【作者】 李玉竹；

【导师】 闫金松；

【作者基本信息】 大连医科大学 ， 内科学， 2017， 硕士

【摘要】 目的:本研究采用回顾性的研究方法,观察分析采用中剂量阿糖胞苷(Intermediate-dose Cytarabine,ID-Ara-C)和高剂量阿糖胞苷(High-dose Cytarabine,HD-Ara-C)巩固治疗急性髓系白血病(Acute Myeloid Leukemia,AML)的疗效及安全性,为AML患者探索最佳的巩固治疗方案提供依据。方法:本研究主要以2011年01月至2016年10月期间,于大连医科大学附属第二医院血液内科收治的49例初发AML成人患者为研究对象,按阿糖胞苷剂量由低到高随机分为3组(A、B、C组),其中主要是应用ID-Ara-C(A组1.0g/m2,每12小时静点1次,d1,d3,d5及B组2.0g/m2,每12小时静点1次,d1,d3,d5)或HD-Ara-C(C组3.0g/m2,每12小时静点1次,d1,d3,d5)单用及联合(去甲氧)柔红霉素、依托泊苷、米托蒽醌等一种其它化疗药物,进行巩固强化治疗。其中ID-Ara-C组共连续完成6个周期,联合用药情况两组均相同,HD-Ara-C组为单用阿糖胞苷,共连续完成3个周期。对入选患者每3个月随访一次,持续随访3-5年。期间采集其基本临床资料,观察比较三组患者用药不良事件的发生率、疾病复发率、5年无病生存率及总体生存率等,采用SPSS19.0统计分析软件进行疗效及安全性统计。结果:选取持续完成HD-Ara-C 3个周期,ID-Ara-C 6个周期治疗并可评价疗效的患者44例,其中男性23例,女性21例(男:女=1.09:1),中位年龄53岁(13岁-66岁),其中A组:58岁(15-66岁);B组:54岁(21-64岁);C组:26岁(13-38岁)。A组及B组年龄≥60岁的共11例(25.0%),C组所有患者年龄均小于40岁,无ECOG评分大于1分者,三组患者年龄分布不全相同,C组患者在年龄上与A组、B组均存在差异,且差异有统计学意义(P<0.05),A组与B组患者年龄分布差异无统计学意义(P=0.15>0.05)。疗效:A组:20例中CR率80%,PR率20%,复发5例(25.0%),死亡6例(30.0%),4例为复发后死亡(20.0%),1例为非复发死亡。B组:14例中CR率85.7%,PR率14.3%,复发5例(35.7%),死亡5例(35.7%),其中4例为复发后死亡(28.6%),1例非复发死亡,死因为化疗间期肺内感染。C组:10例患者均获得CR,复发3例(30.0%),复发后死亡1例(10.0%),1例为复发后应用其他方案再次获得缓解并无病生存。三组复发率差异无统计学意义,(A vs.B,P=0.12;B vs.C,P=0.45;A vs.C,P=0.53)。三组均未达到中位OS、DFS,A组:估算3年OS率为66.2%,3年DFS率为65.5%,5年OS率为53.1%,5年DFS率为52.0%。B组:估算3年、5年OS率均为62.1%,3年、5年DFS率56.3%。C组:估算3年及5年OS率为90.0%,3年及5年DFS率为58.2%。三组OS差异无统计学意义,(A vs.B,P=0.64;B vs.C,P=0.16;A vs.C,P=0.31)。三组DFS差异无统计学意义,(A vs.B,P=0.66;B vs.C,P=0.55;A vs.C,P=0.8)。不良反应:三组患者均出现Ⅳ度骨髓抑制,骨髓抑制持续时间差异无统计学意义(P>0.05),中性粒细胞缺乏持续中位时间为9-11天。三组患者均出现不同程度的感染,A组感染率为50.5%,B组感染率67.9%,1例因感染死亡。C组感染率80.0%。C组总体感染率高于A组(B vs.A,P=0;C vs.A,P=0.006),B组和C组间感染率无差异(P=0.34)。C组肝功能损伤发生率高于A组(P=0.026),胃肠道反应发生率高于其余两组(A vs.C,P=0.0;B vs.C,P=0.014),A组和B组间非感染不良反应发生率相当(P>0.05),三组均无严重心脏、肝脏、肾脏、神经系统功能损伤。结论:本研究中高剂量阿糖胞苷化疗方案应用于年龄<40岁AML,虽在疗效上具备一定的优势,较国内外水平有所提高,但不明显,并且存在较大的毒副反应,使其推广受到限制,需要进一步改进。而中剂量阿糖胞苷可应用于部分年龄>60岁患者,毒副反应相对低,并且具有同高剂量阿糖胞苷相近的疗效,值得我们探索改进。同时本研究初步探讨了阿糖胞苷1g/m2及2g/m2的疗效差别,发现以2g/m2阿糖胞苷巩固治疗AML的5年生存率高,不良反应较1g/m2无明显差别,初步反应2g/m2阿糖胞苷疗效更佳。但我们仍需扩大病例数,进一步研究阿糖胞苷治疗AML的最佳剂量,同时望探讨根据不同患者的年龄、预后分层、融合基因及疾病状态等情况,详细制定个体化治疗方案,寻找新的疗效好、毒性小化疗药物,以进一步提高患者的疗效及长期生存时间。更多还原

【Abstract】 Objective: This study used retrospective method to investigate and analyze the efficacy and safety of intermediate-dose cytarabine(ID-Ara-C)and high-dose cytarabine(HD-Ara-C)in the consolidation treatment of patients with acute myeloid leukemia(AML).To provide the basis for exploring the optimal consolidation treatment for AML patients.Methods: From January 2011 to October 2016,searching for the patients with AML who admitted to the Department of Hematology,total 49 patients,randomly divided into three groups(A,B,C),according to the dose of cytarabine,ID-Ara-C(Group A:1.0g/m2 once every 12 hours,iv,d1,d3,d5,Group B: 2.0 g/m2 once every 12 hours,iv,d1,d3,d5)or HD-Ara-C(Group C:3.0 g/m2 once every 12 hours,iv,d1,d3,d5)were used alone or in combination with any of darubicin,daunorubicin,etoposide,mitoxantrone and other chemotherapy drugs to consolidate the intensive treatment.The use of cytarabine was once every 12 hours,d1,d3,d5,ID-Ara-C group were completed for 6 consecutive cycles,the combination drug of the two groups are the same,HD-AraC group for single use Cytarabine,a total of three consecutive cycles.The patients were followed up every 3 months and lasted for 3 to 5 years.The clinical data were collected and the incidence of disease adverse events,disease recurrence rate,5-year disease-free survival rate(DFS)and 5 year’s overall survival rate(OS)were observed and compared.The efficacy and safety statistics were analyzed by SPSS19.0.Results: A total of 44 patients who underwent HD-Ara-C for 3 cycles,ID-Ara-C for 6 cycles were selected and the efficacy were evaluated.Among them,23 males and21 females(male: female = 1.09:1),median age was 53 years old(13 years old to 66 years old),group A: 58 years old(15-66 years);group B: 54 years old(21-64 years old);group C: 26 years old(13-38 years old).11 patients in A group and B group were older than 60 years old(25.0%),all patients in C group were less than 40 years old,there was no ECOG scores more than one,three groups of patients with age distribution are not all the same,there were statistical significantly differences between group A and C,group B and group C(p < 0.05),no difference between A and B group(p > 0.05).Efficacy:Group A: 20 cases,CR rate was 80%,PR rate was 20%,5 cases of recurrence(25.0%),death in 6 cases(30.0%),4 cases died after recurrence(20.0%),1 case of nonrecurrence death.In group B,the CR rate was 85.7%,the PR rate was 14.3%,the relapse was 5 cases(35.7%)and the death in 5 cases(35.7%).Among them,4 cases died after relapse(28.6%),1 case of death was due to pulmonary infection during chemotherapy.Group C: All patients received CR,relapse in 3 cases(30.0%),1 case of recurrence ended in death(10.0%),1 case relapsed then applicated other chemotherapy to obtain relief and disease-free survival.There was no significant difference in the relapse rate between the three groups(A vs.B,P = 0.12;B vs.C,P = 0.45;A vs.C,P =0.53).Three groups did not reach the median OS,DFS.Group A: the estimated 3-year OS rate was 66.2%,the 3-year DFS rate was 65.5%,the 5-year OS rate was 53.1%,and the 5-year DFS rate was 52.0%.Group B: estimated 3-year and 5-year OS rate were62.1%,3-year and 5-years DFS rate all were 56.3%.Group C: the estimated 3-year and5-year OS rate were 90.0%,3-year and 5-year DFS rate were 58.2%.There were no statistically significant differences in OS rate between the three groups(A vs.B,P =0.64;B vs.C,P = 0.16;A vs.C,P = 0.31).There was no significant difference in DFS among the three groups(A vs.B,P = 0.66;B vs.C,P = 0.55;A vs.C,P = 0.8).Adverse reactions: All groups of patients showed Ⅳ degree myelosuppression,no significant difference.The median time of myelosuppression was 9-11 days.Three groups of patients were infected in varying degrees,infection rate of group A was 50.5%,B group67.9%,1 case died due to infection in group B.The infection rate of group C was 80.0%.The overall infection rate of group C was higher than that of group A(B vs.A,P = 0;C vs.A,P = 0.006).There was no difference in infection rate between group B and group C(P = 0.34).The incidence of liver injury was higher in group C than that in group A(P = 0.026).The incidence of gastrointestinal reaction was higher than that of the other two groups(A vs.C,P = 0.0;B vs.C,P = 0.014).The incidence of non-infected adverse reactions in A group and B group were similar(P > 0.05).There was no significant heart,liver,kidney and nervous system dysfunction in the three groups.Conclusion: In this study,although high-dose cytarabine chemotherapy regimen gained better efficacy in AML patients(≤ 40 years old),there were great toxic side effects.Therefore application was limited and needs further improvement.The median dose of cytarabine can be applied to some patients older than 60 years old,in which the toxicity is relatively low,and has the same efficacy as high-dose cytarabine.Further exploration and improvement need to be done.At the same time,this study indicated the significant difference of the efficacy between cytarabine 1 g/m2 and 2 g/m2.It was found that the 5-year survival rate of indicated AML patients was high,no significantly differences with 1 g/m2 regimen in adverse effects.We preliminarily considerate that the2g/m2 regimen has better treatment efficacy.It is the reason why we still need to expand the number of cases to further optimize the dose of cytarabine in AML treatment regimens,which could improve the current treatment regimens and reduce the toxicity of cytarabine.To study age,prognosis,fusion genes and disease status in AML patients helps to develop better treatment regimens individually,to find new effective and less toxic drugs,and finally to improve the treatment efficacy and extend the survival duration.更多还原