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异基因造血干细胞移植与酪氨酸激酶抑制剂联合化疗治疗费城染色体阳性急性淋巴细胞白血病。

Allogeneic Stem Cell Transplantation versus Tyrosine Kinase Inhibitors Combined with Chemotherapy in Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia.

机构信息

Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China; Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation for the Treatment of Hematological Diseases, Beijing, China.

Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China; Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation for the Treatment of Hematological Diseases, Beijing, China; Peking-Tsinghua Center for Life Sciences, Beijing, China.

出版信息

Biol Blood Marrow Transplant. 2018 Apr;24(4):741-750. doi: 10.1016/j.bbmt.2017.12.777. Epub 2017 Dec 13.

Abstract

Here we compare outcomes between the tyrosine kinase inhibitors (TKIs) plus chemotherapy regimen and allogeneic hematopoietic stem cell transplantation (transplantation cohort) in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and explore factors associated with prognosis. Data from 145 Ph+ ALL patients were analyzed retrospectively. Patients were treated with imatinib plus chemotherapy and then transplantation or continuous TKIs with chemotherapy based on patient preference. A total of 145 Ph+ ALL patients were recruited for this study (median age, 37 years; range, 14 to 65). Among these patients, 81 were men (55.9%) and 86 underwent IKZF1 detection, which identified 59 patients (68.6%) with IKZF1 deletions. After treatment 136 patients (95.8%) achieved complete remission (CR) eventually. With a median follow-up of 33 months (range, 4 to 114) for CR patients, 77 patients (57.9%) underwent transplantation and 56 (42.1%) received continuous TKIs with chemotherapy. At the 4-year follow-up the cumulative incidence of relapse (CIR), disease-free survival (DFS), and overall survival (OS) were 29.4% (95% confidence interval [CI], 24.9% to 34.4%), 60.9% (95% CI, 56.5% to 65.3%), and 69.2% (95% CI, 65.1% to 73.3%), respectively. Multivariate analysis showed that WBC counts < 30 × 10/L at diagnosis (hazard ratio [HR], 4.2; 95% CI, 1.9 to 9.2; P  < .001; HR, 2.6; 95% CI, 1.4 to 4.9; P = .003; HR, 2.7; 95% CI, 1.4 to 5.4; P = .003), 3-log reduction of BCR-ABL levels from baseline after 2 consolidation cycles (HR, 4.4; 95% CI, 1.9 to 9.9; P < .001; HR, 3.1; 95% CI, 1.7 to 5.9; P  < .001; HR, 3.5; 95% CI, 1.9 to 8.7; P = .001; defined as "minimal residual disease low level"), and transplantation (HR, 5.0; 95% CI, 2.2 to 11.2; P  < .001; HR, 3.3; 95% CI, 1.7 to 6.4; P   < .001; HR, 4.1; 95% CI, 1.9 to 8.7; P   < .001) were the favorable factors of CIR, DFS, and OS. According to the first 2 risk factors, CR patients were divided into 3 groups: low risk (no factor, n = 42, 31.6%), intermediate risk (1 factor, n = 73, 54.9%), and high risk (2 factors, n = 18, 13.5%). In the low-risk group at the 4-year follow up no significant difference existed between the transplant and nontransplant arms for the probabilities of CIR (8.5% versus 7.7%, P = .671), DFS (88.2% versus 83.9%, P = .426), and OS (96.6% versus 83.3%, P = .128). In the intermediate- and high-risk groups at the 4-year follow-up, CIR (23.6% versus 36.9%, P = .017; 37.5% versus 100.0%, P   <.001), DFS (62.4% versus 43.8%, P = .048; 56.2% versus 0%, P   <.001), and OS (76.1% versus 47.7%, P = .037; 51.4% versus 6.3%, P = .001) rates were significantly better in the transplant arm than in the nontransplant arm. In surviving patients of the low-risk group, no difference in complete molecular response (CMR) rates (85.7% versus 72.7%, P = .379) between the transplant and nontransplant arms was found. However, in the intermediate-risk group the proportion of CMR was significantly higher in the transplant arm than in the nontransplant arm (82.8% versus 42.9%, P = .006). In the high-risk group 4 of 7 transplant patients (57.1%) were in CMR, and no patients survived in the nontransplant arm. Allogeneic hematopoietic stem cell transplantation confers significant survival advantages for Ph+ ALL patients compared with TKIs plus chemotherapy, especially in intermediate- and high-risk patients.

摘要

我们比较了酪氨酸激酶抑制剂(TKIs)联合化疗方案与费城染色体阳性急性淋巴细胞白血病(Ph+ ALL)患者的异基因造血干细胞移植(移植组)的结果,并探讨了与预后相关的因素。回顾性分析了 145 例 Ph+ ALL 患者的数据。患者接受伊马替尼联合化疗,然后根据患者的意愿进行移植或持续 TKI 联合化疗。本研究共纳入 145 例 Ph+ ALL 患者(中位年龄 37 岁;范围 14 至 65 岁)。其中 81 例为男性(55.9%),86 例行 IKZF1 检测,发现 59 例(68.6%)存在 IKZF1 缺失。治疗后 136 例(95.8%)患者最终获得完全缓解(CR)。CR 患者中位随访时间为 33 个月(范围 4 至 114),77 例(57.9%)行移植,56 例(42.1%)接受持续 TKI 联合化疗。4 年随访时,复发累积发生率(CIR)、无病生存(DFS)和总生存(OS)分别为 29.4%(95%置信区间 [CI],24.9%至 34.4%)、60.9%(95% CI,56.5%至 65.3%)和 69.2%(95% CI,65.1%至 73.3%)。多变量分析显示,诊断时白细胞计数(WBC)<30×10/L(风险比[HR],4.2;95%CI,1.9 至 9.2;P<0.001;HR,2.6;95%CI,1.4 至 4.9;P=0.003;HR,2.7;95%CI,1.4 至 5.4;P=0.003)、巩固治疗 2 个周期后 BCR-ABL 水平降低 3 个对数(HR,4.4;95%CI,1.9 至 9.9;P<0.001;HR,3.1;95%CI,1.7 至 5.9;P<0.001;HR,3.5;95%CI,1.9 至 8.7;P=0.001;定义为“微小残留病低水平”)和移植(HR,5.0;95%CI,2.2 至 11.2;P<0.001;HR,3.3;95%CI,1.7 至 6.4;P<0.001;HR,4.1;95%CI,1.9 至 8.7;P<0.001)是 CIR、DFS 和 OS 的有利因素。根据前 2 个风险因素,CR 患者分为 3 组:低危(无因素,n=42,31.6%)、中危(1 个因素,n=73,54.9%)和高危(2 个因素,n=18,13.5%)。在低危组中,4 年随访时移植组和非移植组的 CIR(8.5%与 7.7%,P=0.671)、DFS(88.2%与 83.9%,P=0.426)和 OS(96.6%与 83.3%,P=0.128)的概率无显著差异。在中危和高危组中,4 年随访时的 CIR(23.6%与 36.9%,P=0.017;37.5%与 100.0%,P<0.001)、DFS(62.4%与 43.8%,P=0.048;56.2%与 0%,P<0.001)和 OS(76.1%与 47.7%,P=0.037;51.4%与 6.3%,P=0.001)在移植组明显优于非移植组。在低危组存活患者中,移植组与非移植组的完全分子缓解(CMR)率(85.7%与 72.7%,P=0.379)无差异。然而,在中危组中,移植组的 CMR 比例明显高于非移植组(82.8%与 42.9%,P=0.006)。在高危组中,7 例移植患者中有 4 例(57.1%)达到 CMR,非移植组无患者存活。与 TKIs 联合化疗相比,异基因造血干细胞移植可为 Ph+ ALL 患者带来显著的生存优势,尤其在中危和高危患者中。

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