Clinical features and outcomes of childhood acute lymphoblastic leukemia with hyperleukocytosis at diagnosis
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摘要: 目的 分析儿童高白细胞性急性淋巴细胞白血病(ALL)的临床特征并评估预后。方法 回顾性收集2015年1月—2020年6月诊断的244例初治ALL患儿的临床资料，均按照CCCG-ALL 2015骨架方案诊疗，随访至2021年12月。以初诊白细胞计数(WBC)50×109/L为界将患儿分为高白组(47例)和非高白组(197例)，比较2组间临床特征、治疗反应、总生存率及无事件生存率。结果 244例ALL患儿中，男147例，女97例，男∶女为1.5∶1.0；中位初诊年龄4.9岁；低危组132例，中危组108例，高危组4例。初诊高白细胞血症的发生率为19.3%(47/244)，初诊WBC与初诊外周血幼稚细胞比例呈线性正相关(P< 0.001)。与非高白组比较，高白组肝大、脾大、T系及BCR-ABL1阳性ALL患儿的比例更高(P< 0.05)；高白组诱导治疗第19天MRD≥1%的比例更高(P=0.003)，而第46天MRD在2组中分布差异无统计学意义(P=0.170)。中位随访52个月，总复发率为14.3%，5年总生存率为(90.6%±2.0%)，5年无事件生存率为(80.4%±2.8%)。与非高白组比较，高白组总复发率更高、总生存率及无事件生存率更低，差异均有统计学意义(P< 0.05)。多因素Cox回归分析显示，初诊高白细胞血症、KMT2A重排及第46天MRD≥0.01%是ALL患儿无事件生存的独立危险因素(P< 0.05)。结论 高白细胞ALL患儿初诊特征有肝大、脾大、较高比例的T系及BCR-ABL1，初诊外周血幼稚细胞比例更高，早期治疗反应欠佳，预后不良。Abstract: Objective To evaluate clinical features and outcomes of childhood acute lymphoblastic leukemia(ALL) with different white blood cell counts(WBC) at diagnosis.Methods A total of 244 patients with ALL were retrospectively included who were newly diagnosed from January 2015 to June 2020 and treated by CCCG-ALL 2015 protocol. The last follow-up time-point was December 2021. Children were divided into the hyperleukocytosis group(47 cases) and the non-hyperleukocytosis group(197 cases) by WBC at diagnosis, and clinical features, minimal residual disease(MRD) and outcomes between the 2 groups were evaluated.Results Among 244 children, there were 147 males and 97 females. The ratio of males to females was 1.5 ∶ 1.0. The median age of initial diagnosis was 4.9 years. There were 132 cases in the low-risk group, 108 cases in the medium-risk group, and 4 cases in the high-risk group. The incidence of newly diagnosed hyperleukocytemia(WBC≥50×109/L) was 19.3%(47/244). There was a linear positive correlation between newly diagnosed WBC and the proportion of immature cells in peripheral blood(P< 0.001). Compared with the non-hyperleukocytemia group, the proportions of children with hepatomegaly, splenomegaly, T-lineage, and BCR-ABL1 positive ALL in the hyperleukocytemia group were significantly higher(P< 0.05). The proportion of MRD≥1% on the 19th day of induction treatment in the hyperleukocytemia group was significantly higher(P=0.003), while there was no significant difference in the distribution of MRD on the 46th day between the 2 groups(P=0.170). After a median follow-up of 52 months, the overall recurrence rate was 14.3%, the 5-year overall survival rate was(90.6%±2.0%), and the 5-year event-free survival rate was(80.4%±2.8%). Compared with the non-hyperleukocytemia group, patients in the hyperleukocytemia group had a higher overall recurrence rate, lower overall survival rate, and event-free survival rate(P< 0.05). Multivariate Cox regression analysis showed that hyperleukocytosis at diagnosis, KMT2A-rearrangement, and MRD≥0.01% on the 46th day of induction were independent risk factors for event-free survival(P< 0.05).Conclusion Children with hepatomegaly, splenomegaly, T-lineage, and BCR-ABL1 ALL have a higher incidence of hyperleukocytosis at diagnosis. Children with hyperleukocytosis ALL have a higher proportion of immature cells in peripheral blood at diagnosis, with poorer treatment response and prognosis.
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Key words:
- children /
- acute lymphoblastic leukemia /
- white blood cell count /
- hyperleukocytosis /
- prognosis
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表 1 高白组与非高白组间临床特征比较
例(%) 临床特征 白细胞减少组(64例) WBC 4.0×109/L~49.9×109/L组(133例) 高白组(47例) P 最终危险度 < 0.001 低危 47(73.4) 76(57.1) 9(19.1) 中危 17(26.6) 55(41.4) 36(76.6) 高危 0 2(1.5) 2(4.3) 初诊年龄 0.368 < 10岁 54(84.4) 118(88.7) 38(80.9) ≥10岁 10(15.6) 15(11.3) 9(19.1) 性别 0.075 男 38(59.4) 74(55.6) 35(74.5) 女 26(40.6) 59(44.4) 12(25.5) 肝大 0.008 无 32(50.0) 55(41.4) 10(21.3) 有 32(50.0) 78(58.6) 37(78.7) 脾大 0.009 无 34(53.1) 64(48.1) 12(25.5) 有 30(46.9) 69(51.9) 35(74.5) 中枢神经系统/睾丸浸润 0.392 无 62(96.9) 130(97.7) 44(93.6) 有 2(3.1) 3(2.3) 3(6.4) 免疫表型 < 0.001 B系 61(95.3) 124(93.2) 33(70.2) T系 3(4.7) 9(6.8) 14(29.8) ETV6-RUNX1/t(12；21) 0.880 阴性 52(81.3) 106(79.7) 39(83.0) 阳性 12(18.8) 27(20.3) 8(17.0) TCF3-PBX1/t(1；19) 0.065 阴性 63(98.4) 124(93.2) 47(100.0) 阳性 1(1.6) 9(6.8) 0 BCR-ABL1/t(9；22) < 0.001 阴性 62(96.9) 130(97.7) 39(83.0) 阳性 2(3.1) 3(2.3) 8(17.0) KMT2A重排 0.294 阴性 63(98.4) 124(93.2) 44(93.6) 阳性 1(1.6) 9(6.8) 3(6.4) 核型 0.173 高二倍体 50(78.1) 110(82.7) 4(8.5) 其他 14(21.9) 23(17.3) 43(91.5) D19 MRD 0.003 < 1% 57(89.1) 113(85.0) 31(66.0) ≥1% 7(10.9) 20(15.0) 16(34.0) D46 MRD 0.170 < 0.01% 61(95.3) 117(88.0) 40(85.1) ≥0.01% 3(4.7) 16(12.0) 7(14.9) 
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表 2 ALL患儿EFS的单因素分析
因素 5年EFS率/% P 因素 5年EFS率/% P 估计值 标准误 估计值 标准误 最终危险度 TCF3-PBX1/t(1；19) 0.541 低危 86.2 3.4 0.013 阴性 80.0 2.9 中高危 73.7 4.4 阳性 90.0 9.5 初诊年龄 BCR-ABL1/t(9；22) 0.140 < 10岁 80.9 3.0 0.476 阴性 81.3 2.8 ≥10岁 77.2 7.8 阳性 62.3 15.0 性别 KMT2A重排 0.001 男 74.9 3.9 0.022 阴性 81.9 2.8 女 89.0 3.3 阳性 51.9 14.3 初诊WBC < 0.001 核型 0.476 < 50×109/L 84.8 2.8 高二倍体 79.5 3.1 ≥50×109/L 61.9 7.7 其他 86.1 6.0 初诊外周血幼稚细胞比例 0.008 D19 MRD 0.006 < 30% 88.3 3.4 < 1% 83.9 2.8 ≥30% 73.5 4.2 ≥1% 65.5 7.5 免疫表型 0.084 D46 MRD 0.001 B系 81.4 2.9 < 0.01% 84.0 2.7 T系 71.9 9.1 ≥0.01% 55.1 10.2 ETV6-RUNX1/t(12；21) 0.464 阴性 80.2 3.0 阳性 81.8 6.3
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表 3 ALL患儿EFS的单因素和多因素分析
因素 EFS单因素分析 EFS多因素分析 HR(95%CI) P HR(95%CI) P 最终危险度(低危vs中高危) 2.17(1.16~4.09) 0.016 0.91(0.41~2.02) 0.811 性别(男vs女) 0.45(0.22~0.91) 0.027 0.49(0.24~1.02) 0.056 初诊WBC(< 50×109/L vs ≥50×109/L) 2.99(1.60~5.57) 0.001 2.58(1.30~5.09) 0.006 KMT2A重排(阴性vs阳性) 3.69(1.55~8.77) 0.003 3.10(1.22~7.84) 0.017 D19 MRD(< 1% vs ≥1%) 2.40(1.26~4.55) 0.008 1.20(0.50~2.88) 0.306 D46 MRD(< 0.01% vs ≥0.01%) 3.07(1.54~6.11) 0.001 2.60(1.08~6.27) 0.033
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