FLAG和MEA方案治疗难治复发性急性髓系白血病的Meta分析
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摘要
目的:系统评价氟达拉滨+阿糖胞苷+重组人粒细胞集落刺激因子(FLAG)和米托蒽醌+依托泊苷+阿糖胞苷(MEA)方案治疗难治复发性急性髓系白血病(RRAML)的疗效及不良反应。方法:计算机检索Pub Med、Cochrane Library、Web of Science、VIP、Wan Fang Data、CNKI、CBM等数据库发表的关于FLAG和MEA方案治疗RRAML的随机对照试验(RCT)。由两位研究者独立进行文献筛选、资料提取和质量评价后,采用Rev Man 5. 0软件进行Meta分析。结果:共纳入6个研究,299例患者。Meta分析结果显示:FLAG方案和MEA方案治疗RRAML时,两者的CR[RR=1. 49,95%CI(0. 92,2. 43),P=0. 11]及PR[RR=1. 38,95%CI(0. 82,2. 32),P=0. 23]无明显差异,但FLAG方案治疗组的总有效率高于MEA方案治疗组,两组的差异有统计学意义[RR=1. 98,95%CI(1. 21,3. 24),P=0. 006],其真菌感染率亦高于MEA组,两组的差异有统计学意义[RR=2. 17,95%CI(1. 09,4. 31),P=0. 03]。结论:FLAG方案治疗RRAML的总有效率高于MEA方案,但其真菌感染率亦高。受纳入研究的数量及质量限制,本系统评价结论仍需进一步开展更多大样本、严格设计的随机对照试验加以验证。
Objective: To systematically evaluate the effectiveness and adverse reaction of FLAG and MEA in the treatment of refractory and relapse acute myeloid leukemia( RRAML). Methods: Such databases as Pub Med,Cochrane Library,Web of Science,VIP,Wan Fang Data,CNKI,CBM were searched to collect the randomized controlled trials( RCTs) on FLAG and MEA in treating refractory and relapse acute myeloid leukemia. Document selection and data fetch and the quality of included studies was evaluated by two reviewers in-dependently,and then Meta-analyses were performed using Review Manager 5. 0 software. Results: A total of six studies involving 299 patients were included. Results of Meta-analyses showed that when FLAG and MEA were used in the treatment of refractory and relapse acute myeloid leukemia,significant differences were found in the total effective rate( RR = 1. 98,95% CI: 1. 21 to 3. 24,P = 0. 006),but no significant difference was found in complete remission( RR = 1. 4 9,9 5 % CI : 0. 9 2to 2. 43,P = 0. 11) and partial remission( RR = 1. 38,95% CI: 0. 82 to 2. 32,P = 0. 23). And the fungal infection rate after treatment were also significant differences( RR = 2. 17,95% CI: 1. 09 to 4. 31,P = 0. 03). Conclusion: In the total effective rate of treatment for refractory and relapse acute myeloid leukemia,the FLAG regimen is superior to MEA regimen,but the fungal infection rate was also higher. However,all these findings should be further confirmed with more large sample and well-designed RCTs.
Objective: To systematically evaluate the effectiveness and adverse reaction of FLAG and MEA in the treatment of refractory and relapse acute myeloid leukemia( RRAML). Methods: Such databases as Pub Med,Cochrane Library,Web of Science,VIP,Wan Fang Data,CNKI,CBM were searched to collect the randomized controlled trials( RCTs) on FLAG and MEA in treating refractory and relapse acute myeloid leukemia. Document selection and data fetch and the quality of included studies was evaluated by two reviewers in-dependently,and then Meta-analyses were performed using Review Manager 5. 0 software. Results: A total of six studies involving 299 patients were included. Results of Meta-analyses showed that when FLAG and MEA were used in the treatment of refractory and relapse acute myeloid leukemia,significant differences were found in the total effective rate( RR = 1. 98,95% CI: 1. 21 to 3. 24,P = 0. 006),but no significant difference was found in complete remission( RR = 1. 4 9,9 5 % CI : 0. 9 2to 2. 43,P = 0. 11) and partial remission( RR = 1. 38,95% CI: 0. 82 to 2. 32,P = 0. 23). And the fungal infection rate after treatment were also significant differences( RR = 2. 17,95% CI: 1. 09 to 4. 31,P = 0. 03). Conclusion: In the total effective rate of treatment for refractory and relapse acute myeloid leukemia,the FLAG regimen is superior to MEA regimen,but the fungal infection rate was also higher. However,all these findings should be further confirmed with more large sample and well-designed RCTs.
引文
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[4]Zhang Liang,Zhou Hui,Chen Xiaohui.Efficacy and safety of MEAcompared with FLAG in the treatment of refractory and relapsed acute myeloid leukemia[J].Practical Pharmacy And Clinical Remedies,2014,17(11):1500-1503.[章亮,周晖,陈小会.MEA与FLAG方案治疗难治性复发性急性髓系白血病疗效及安全性分析[J].实用药物与临床,2014,17(11):1500-1503.]
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[7]Liu Hui.Comparison on therapeutic effect of FLAG regime and MEA regime on refractory and relapse acute leukemia[J].Journal of Modern Medicine and Health,2013,29(10):1520-1521.[刘慧.FLAG方案和MAE方案治疗难治复发急性髓系白血病疗效比较[J].现代医药卫生,2013,29(10):1520-1521.]
[8]Liao Yongmei,Wang Lin,He Xuehua.Therapeutic effect of FLAGregime and MEA regime on refractory and relapse acute leukemia[J].Military Medical Journal of South China,2014,28(8):835-836.[廖永梅,王淋,何雪花.FLAG方案及MAE方案治疗难治性复发性急性髓系白血病的疗效分析[J].华南国防医学杂志,2014,28(8):835-836.]
[9]Zhang Zhinan,Shen Ti.The third edition blood disease diagnostic and curative standard[J].Beijing:Science Press,2007:172-176.[张之南,沈悌.血液病诊断及疗效标准[J].北京:北京科学技术出版社,2007:172-176.]
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[12]Muluneh B,Buhlinger K,Deal AM,et al.A comparison of clofarabine-based(GCLAC)and cladribine-based(CLAG)salvage chemotherapy for relapsed/refractory AML[J].Clin Lymphoma Myeloma Leuk,2018,18(1):e13-e18.
[13]Fiegl M,Unterhalt M,Kern W,et al.Chemomodulation of sequential high-dose cytarabine by fludarabine in relapsed or refractory acute myeloid leukemia:a randomized trial of the AMLCG[J].Leukemia,2014,28(5):1001-1007.
[14]Camera A,Rinaldi CR,Palmieri S,et al.Sequential continuous infusion of fludarabine and cytarabine associated with liposomal daunorubicin(DaunoXome)(FLAD)in primary refractory or relapsed adult acute myeloid leukemia patients[J].Ann Hematol,2009,88(2):151-158.
[15]Borthakur G,Kantarjian H,Wang X,et al.Treatment of corebinding-factor in acute myelogenous leukemia with fludarabine,cytarabine,and granulocyte colony-stimulating factor results in improved event-free survival[J].Cancer,2008,113(11):3181-3185.
[16]Claus R,Wilop S,Hielscher T,et al.A systematic comparison of quantitative high-resolution DNA methylation analysis and methylation-specific PCR[J].Epigenetics,2012,7(7):772-780.
[17]Ge Jian,Zeng Qingshu,Yang Mingzhen,et al.The therapeutic effect of CAG regimen and FLAG regimen on patients with refractory or relapsed acute myeloid leukemia[J].Anhui Medical Journal,2012,33(3):268-270.[葛健,曾庆曙,杨明珍,等.CAG与FLAG方案治疗难治或复发急性髓系白血病的疗效初步研究[J].安徽医学,2012,33(3):268-270.]
[18]Lee SS,Lee JH,Kim DY,et al.Single-dose mitoxantrone in combination with continuous infusion intermediate-dose cytarabine plus etoposide for treatment of refractory or early relapsed acute myeloid leukemia[J].Leuk Res,2009,33(4):511-517.
[19]Halpern AB,Othus M,Huebner EM,et al.Mitoxantrone,etoposide and cytarabine following epigenetic priming with decitabine in adults with relapsed/refractory acute myeloid leukemia or other high-grade myeloid neoplasms:a phase 1/2 study[J].Leukemia,2017,31(12):2560-2567.
[20]Schlenk RF,Muller-Tidow C,Benner A,et al.Relapsed/refractory acute myeloid leukemia:any progress[J]?Curr Opin Oncol,2017,29(6):467-473.
[2]Sepehrizadeh Z,Mohammadi M,Emami A,et al.Assessment of cytokine expression profile in acute myeloid leukemia patients before and after chemotherapy[J].Turk J Haematol,2014,31(2):149-154.
[3]Yu Dan,Zhang Nian,Yi Xue,et al.Therapeutic effect of FLAG regime and MEA regime on refractory and relapse acute leukemia[J].Journal of Chinese Practical Diagnosis and Therapy,2013,27(11):1076-1081.[余丹,张念,易雪,等.FLAG和MEA方案治疗难治复发性急性髓系白血病疗效分析[J].中华实用诊断与治疗杂志,2013,27(11):1076-1081.]
[4]Zhang Liang,Zhou Hui,Chen Xiaohui.Efficacy and safety of MEAcompared with FLAG in the treatment of refractory and relapsed acute myeloid leukemia[J].Practical Pharmacy And Clinical Remedies,2014,17(11):1500-1503.[章亮,周晖,陈小会.MEA与FLAG方案治疗难治性复发性急性髓系白血病疗效及安全性分析[J].实用药物与临床,2014,17(11):1500-1503.]
[5]Li Weiming,Zhang Min,He Jing,et al.Clinical observation of FLAG regime and MEA regime on refractory and relapse acute leukemia[J].Clinical Focus,2006,21(7):500-501.[黎纬明,张敏,何静,等.FLAG与MEA方案治疗复发难治成人急性髓细胞白血病的临床观察[J].临床荟萃,2006,21(7):500-501.]
[6]Zhang Chunmei,Sun Zhaogang,Bai Guanchen,et al.Effect comparison of FLAG regime and MEA regime on refractory and relapse acute leukemia[J].Medical Journal of Shandong,2012,52(11):60-61.[张春梅,孙兆刚,白观臣,等.FLAG方案及MEA方案治疗难治性和复发性AML的效果比较[J].山东医药,2012,52(11):60-61.]
[7]Liu Hui.Comparison on therapeutic effect of FLAG regime and MEA regime on refractory and relapse acute leukemia[J].Journal of Modern Medicine and Health,2013,29(10):1520-1521.[刘慧.FLAG方案和MAE方案治疗难治复发急性髓系白血病疗效比较[J].现代医药卫生,2013,29(10):1520-1521.]
[8]Liao Yongmei,Wang Lin,He Xuehua.Therapeutic effect of FLAGregime and MEA regime on refractory and relapse acute leukemia[J].Military Medical Journal of South China,2014,28(8):835-836.[廖永梅,王淋,何雪花.FLAG方案及MAE方案治疗难治性复发性急性髓系白血病的疗效分析[J].华南国防医学杂志,2014,28(8):835-836.]
[9]Zhang Zhinan,Shen Ti.The third edition blood disease diagnostic and curative standard[J].Beijing:Science Press,2007:172-176.[张之南,沈悌.血液病诊断及疗效标准[J].北京:北京科学技术出版社,2007:172-176.]
[10]O'Donnell MR,Tallman MS,Abboud CN,et al.Acute myeloid leukemia,version 3.2017,NCCN clinical practice guidelines in oncology[J].J Natl Compr Canc Netw,2017,15(7):926-957.
[11]Leukemia and Lymphoma Group,Chinese Society of Hematology,Chinese Medical Associatino.The guidelines for diagnosis and treatment of acute myelogenous leukemia(relapse/refractory)in China(2017)[J].Chin J Hematol,2017,38(3):183-184.[中华医学会血液学分会白血病淋巴瘤学组.复发难治性急性髓系白血病中国诊疗指南(2017年版)[J].中华血液学杂志,2017,38(3):183-184.]
[12]Muluneh B,Buhlinger K,Deal AM,et al.A comparison of clofarabine-based(GCLAC)and cladribine-based(CLAG)salvage chemotherapy for relapsed/refractory AML[J].Clin Lymphoma Myeloma Leuk,2018,18(1):e13-e18.
[13]Fiegl M,Unterhalt M,Kern W,et al.Chemomodulation of sequential high-dose cytarabine by fludarabine in relapsed or refractory acute myeloid leukemia:a randomized trial of the AMLCG[J].Leukemia,2014,28(5):1001-1007.
[14]Camera A,Rinaldi CR,Palmieri S,et al.Sequential continuous infusion of fludarabine and cytarabine associated with liposomal daunorubicin(DaunoXome)(FLAD)in primary refractory or relapsed adult acute myeloid leukemia patients[J].Ann Hematol,2009,88(2):151-158.
[15]Borthakur G,Kantarjian H,Wang X,et al.Treatment of corebinding-factor in acute myelogenous leukemia with fludarabine,cytarabine,and granulocyte colony-stimulating factor results in improved event-free survival[J].Cancer,2008,113(11):3181-3185.
[16]Claus R,Wilop S,Hielscher T,et al.A systematic comparison of quantitative high-resolution DNA methylation analysis and methylation-specific PCR[J].Epigenetics,2012,7(7):772-780.
[17]Ge Jian,Zeng Qingshu,Yang Mingzhen,et al.The therapeutic effect of CAG regimen and FLAG regimen on patients with refractory or relapsed acute myeloid leukemia[J].Anhui Medical Journal,2012,33(3):268-270.[葛健,曾庆曙,杨明珍,等.CAG与FLAG方案治疗难治或复发急性髓系白血病的疗效初步研究[J].安徽医学,2012,33(3):268-270.]
[18]Lee SS,Lee JH,Kim DY,et al.Single-dose mitoxantrone in combination with continuous infusion intermediate-dose cytarabine plus etoposide for treatment of refractory or early relapsed acute myeloid leukemia[J].Leuk Res,2009,33(4):511-517.
[19]Halpern AB,Othus M,Huebner EM,et al.Mitoxantrone,etoposide and cytarabine following epigenetic priming with decitabine in adults with relapsed/refractory acute myeloid leukemia or other high-grade myeloid neoplasms:a phase 1/2 study[J].Leukemia,2017,31(12):2560-2567.
[20]Schlenk RF,Muller-Tidow C,Benner A,et al.Relapsed/refractory acute myeloid leukemia:any progress[J]?Curr Opin Oncol,2017,29(6):467-473.