Second allogeneic hematopoietic stem cell transplantation for pediatric acute leukemia patients relapsed after the first hematopoietic stem cell transplantation
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摘要: 目的 旨在评估第2次异基因造血干细胞移植(second allogeneic hematopoietic stem cell transplantation，allo-HSCT2)对于治疗第1次allo-HSCT(allo-HSCT1)后复发的儿童急性白血病患者的疗效以及影响预后因素。方法 回顾性分析2012年11月—2021年10月接受allo-HSCT2作为挽救治疗allo-HSCT1后复发的74例儿童急性白血病患者。其中allo-HSCT2的中位年龄为11.9(3.0~17.0)岁。allo-HSCT1移植后中位复发时间为8.0(2.0~72.0)个月，其中26例伴有髓外病变。患者在allo-HSCT2前，造血细胞移植合并症指数(HCT-CI)积分54例为0分，11例为1分，9例≥2分；其中37例接受了嵌合抗原受体T细胞(CAR-T)的治疗；疾病状态：38例完全缓解(CR)/微小残留白血病(MRD)-，20例CR/MRD+，16例未缓解(NR)。allo-HSCT2供者类型为同胞全合(MSD)2例，无关供者(MUD)8例，半相合供者(HID)64例，其中72例(97.3%)更换了不同的供者，57例(77.0%)供者HLA有新的错配单倍型。结果 中位随访时间25.0(6.0~96.0)个月，2年总体生存(OS)率和无白血病生存(LFS)率分别为(40.8±6.3)%和(40.8±6.3)%，2年累计复发率(CIR)和治疗相关死亡率(TRM)分别为(33.7±7.5)%和(37.9±6.3)%。在Cox回归中，多因素分析显示患者allo-HSCT2前疾病状态为CR/MRD-和HCT-CI积分为0，具有更高的OS率和LFS率，更低的CIR。33例具备2项有利因素的患者(allo-HSCT2移植前疾病状态为CR/MRD-和HCT-CI积分为0)，OS和LFS明显优于具有一项或者不具备有利因素的患者[(55.8±9.3)% vs (39.0±10.0)% vs (21.0±12.6)%，P=0.001)]，LFS[(55.7±9.3)% vs (38.0±10.1)% vs (21.0±12.6)%，P=0.001)]、CIR明显降低[(7.9±5.4)% vs (45.3±2.2)% vs 100.0%，P=0.001)]。结论 allo-HSCT2是治愈儿童急性白血病allo-HSCT1后复发后的有效方法，allo-HSCT2前疾病状态为CR/MRD-和HCT-CI积分为0的患者能最大程度从中受益。
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关键词:
- 第2次异基因造血干细胞移植 /
- 复发 /
- 儿童 /
- 急性白血病
Abstract: Objective To evaluate the efficacy and prognostic factors of the second allo-HSCT(allo-HSCT2) for pediatric acute leukemia patients relapsed after the first allo-HSCT(allo-HSCT1).Methods It retrospectively analyzed 74 pediatric acute leukemia patients who received allo-HSCT2 as salvage therapy for relapsed after allo-HSCT1 from November 2012 to October 2021. The median age at allo-HSCT2 was 11.9(3.0-17.0) years. The median recurrence time after allo-HSCT1 was 8.0(2.0-72.0) months, of which 26 cases with extramedullary lesions. Before allo-HSCT2, the HCT-CI score of 54 cases was 0, 11 cases was 1, and the score ≥ 2 was 9 cases; among them, 37 cases were received with chimeric antigen receptor T cells therapy(CAR-T); disease status before allo-HSCT2 at CR/MRD negative in 38 cases, at CR/MRD positive in 20 cases, the left at NR status. Second donor type were MSD in 2 cases, MUD in 8 cases and HID in 64 cases, of which 72 cases(97.3%) changed different donors, and 57 second donor(77.0%) had new mismatched haplotype.Results The median follow-up time of survivor was 25(6-96) months, 2 years OS and LFS were(40.8±6.3)% and(40.8±6.3)% respectively, and the 2-year CIR and TRM were(33.7±7.5)% and(37.9±6.3)% respectively. In Cox regression, multivariate analysis showed the patient's disease status before allo-HSCT2 at CR/MRD- and HCT-CI score(0) had higher OS and LFS and lower CIR. 33 patients with two favorable factors(the disease status at CR/MRD-and HCT-CI score were 0), OS and LFS were significantly higher than those with one or without favorable factors([55.8±9.3]% vs [39.0±10.0]% vs [21.0±12.6]%, P=0.001), LFS([55.7±9.3]% vs [38.0±10.1]% vs [21.0±12.6]%, P=0.001), and CIR was significantly lower([7.9±5.4]% vs [45.3±2.2]% vs 100.0%, P=0.001).Conclusion allo-HSCT2 is an effective therapy for pediatric acute leukemia patients relapsed after allo-HSCT1; patients with disease status at CR/MRD- and HCT-CI score of 0 before allo-HSCT2 can get maximal benefit from it. -
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表 1 患者的疾病以及移植特征
特征 allo-HSCT1 allo-HSCT2 男/例(%) 49(66.2) 移植时中位年龄/岁 11.9(3.0~17.0) 疾病诊断/例(%) AML 29(39.2) ALL 45(60.8) B细胞 40(54.0) T细胞 5(6.7) 诊断到allo-HSCT2的中位时间/月 28(8~162) allo-HSCT1后复发的中位时间/月 8(2~72) 移植前疾病状态/例(%) CR1/MFC-MRD+ 41(36.4)/11(14.8) ≥CR2/MFC-MRD+ 24(20.2)/4(5.4) 58(78.3)/20(27.0) 进展期 9(12.1) 16(21.6) 合并TP53突变/例(%) 4(5.4) 移植前有髓外病变/例(%) 11(14.8) 26(35.1) allo-HSCT1复发后接受过CAR-T治疗/例(%) 37(50.0) 供者类型/例(%) MSD 18(30.5) 2(2.4) MUD 8(12.3) 8(18.2) HID 43(51.7) 64(79.3) UCBD 5(3.4) allo-HSCT1后出现aGVHD/例(%) 27(36.4) allo-HSCT1后出现cGVHD/例(%) 9(12.1) allo-HSCT2供受者性别关系/例(%) 男供男 39(52.7) 20(27.0) 男供女 10(13.5) 17(22.9) 女供女 15(20.2) 8(10.8) 女供男 10(13.5) 29(39.1) allo-HSCT2前HCT-CI积分/例(%) 0 54(72.9) 1 11(14.8) ≥ 2 9(12.1) 移植供者来源/例(%) 父母 36(48.6) 56(75.6) 同胞 25(33.7) 4(5.4) 旁系半相合 3(4.0) 无关供者 13(17.5) 8(1.8) allo-HSCT2供者对比allo-HSCT1供者/例(%) 不同 72(97.2) 有新的错配单倍型 57(77.0) 二次移植间隔时间/例(%) ≤12个月 31(41.8) allo-HSCT2预处理方案/例(%) TBI-为基础的清髓 60(81.0) 50(67.5) BU-为基础的清髓 14(18.9) 23(3.1) Mel-为基础的清髓 1(1.3) CR：完全缓解；CR1:第1次完全缓解；CR2:第2次完全缓解；MFC：多色流式细胞术。 
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表 2 单因素分析移植前各项预后因素
影响因素 P OS LFS CIR TRM 疾病类型(AML vs ALL) 0.31 0.31 0.14 0.93 allo-HSCT1供者类型(MSD vs MUD vs HID vs UCB) 0.55 0.55 0.76 0.51 allo-HSCT1复发后接受过CAR-T治疗(是vs否) 0.03 0.03 0.03 0.28 allo-HSCT1和HSCT2间隔时间(< 12个月vs ≥12个月) 0.49 0.49 0.61 0.20 allo-HSCT1后复发的时间(< 9个月vs ≥9个月) 0.04 0.04 0.08 0.22 allo-HSCT1前疾病状态(CR/MRD-vs CR/MRD+vs NR) 0.53 0.53 0.73 0.60 合并TP53突变(有vs无) 0.40 0.40 0.12 0.86 allo-HSCT1后合并aGVHD(是vs否) 0.13 0.13 0.69 0.11 allo-HSCT1后合并cGVHD(是vs否) 0.77 0.77 0.37 0.72 伴有髓外并病变(是vs否) 0.92 0.30 0.39 0.57 allo-HSCT2供者类型(MSD vs MUD vs HID) 0.09 0.10 0.36 0.10 allo-HSCT2预处理方案(TBI-为基础vs Bu-为基础vs Mel) 0.52 0.52 0.91 0.36 allo-HSCT2有新的错配单倍型(有vs无) 0.19 0.19 0.05 0.88 allo-HSCT2供受者性别关系(男供男vs男供女vs女供女vs女供男) 0.83 0.83 0.52 0.81 allo-HSCT2供者来源(父母vs同胞vs旁系单倍型vs无关) 0.69 0.02 0.71 0.08 allo-HSCT2前疾病状态(CR/MRD-vs CR/MRD+vs NR) 0.01 0.01 0 0.01 诊断到allo-HSCT2的时间(< 28个月vs ≥28个月) 0.15 0.15 0.25 0.30 allo-HSCT2前HCT-CI积分(0 vs ≥1) 0 0 0.01 0.06
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表 3 多因素分析allo-HSCT2移植前预后因素
因素 HR(95%CI) P OS allo-HSCT2前疾病状态(CR/MRD-vs CR/MRD+vs NR) 1.509(1.021~2.232) 0.039 allo-HSCT2前HCT-CI积分(0 vs ≥1) 2.295(1.284~4.102) 0.005 allo-HSCT1后复发的时间(< 9个月vs ≥9个月) 0.387(0.092~1.610) 0.190 allo-HSCT1复发后接受过CAR-T治疗(是vs否) 0.494(0.152~1.561) 0.239 LFS allo-HSCT2前疾病状态(CR/MRD-vs CR/MRD+vs NR) 1.509(1.021~2.232) 0.039 allo-HSCT2前HCT-CI积分(0 vs ≥1) 2.295(1.284~4.102) 0.005 allo-HSCT1后复发的时间(< 9个月vs ≥9个月) 0.387(0.092~1.610) 0.190 allo-HSCT1复发后接受过CAR-T治疗(是vs否) 0.494(0.152~1.561) 0.239 CIR allo-HSCT2前疾病状态(CR/MRD-vs CR/MRD+vs NR) 3.261(1.474~7.216) 0.004 allo-HSCT2前HCT-CI积分(0 vs ≥1) 0.417(1.642~12.428) 0.003 allo-HSCT2供者是否有新的错配单倍型(有vs无) 3.736(1.444~9.663) 0.007 allo-HSCT1后复发的时间(< 9个月vs ≥9个月) 1.709(1.292~2.261) 0.089 allo-HSCT1复发后接受过CAR-T治疗(是vs否) 1.885(0.4163~2.854) 0.410 TRM allo-HSCT2前HCT-CI积分(0 vs ≥1) 2.032(0.995~4.432) 0.050
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