according to the Kaplan-Meier method and compared by Log-rank test. Cox proportional hazards model was used for multivariate analysis. Results: Of the 7 640 enrolled patients, there were 4 521 males and 3 119 females, 7 508 (98.3%) entered complete remission. The 5-year EFS was 60.1% (95%CI 49.8%-72.5%) in the Ph-D group and 39.4% (95%CI 26.9%-57.7%) in the Ph-I group (χ2=5.00, P=0.020). Between patients with lower risk (LR) and intermediate and higher risk (I/HR) treated with (group A) or without (group B) additional pulse of vincristine plus dexamethasone, there were no difference in 5-year EFS and OS. The one-sided 95% upper confidence bound for the difference in 5-year EFS and OS were 0.02 and 0.01 for LR, 0.05 and 0.01 for I/HR, establishing non-inferiority, lower than 0.05. The follow-up time was 3.5 (2.4,4.8) years. The 5-year OS was 90.9% (95%CI 90.2%-91.7%), and EFS was 80.1% (95%CI 79.0%-81.2%). The 5-year cumulative risk of any relapse was 15.3% (95%CI 14.3%-16.3%).The cumulative risk of isolated central nervous system (CNS) relapse was 1.9% (95%CI 1.6%-2.2%), and any CNS relapse 2.7% (95%CI 2.3%-3.1%). The 5-year cumulative risk of death during remission was 1.3% (95%CI 1.0%-1.6%). In the multivariate analysis, the independent factors associated with inferior EFS of patients with B-ALL were age≥10 years, male sex, white blood cell count ≥50×109/L, CNS2 or CNS3 status, BCR-ABL fusion, KMT2A rearrangements, without ETV6-RUNX1 fusion and the presence of MRD>0.01% at day 19 or 46 (all P<0.05). Among patients with T-ALL, the significant predictors for lower EFS were the BCR-ABL1 fusion and MRD≥0.10% at day 46 (both P<0.05). Conclusions: Patients treated with CCCG-ALL-2015 protocol without the use of prophylactic cranial irradiation have favorable outcomes, and the cumulative risk of isolated CNS relapse and cumulative risk of death during remission are low. Intensive chemotherapy including dasatinib yield superior results compared to imatinib in the treatment of Ph+ALL. Vincristine plus dexamethasone pulses can be omitted for ALL children without decrease in treatment ontcome during the latter half of continuation therapy.目的： 评价中国抗癌协会小儿肿瘤专业委员会急性淋巴细胞白血病2015研究（CCCG-ALL-2015）方案治疗儿童急性淋巴细胞白血病（ALL）的临床效果及主要预后相关因素。 方法： 采用CCCG-ALL-2015统一方案对2015年1月1日至2019年12月31日就诊于CCCG-ALL协作组20家医院的7 640例初诊ALL患儿进行分层治疗。根据临床及生物学特征进行危险度分组，并根据诱导治疗第19天、46天微小残留病（MRD）结果调整危险度，不同危险度予以不同强度的化疗，全程无放疗。方案设计2个随机对照研究：费城染色体阳性ALL（Ph+ALL）患儿在化疗基础上随机接受达沙替尼（Ph-D组）或伊马替尼（Ph-I组）治疗；根据维持治疗后期是否加用7个周期的地塞米松和长春新碱随机分为两组（A组为加用，B组为不加用），比较两组生存率差异。总生存率（OS）和无事件生存率（EFS）分析采用Kaplan-Meier生存分析法，组间生存率比较采用Log-rank检验，多因素分析采用Cox回归多因素模型。 结果： 共7 640例患儿入组，男4 521例、女3 119例。7 508例获得完全诱导缓解，诱导缓解率为98.3%。189例Ph+ALL患儿随机研究显示，达沙替尼（Ph-D）5年EFS优于伊马替尼（Ph-I）［60.1%（95%CI 49.8%~72.5%）比39.4%（95%CI 26.9%~57.7%），χ2=5.00，P=0.020］。维持治疗期间是否加用地塞米松和长春新碱随机研究显示，低危患儿A、B两组间EFS和OS差值单侧95%CI上限分别为0.02和0.01，中、高危患儿A、B两组间EFS和OS差值单侧95%CI上限分别为0.05和0.01，小于预设的非劣效边界值0.05。整组患儿随访3.5（2.4，4.8）年，5年OS和EFS分别为90.9%（95%CI 90.2%~91.7%）和80.1%（95%CI 79.0%~81.2%），累积复发率15.3%（95%CI 14.3%~16.3%），单纯中枢神经系统（CNS）累积复发率为1.9%（95%CI 1.6%~2.2%），累及CNS累积复发率为2.7%（95%CI 2.3%~3.1%）。5年治疗相关累积病死率为1.3%（95%CI 1.0%~1.6%）。多因素分析发现B-ALL中，年龄≥10岁、男性、初诊白细胞计数≥50×109/L、初诊时中枢类型为CNS2或CNS3、有BCR-ABL融合基因、KMT2A基因重排、无ETV6-RUNX1融合基因、诱导第19天、第46天MRD>0.01%均为预后不良因素（均P<0.05）；T-ALL中有BCR-ABL融合基因、诱导第46天MRD>0.10%为预后不良因素（均P<0.05）。 结论： 无颅脑预防性放疗的CCCG-ALL-2015方案远期预后良好，CNS复发率低，治疗相关病死率低，达沙替尼在Ph+ALL中比伊马替尼更有效。维持治疗后期去掉长春新碱和地塞米松并不降低预后。.