大剂量柔红霉素联合标准剂量阿糖胞苷对中青年初发急性髓系白血病患者的近、远期疗效

Short-term and long-term efficacy of high-dose Daunorubicin combined with standard dose Ara-C in young and middle-aged patients with acute myeloid leukemia

摘要:

目的分析大剂量柔红霉素（DNR）联合标准剂量阿糖胞苷（Ara-C）对中青年初发急性髓系白血病（AML）患者的近、远期效果。方法选取2011年1月-2015年5月该院血液内科收治的并接受的大剂量[60mg/（m2·d）]DNR 联合100 mg/（m2·d）Ara-C 的DA 方案行诱导化疗的133 例中青年初治AML 患者为研究对象，归为观察组。并随机选择同期该院接受标准剂量DA 诱导方案[45 mg/（m2·d）DNR 联合100 mg/（m2·d）Ara-C]的125例中青年初治AML 患者为对照组。比较两组的完全缓解率（CR）、各不良反应的发生率、早期死亡率、血中性粒细胞绝对计数（ANC）减少的持续时间以及血小板（PLT）减少持续时间，并均进行随访，截止至2016 年12月，比较两组的1、2 及3 年的总生存率（OS）和无瘤生存率（DFS），采用单因素与多因素Cox 比例风险模型筛选出影响达到CR的观察组患者OS 和DFS 的影响因素。结果①两组的化疗前基线资料比较，差异无统计学意义（p >0.05），具有可比性。②观察组、对照组患者行1 个疗程诱导化疗后的CR 率分别为67.7%和57.6%，两组比较差异无统计学意义（p >0.05）。观察组患者2 个疗程诱导化疗后的总CR 率为82.0%，高于对照组的70.4%，差异有统计学意义（p <0.05）。两组的各不良反应发生率、早期死亡率、ANC 和PLT 减少的持续时间比较，差异无统计学意义（p >0.05）。③经过诱导化疗达到CR后，两组分别有103 例（95.%）和84 例（67.2%）患者均行1～4 个疗程的巩固化疗，之后分别有21 例（15.8%）、17 例患者（13.6%）行异基因造血干细胞移植，2 例（1.5%）、1 例（0.8%）行自体造血干细胞移植。截止至末次随访时，两组患者的中位随访时间分别为26.8 和28.0个月，两组化疗后1、2 及3 年的OS 和DFS 比较，差异无统计学意义（p >0.05）。④多因素Cox 回归分析结果表明，对观察组患者诱导化疗达到CR 的109 例患者而言，预后危险分层、接受≥2 个疗程大剂量Ara-C 巩固化疗是影响患者OS 的影响因素（p <0.05）；预后危险分层、FMS 样的酪氨酸激酶3 -内部串联重复（FLT3-ITD）突变阳性是影响患者DFS 的影响因素（p <0.05）。结论与标准剂量DNR 相比，大剂量DNR 联合标准剂量Ara-C 能提高中青年初发AML 患者的CR 率，且不增加不良反应的发生风险，但对改善其远期生存状况未见明显优势。

Abstract:

Objective To analyse the short-term and long-term efficacy of high-dose Daunorubicin (DNR) combined with standard dose cytarabine (Ara-C) in young and middle-aged patients with acute myeloid leukemia (AML). Methods Totally 133 young and middle-aged patients with newly diagnosed AML received high-dose [60 mg/(m2·d)] DNR combined with standard dose [100 mg/(m2·d)] of Ara-C from January 2011 to May 2015 were enrolled for study in observation group. And 125 young and middle-aged patients with newly diagnosed AML received standard dose DA induction therapy [45 mg/(m2·d) DNR combined with 100mg /(m2·d) Ara-C] during the same period were randomly selected for study in control group. Complete remission (CR) rate, the incidence of adverse reactions, early mortality, duration of reduction of blood absolute neutrophil count (ANC) and PLT were compared between the two groups. All cases were followed up until December 2016. 1-, 2-, 3-year overall survival (OS) and disease-free survival (DFS) were compared between the two groups. Univariate and multivariate Cox proportional hazard model were used to screen out the independent related factors for OS and DFS of patients reached CR in the observation group. Results There were no statistically significant differences in baseline data before treatment between the two groups (p > 0.05). The CR rates after 1 course of induction chemotherapy in the observation group and the control group were 67.7% and 57.6%, respecfively and there was no significant difference between them (p > 0.05). The total CR rate after 2 courses in the observation group was 82.0% which was significantly higher than 70.4% in the control group (p < 0.05). There were no significant differences in the incidences of all adverse reactions, early mortality, duration of ANC and PLT reduction between the two groups (p > 0.05). Researching CR after induction chemotherapy, 103 cases (95%) and 84 cases (67.2%) in the two groups received 1-4 courses of consolidation chemotherapy, then 21 cases (15.8%) and 17 cases (13.6%) underwent allogeneic hematopoietic stem cell transplantation, 2 cases (1.5%) and 1 case (0.8%) underwent autologous hematopoietic stem cell transplantation. At the end of the last follow-up, the median follow-up time was 26.8 months and 28 months in the two groups. There were no statistically significant differences in 1-, 2- and 3-year OS or DFS after chemotherapy between the two groups (p > 0.05). Multivariate Cox regression analysis results showed that for the 109 cases of patients reached CR after induction chemotherapy in the observation group, prognostic risk stratification and receiving more than 2 courses of high-dose Ara-C consolidation chemotherapy were the independent related factors of OS (p < 0.05), and prognostic risk stratification and FLT3-ITD mutation were the independent related factors of DFS (p < 0.05). Conclusions Compared with standard dose DNR, high-dose DNR combined with standard dose Ara-C can significantly improve the CR rate in young and middle-aged patients with AML and does not increase the risks of adverse reactions, but there is no obvious advantage in improvement of long-term survival.