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