Wu X J, Liao N, Mai H R, Li X Y, Wan W Q, Yang L H, Huang L B, Luo X Q, Tian C, Chen Q W, Long X J, He Y Y, Wang Y, Li Z G, Xu H G
Department of Hematology and Oncology, Children's Medical Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
Department of Pediatrics, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China.
Zhonghua Er Ke Za Zhi. 2024 Mar 25;62(4):337-344. doi: 10.3760/cma.j.cn112140-20230729-00046.
To evaluate the role of minimal residual disease (MRD) monitoring during early induction therapy for the treatment of childhood acute lymphoblastic leukemia (ALL). This was a multicenter retrospective cohort study. Clinical data of 1 164 ALL patients first diagnosed between October 2016 and June 2019 was collected from 16 hospitals in South China Children's Leukemia Group. According to MRD assay on day 15 of early induction therapy, they were divided into MRD<0.10% group, MRD 0.10%-<10.00% group and MRD≥10.00% group. According to MRD assay on day 33, they were divided into MRD<0.01% group, MRD 0.01%-<1.00% group and MRD≥1.00% group. Age, onset white blood cell count, central nervous system leukemia (CNSL), molecular genetic characteristics and other data were compared between groups. Kaplan-Meier method was used for survival analysis. Cox regression model was used to analyze prognostic factors. Of the 1 164 enrolled patients, there were 692 males and 472 females. The age of diagnosis was 4.7 (0.5, 17.4) years. The white blood cell count at initial diagnosis was 10.7 (0.4, 1 409.0) ×10/L. Among all patients, 53 cases (4.6%) had CNSL. The follow-up time was 47.6 (0.5, 68.8) months. The 5-year overall survival (OS) and 5-year relapse-free survival (RFS) rates were (93.1±0.8) % and (90.3±1.1) %. On day 15 of early induction therapy, there were 466 cases in the MRD<0.10% group, 523 cases in the MRD 0.10%-<10.00% group and 175 cases in the MRD≥10.00% group. The 5-year OS rates of the MRD<0.10% group, MRD 0.10%-<10.00% group and MRD≥10.00% group were (95.4±1.0) %, (93.3±1.1) %, (85.4±2.9) %, respectively, while the RFS rates were (93.2±1.6) %, (90.8±1.4) %, (78.9±4.3) %, respectively (=16.47, 21.06, both <0.05). On day 33 of early induction therapy, there were 925 cases in the MRD <0.01% group, 164 cases in the MRD 0.01%-<1.00% group and 59 cases in the MRD≥1.00% group. The 5-year RFS rates in the MRD 0.01%-<1.00% group was lowest among three groups ((91.4±1.2) % (84.5±3.2) % (87.9±5.1) %). The difference between three groups is statistically significant (=9.11, =0.010). Among ALL patients with MRD≥10.00% on day 15 of induction therapy, there were 80 cases in the MRD <0.01% group on day 33, 45 cases in the MRD 0.01%-<1.00% group on day 33 and 45 cases in the MRD≥1.00% group on day 33. The 5-year RFS rates of three groups were (83.9±6.0)%, (67.1±8.2)%, (83.3±6.9)% respectively (=6.90, =0.032). Univariate analysis was performed in the MRD≥10.00% group on day 15 and the MRD 0.01%-<1.00% group on day 33.The 5-year RFS rate of children with CNSL was significantly lower than that without CNSL in the MRD≥10.00% group on day 15 ((50.0±20.4)% (80.3±4.4)%,=4.13,=0.042). Patients with CNSL or MLL gene rearrangement in the MRD 0.01%-<1.00% group on day 33 had significant lower 5-year RFS rate compared to those without CNSL or MLL gene rearrangement ((50.0±25.0)% (85.5±3.1)%,=4.06,=0.044;(58.3±18.6)% (85.7±3.2)%,=9.44,=0.002). Multivariate analysis showed that age (=0.58, 95% 0.35-0.97) and white blood cell count at first diagnosis (=0.43, 95% 0.27-0.70) were independent risk factors for OS. The MRD level on day 15 (=0.55,95% 0.31-0.97), ETV6-RUNX1 fusion gene (=0.13,95% 0.03-0.54), MLL gene rearrangement (=2.55,95% 1.18-5.53) and white blood cell count at initial diagnosis (=0.52,95% 0.33-0.81) were independent prognostic factors for RFS. The higher the level of MRD in early induction therapy, the worse the OS. The MRD levels on day 15 is an independent prognostic factor for RFS.The MRD in early induction therapy guided accurate risk stratification and individualized treatment can improve the survival rate of pediatric ALL.
评估微小残留病（MRD）监测在儿童急性淋巴细胞白血病（ALL）早期诱导治疗中的作用。这是一项多中心回顾性队列研究。收集了2016年10月至2019年6月期间首次诊断的1164例ALL患者的临床数据，这些数据来自华南儿童白血病协作组的16家医院。根据早期诱导治疗第15天的MRD检测结果，将患者分为MRD<0.10%组、MRD 0.10%-<10.00%组和MRD≥10.00%组。根据第33天的MRD检测结果，将患者分为MRD<0.01%组、MRD 0.01%-<1.00%组和MRD≥1.00%组。比较各组之间的年龄、发病时白细胞计数、中枢神经系统白血病（CNSL）、分子遗传学特征等数据。采用Kaplan-Meier法进行生存分析。使用Cox回归模型分析预后因素。在1164例入组患者中，男性692例，女性472例。诊断年龄为4.7（0.5，17.4）岁。初诊时白细胞计数为10.7（0.4，1409.0）×10/L。所有患者中，53例（4.6%）患有CNSL。随访时间为47.6（0.5，68.8）个月。5年总生存率（OS）和5年无复发生存率（RFS）分别为（93.1±0.8）%和（90.3±1.1）%。在早期诱导治疗第15天，MRD<0.10%组有466例，MRD 0.10%-<10.00%组有523例，MRD≥10.00%组有175例。MRD<0.10%组、MRD 0.10%-<10.00%组和MRD≥10.00%组的5年OS率分别为（95.4±1.0）%、（93.3±1.1）%、（85.4±2.9）%，而RFS率分别为（93.2±1.6）%、（90.8±1.4）%、（78.9±4.3）%（χ²=16.47，χ²=21.06，均<0.05）。在早期诱导治疗第33天，MRD<0.01%组有925例，MRD 0.01%-<1.00%组有164例，MRD≥1.00%组有59例。MRD 0.01%-<1.00%组的5年RFS率在三组中最低（（91.4±1.2）% （84.5±3.2）% （87.9±5.1）%）。三组之间的差异具有统计学意义（χ²=9.11，P=0.010）。在诱导治疗第15天MRD≥10.00%的ALL患者中，第33天MRD<0.01%组有80例，MRD 0.01%-<1.00%组有45例，MRD≥1.00%组有45例。三组的5年RFS率分别为（83.9±6.0）%、（67.1±8.2）%、（83.3±6.9）%（χ²=6.90，P=0.032）。对诱导治疗第15天MRD≥10.00%组和第33天MRD 0.01%-<1.00%组进行单因素分析。在诱导治疗第15天MRD≥10.00%组中伴CNSL的儿童5年RFS率显著低于不伴CNSL的儿童（（50.0±20.4）% （80.3±4.4）%，χ²=4.13，P=0.042）。在第33天MRD 0.01%-<1.00%组中伴CNSL或MLL基因重排的患者5年RFS率显著低于不伴CNSL或MLL基因重排的患者（（50.0±25.0）% （85.5±3.1）%，χ²=4.06，P=0.044；（58.3±18.6）% （85.7±3.2）%，χ²=9.44，P=0.002）。多因素分析显示年龄（β=0.58，95%CI 0.35-0.97）和初诊时白细胞计数（β=0.43，95%CI 0.27-0.70）是OS的独立危险因素。第15天的MRD水平（β=0.55，95%CI 0.31-0.97）、ETV6-RUNX1融合基因（β=0.13，95%CI 0.03-0.54）、MLL基因重排（β=2.55，95%CI 1.18-5.53）和初诊时白细胞计数（β=0.52，95%CI 0.33-0.81）是RFS的独立预后因素。早期诱导治疗中MRD水平越高，OS越差。第15天的MRD水平是RFS的独立预后因素。早期诱导治疗中的MRD指导精确的风险分层和个体化治疗可提高儿童ALL的生存率。
