山东大学齐鲁医院阿糖胞苷巩固治疗85例AML（非M3）患者的疗效和不良反应分析

发布时间：2018-03-20 13:42

  本文选题：急性髓系白血病　切入点：大剂量阿糖胞苷　出处：《山东大学》2017年硕士论文　论文类型：学位论文

【摘要】：背景:急性髓系白血病(acute myeloid leukemia,AML)是起源于髓系造血干/祖细胞的恶性克隆性疾病,也是成人急性白血病中最常见的类型。在全世界范围内,每年都有大约30万的患者被确诊为AML。AML具有起病急、病情重、易复发等特点,预后较差。因此,如何在AML确诊后及时有效地控制病情并预防疾病复发是目前临床AML治疗过程中面临的一项严峻挑战。根据NCCN指南,目前AML治疗策略主要包括:诱导缓解治疗、缓解后的巩固治疗、挽救治疗、中枢神经系统白血病的预防以及监测、支持治疗、造血干细胞移植等。近几十年来,国际上普遍认可的AML的诱导缓解治疗始终以"3+7"方案为主,即标准剂量的阿糖胞苷(Ara-c,d1-7)联合蒽环或蒽醌类的药物(d1-3)。随着AML治疗水平的提高,约60%-80%的患者经诱导缓解阶段的治疗后可达到完全缓解(complete remission,CR)。然而,绝大多数完全缓解后的患者若未行后续的巩固治疗,病情将会在6-12月以内复发。而一旦复发,病人的耐药性会显著增加,预后极差。因此,AML完全缓解后的巩固治疗始终是AML治疗当中不可忽视的环节。国内外各项临床试验以及大样本的数据显示,含有大剂量阿糖胞苷(High Dose Ara-c,HDAra-c)的化疗方案是目前临床上AML巩固治疗阶段最主要的治疗方案。然而,阿糖胞苷(Ara-c)具有多种不良反应,包括血液学毒性、胃肠道不良反应、皮疹、结膜炎、发热、肾毒性、口腔溃疡等等。大剂量阿糖胞苷应用时会引起严重的骨髓抑制,表现为贫血、粒细胞缺乏、血小板减少等,从而造成一系列的不良反应。国内外目前针对不同剂量、不同疗程Ara-c在AML巩固治疗阶段疗效和不良反应的报道很多,但尚未有一个统一的结论。因此关于阿糖胞苷在AML患者巩固治疗阶段应用剂量、疗程的选择尚未达成完全统一的共识,还有许多问题有待探索和解决。目的:本研究旨在分析山东大学齐鲁医院85例初诊AML(非M3型)患者巩固化疗阶段采用不同剂量、不同疗程的阿糖胞苷的疗效和不良反应,以期探索出阿糖胞苷巩固化疗的最佳方案,从而对AML的临床治疗具有借鉴和参考价值。方法:收集山东大学齐鲁医院自2010年1月至2016年12月期间收治的初诊的急性髓系白血病AML病例85例,均经MICM标准确诊为AML(非M3型)。所有的患者经诱导缓解治疗后均达到CR,巩固治疗阶段分别应用含有不同剂量、不同疗程Ara-c单药或联合的方案化疗。收集患者的年龄、性别、初诊时血常规(白细胞、血红蛋白、血小板)、骨髓原始细胞、染色体、融合基因等各项临床资料,并通过电话、门诊等方式对患者进行随访。根据巩固治疗阶段应用Ara-c剂量、疗程的不同对患者进行分组:(1)根据Ara-c单次剂量不同将85例患者分为 2 组,HDAra-c 组(2-3g/m2q12h,d1-3)和非 HDAra-c 组(中、标准剂量);(2)HDAra-c组根据总累积剂量不同分为3组,HDAra-c-1组(累积剂量18 g/m2),HDAra-c-2 组(累积剂量 18-36g/m2)和 HDAra-c-3 组(累积剂量≥36g/m2);(3)HDAra-c组根据疗程的不同分为2组,HDAra-c疗程1组(1-2个疗程)和HDAra-c疗程2组(3-4个疗程)(4)非HDAra-c组根据总累积剂量不同分为3组,非HDAra-c-1组(累积剂量9g/m2),非HDAra-c-2组(累积剂量9-18g/m2)以及非HDAra-c-3组(累积剂量≥18g/m2)。对上述各个分组的患者的无复发生存率(relapse-free survival,RFS)和总生存率(overall survival,OS)等指标进行对比评估,并分析HDAra-c组化疗期间的不良事件。结果:1.本研究共收集85例初诊AML患者,年龄在14-60岁,中位年龄38岁。随访时间为83个月,中位随访时间42个月。患者总体1年的RFS率和OS率分别为83.2%和84.7%;2年的RFS率和OS率分别为59.7%和78.6%。患者总体未达到中位总体生存期(OS)。2.各分组之间疗效对比(1)按 Ara-c 单次剂量不同分为 2 组,HDAra-c 组(2-3g/m2q12h,d1-3)53例患者,非HDAra-c组(中、标准剂量)有32例患者。HDAra-c组与非HDAra-c组RFS率和OS率相对比:HDAra-c组患者1年的RFS率为87.6%,2年的RFS率为66.6%;非HDAra-c组1年的RFS率为67.3%,2年的RFS率为50.5%。两组对比,HDAra-c组在2年RFS率上有显著优势(66.6%vs50.5%.P=0.006)。COX多因素分析单次剂量分组对患者的RFS来说是独立的影响因素(P=0.004,HR=0.347.95%CI 0.170-0.708)。HDAra-c 组患者1年的OS率为89.5%,2年的OS率77.2%;非HDAra-c组1年的OS率为78.7%,2年的OS率62.7%。HDAra-c组相对于非HDAra-c组在2年OS率优势也较为明显(77.2%vs62.7%.P=0.043)。COX多因素分析单次剂量分组对患者的 OS 来说是潜在的影响因素(P=0.093,HR=0.467,95%CI 0.192-1.137)。(2)HDAra-c组按照总累积剂量分为3组:HDAra-c-1组(累积剂量18 g/m2)共16例,HDAra-c-2组(累积剂量18-36g/m2)共18例,HDAra-c-3组(累积剂量≥36g/m2)共19例。对三组之间RFS和OS进行对比分析:在RFS上,HDAra-c-3组(累积剂量≥36g/m2)显著优于HDAra-c-1组(累积剂量18 g/m2)(P=0.041);HDAra-c-2 组(累积剂量 18-36g/m2)与 HDAra-c-1 组(累积剂量18 g/m2)相比较,差异虽无显著统计学意义,但有改善的趋势(P=0.069);HDAra-c-3 组(累积剂量≥36g/m2)与 HDAra-c-2 组(累积剂量18-36g/m2)相比在RFS上无显著优势(P=0.103)。COX多因素分析提示总累积剂量是RFS的潜在影响因素(总P=0.066,HDAra-c-1组vs HDAra-c-3组:P=0.062,HR=4.297,95%CI 0.932-19.808;HDAra-c-2 组 vs HDAra-c-3 组:P=0.020,HR=7.904,95%CI 1.378-45.345)。在 OS 上,HDAra-c-3 组(累积剂量≥36g/m2)与另外两组相比较差异无显著统计学意义(总P=0.772,HDAra-c-1组vs HDAra-c-3 组:P=0.420,HR=1.854,95%CI 0.414-8.306;HDAra-c-2 组 w HDAra-c-3 组:P=0.654,HR=1.443,95%CI 0.290-7.172)。(3)HDAra-c组按照疗程分为2组:HDAra-c疗程1组(1-2个疗程)31例,HDAra-c疗程2组(3-4个疗程)22例。对比两个疗程组之间RFS和OS,得出结果:在RFS上,疗程2组(3-4个疗程)比疗程1组(1-2个疗程)有显著优势(P=0.03),差异有统计学意义。COX多因素分析提示疗程分组是RFS的潜在影响因素(P=0.098,HR=0.615,95%CI 0.346-1.093)。在 OS 上,疗程 2 组(3-4个疗程)相比于疗程1组(1-2个疗程)无显著优势(P=0.228)。(4)非HDAra-c组按照总累积剂量分为3组:非HDAra-c-1组(累积剂量9g/m2)17 例,非 HDAra-c-2 组(累积剂量 9-18g/m2)5 例,非 HDAra-c-3 组(累积剂量≥18g/m2)10例。对比3组之间RFS和OS:在RFS上,非HDAra-c-3组(累积剂量≥18g/m2)上与非HDAra-c-1组(累积剂量9g/m2)和非HDAra-c-2组(累积剂量9-18g/m2)之间对比均有显著优势(非HDAra-c-1组vs非HDAra-c-3组:P=0.002;非HDAra-c-2组vs非HDAra-c-3组:P=0.04),差异有统计学意义。非HDAra-c-1组(累积剂量9g/m2)和非HDAra-c-2组(累积剂量9-18g/m2)之间在RFS上无显著优势(P=0.850)。COX多因素分析提示累积剂量分组是RFS的主要影响因素(P=0.047,HR=2.013,95%CI 1.009-4.017)。在OS,非HDAra-c-3组(累积剂量≥18g/m2)相对于非HDAra-c-1组(累积剂量9g/m2)有显著优势(P=0.027)。非HDAra-c-3组(累积剂量≥18g/m2)与非HDAra-c-2组(累积剂量9-18g/m2)以及非HDAra-c-1组(累积剂量9g/m2)与非HDAra-c-2组(累积剂量9-18g/m2)之间对比差异无显著统计学意义。3.HDAra-c组不良反应发生情况:(1)患者HDAra-c巩固化疗后的血液学不良反应:Ⅳ度骨髓抑制的发生率为 84.9%,NEU0.5*109/L、NEU0.2*109/L 以及 PLT20*109/L 的中位持续时间分别为 7(2-14)d、6(1-12)d 以及 6(2-]3)d。(2)患者HDAra-c巩固化疗后的非血液学不良反应:化疗后粒缺期感染(上呼吸道感染、肺部感染、肛周感染等)率88.7%,发热率81.1%,肝脏毒性的发生率为32%,Ⅰ～Ⅲ级胃肠道不良反应的发生率为26.4%,皮疹发生率11.3%,结膜炎发生率9.4%。无严重心功能不全以及神经系统毒性发生。结论:1.巩固化疗阶段应用HDAra-c相对于非HDAra-c化疗方案在提高AML(非M3)患者的RFS率和OS率上有较显著的优势。2.HDAra-c累积剂量≥36g/m2相对于HDAra-c累积剂量18 g/m2在延长AML(非M3)患者的RFS上有显著优势;HDAra-c3-4个疗程相对于HDAra-c 1-2个疗程化疗方案在延长RFS上也有显著优势。3.AML(非M3)患者可耐受HDAra-c巩固治疗。
[Abstract]:Background: acute myeloid leukemia (acute myeloid, leukemia, AML) is originated from myeloid hematopoietic stem / progenitor cells of malignant clonal disease, is also the most common type of adult acute leukemia. In the whole world, every year there are about 300 thousand of the patients were diagnosed as AML.AML with acute onset, severe illness. So easy to relapse, poor prognosis. Therefore, how to AML after diagnosis timely and effectively control the disease and prevent the recurrence of the disease is a severe challenge currently faced in the process of clinical treatment of AML. According to the NCCN guidelines, the AML treatment strategies include: induction therapy, post remission consolidation therapy, salvage therapy, central nervous the system of leukemia prevention and monitoring, supportive therapy, hematopoietic stem cell transplantation. In recent decades, internationally recognized AML induction therapy are always dominated by the "3+7" program, which is a standard dose of Ara Glycosides (Ara-c, D1-7) combined with anthracycline or anthraquinone drugs (D1-3) with AML. The improvement of treatment, about 60%-80% of patients after induction of remission stage after treatment can achieve complete remission (complete, remission, CR). However, most of the patients after complete remission without subsequent consolidation therapy. The illness will be recurred in 6-12 months. But once patients relapse, drug resistance will increase significantly, the prognosis is poor. Therefore, the consolidation treatment of AML after complete remission is always a part that can not be ignored. AML treatment at home and abroad of the clinical trials and large sample data show that with high dose cytarabine (High Dose Ara-c HDAra-c), chemotherapy regimen is currently in clinical stage AML consolidation therapy is the most important. However, cytarabine (Ara-c) with a variety of adverse reactions, including hematological toxicity, gastrointestinal adverse reactions, skin rash, conjunctivitis, fever, Renal toxicity, oral ulcer and so on. High dose cytarabine application can cause severe bone marrow suppression, manifested as anemia, neutropenia, thrombocytopenia, resulting in a series of adverse reactions at home and abroad. According to different dosage, different courses of Ara-c consolidation phase of treatment efficacy and adverse reactions of AML in many reports but there is not a unified conclusion. Therefore a cytarabine consolidation stage application dose treatment in patients with AML, no consensus course selection, there are many problems need to be solved. Objective: This study aimed to analyze the Qilu Hospital of Shandong University in 85 newly diagnosed AML (non M3) patients with different stages of consolidation chemotherapy dose, efficacy and adverse reactions of different courses of cytarabine, in order to explore the best scheme of cytarabine chemotherapy, and clinical treatment of AML with reference and Reference value. Methods: acute myeloid collected from Qilu Hospital of Shandong University from January 2010 to December 2016 during the newly diagnosed leukemia AML 85 cases were diagnosed as AML by MICM standard (non M3). All of the patients after induction of remission after treatment reached CR, stage of consolidation therapy were applied with different doses, different courses of Ara-c monotherapy or combination chemotherapy were collected. The age, gender, initial blood (white blood cell, hemoglobin, platelet), bone marrow primitive cells, chromosome, fusion gene and other clinical data, and through the way of telephone, outpatient follow-up of patients. According to the consolidation phase of treatment dose of Ara-c, the different course of treatment the patients were divided into two groups: (1) according to the different single dose of Ara-c 85 patients were divided into 2 groups, group HDAra-c (2-3g/m2q12h, D1-3) and non HDAra-c group (in standard dose); (2) according to the HDAra-c group The total cumulative dose were divided into 3 groups, group HDAra-c-1 (cumulative dose of 18 g/m2), group HDAra-c-2 (cumulative dose 18-36g/m2) and group HDAra-c-3 (cumulative dose of more than 36g/m2); (3) HDAra-c group according to different treatment for 2 groups, HDAra-c treatment group 1 (1-2 cycles) and HDAra-c treatment group (2 3-4 course) (4) non HDAra-c group according to the total cumulative dose were divided into 3 groups, HDAra-c-1 group (cumulative dose 9g/m2) and non HDAra-c-2 group (cumulative dose 9-18g/m2) and non HDAra-c-3 group (cumulative dose of more than 18g/m2). The relapse free survival rate for each group of patients (relapse-free survival, RFS the total survival rate (overall) and survival, OS) were compared to assess and analyze the adverse events during HDAra-c chemotherapy group. Results: 1. this study collected 85 cases of newly diagnosed AML patients at the age of 14-60, the median age was 38 years. The follow-up time was 83 months, median follow-up time of 42 June. 鎮ｈ，

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