Search JIM Advanced Search

Journal of Chinese Integrative Medicine ›› 2009, Vol. 7 ›› Issue (9): 801-808.doi: 10.3736/jcim20090901

• Systematic Review •     Next Articles

Efficacy of arsenic trioxide for acute promyelocytic leukemia: A systematic review and meta-analysis

Shuang-nian Xua,Jie-ping Chena,Jian-ping Liub,Yun Xiab   

  1. a Center for Hematology,Southwest Hospital, Third Military Medical University, Chongqing 400038, China
    b Center for Evidence-Based Medicine,Beijing University of Chinese Medicine, Beijing 100029, China
  • Received:2009-06-04 Accepted:2009-08-04 Online:2009-09-20 Published:2009-09-15
  • Contact: Jie-ping Chen, Jian-ping Liu;


To systematically review the efficacy and safety of arsenic trioxide (ATO) in treatment of acute promyelocytic leukemia (APL).

The Cochrane Library (Issue 1, 2009), Cochrane Central Register of Controlled Trials (from 1970 to January 2009), MEDLINE (from 1978 to October 2008), EMBASE (from 1950 to March 2009), Chinese Biological Medical Literature Database (from 1978 to December 2008), China National Knowledge Infrastructure (CNKI, from 1994 to December 2008), and China Medical Academic Conference Database (from 1994 to December 2008) were electronically searched. We also searched the Meta-Register of controlled trials, Conference Proceedings of American Society of Hematology (from 1946 to December 2008) and Conference Proceedings of American Society of Clinical Oncology (from 1946 to December 2008) on the internet for grey literature. The related journals in the library of Third Military Medical University were hand-searched. The randomized controlled trials (RCTs) of ATO in treatment of APL were included. We adopted complete remission, overall survival rate, disease free survival rate, time to complete remission, relapse rate, mortality and adverse reactions as outcome indicators. Data were entered and analyzed with the Cochrane review manager software 5.0 (RevMan 5.0).

After merger of the included trials, five eligible RCTs with 328 cases were included. All the RCTs focused on the comparison of all-trans retinoic acid (ATRA) plus ATO regimen with ATRA monotherapy. Meta-analysis showed that the effect indexes for time to complete remission, two-year disease free survival rate, relapse rate, incidence of edema and incidence rate of QT interval prolongation were –1.20 [–1.68, –0.72], 8.64 [1.66,45.00], 0.21 [0.09,0.47], 4.16 [1.46,11.79] and 22.10 [2.75,177.49], respectively. The influences on other outcome indicators such as complete remission and leukocytosis were statistically non-significant.

ATO can prolong disease free survival and reduce the time to complete remission and relapse rate of newly diagnosed APL patients, and increase the incidence of edema and prolongation of corrected QT interval during the treatment. Due to limitation of the included trials, this conclusion needs to be validated by further studies.

Key words: Arsenic trioxide, Leukemia, Promyelocytic, Acute, Randomized controlled trial, Systematic review, Meta-analysis

Figure 1

Flow diagram of literature searching and screening"

Table 1

Basic characteristics of the included studies"

Study Cases* Male/Female Median age (years) White blood cell count ($\bar{x}$±s, 109/L) Treatment program
ATO (–) group ATO (+) group ATO (–) group ATO (+) group ATO (–) group ATO (+) group ATO (–) group ATO (+) group ATO (–) group ATO (+) group
Shen et al[14] 20 21 12/8 9/12 30.5 34 Did not report Did not report ATRA 25 mg/(m2·d) ATO 0.16 mg/(kg·d); ATRA 25 mg/(m2·d)
Su et al [15] 30 40 12/18 18/22 31 37.2 11.9±21.5 15.7±20.6 ATRA 25 mg/(m2·d) ATO 0.16 mg/(kg·d); ATRA 30-40 mg/d
Ren et al [16] 52 43 30/22 23/20 32 34 11.9±21.5 13.6±23.9 ATRA 25 mg/(m2·d) ATO 10 mg/d; ATRA 25 mg/(m2·d)
Yang et al[17] 11 15 4/7 5/10 41 39 Did not report Did not report ATRA 30-60 mg/d ATO 10 mg/d; ATRA 30-60 mg/d
Zhou et al [9,10,11,12,13] 48 48 30/18 28/20 23 21 7.8±3.0 8.2±2.5 ATO 0.16 mg/(kg·d), routine intravenous infusion (30-40 drops per minute) ATO 0.16 mg/(kg·d), continuous slow intravenous infusion (8 drops per minute)

Figure 2

Bias risk from the included trials"

Figure 3

Summary of the bias risk from the included trials"

Figure 4

Effects of adding ATO on complete remission rate of APL patients"

Figure 5

Effects of adding ATO on the relapse rate of APL patients"

[1] Lu DP. Therapeutics of leukemia[M]. Beijing: Science Press, 1992: 152
陆道培 . 白血病治疗学[M]. 北京: 科学出版社, 1992: 152
[2] Ribeiro RC, Rego E . Management of APL in developing countries: epidemiology, challenges and opportunities for international collaboration[J]. Hematology Am Soc Hematol Educ Program, 2006: 162-168
[3] Ribeiro RC, Rego E . Acute promyelocytic leukemia: from highly fatal to highly curable[J]. Blood, 2008,111(5):2505-2515
doi: 10.1182/blood-2007-07-102798
[4] Kelaidi C, Ades L, Chevret S, Sanz M, Guerci A , Thomas X, de Botton S, Raffoux E, Rayon C, Fegueux N, Bordessoule D, Rigal-Huguet F, Link H, Stoppa A, Vekhoff A, Meyer-Monard S, Castaigne S, Dombret H, Degos L, Fenaux P. Late first relapses in APL treated with all-trans-retinoic acid- and anthracycline-based chemotherapy: The European APL group experience(APL 91 and APL 93 trials)[J]. Leukemia, 2006,20(5):905-907
doi: 10.1038/sj.leu.2404158
[5] Zhang TD, Li YS . Clinical analysis and experimental study of Ailing Ⅰ in treatment of acute promyelocytic leukemia[J]. Zhong Xi Yi Jie He Za Zhi, 1984,4(1):19-20
张亭栋, 李元善 . 癌灵Ⅰ号治疗急性粒细胞白血病临床分析及实验研究[J]. 中西医结合杂志, 1984,4(1):19-20
[6] Ma J . Review of progress on treatment of acute promyelocytic leukemia with arsenic trioxide[J]. Guo Ji Shu Xue Yu Xue Ye Xue Za Zhi, 2007,30(3):210-213
doi: 10.3760/cma.j.issn.1673-419X.2007.03.004
马军 . 三氧化二砷治疗急性早幼粒细胞白血病的回顾及进展[J]. 国际输血和血液学杂志, 2007,30(3):210-213
doi: 10.3760/cma.j.issn.1673-419X.2007.03.004
[7] Higgins JPT , Green S . Cochrane Handbook for Systematic Reviews of Interventions Version 5. 0. 0 [updated February] 2008[M]. Oxford: The Cochrane Library,2008
[8] Tierney JF, Stewart LA, Ghersi D, Burdett S , Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis[J]. Trials, 2007, 8: 16
doi: 10.1186/1745-6215-8-16 pmid: 1920534
[9] Zhou J, Meng R, Wang Y, Yang BF . Clinical observation and following up of two administration methods of arsenic trioxide in treatment of acute promyelocytic leukemia[J]. Zhonghua Yi Xue Za Zhi, 2004,84(5):405-408
doi: 10.3760/j:issn:0376-2491.2004.05.015
周晋, 孟然, 王艳, 杨宝峰 . 三氧化二砷不同给药方法治疗急性粒细胞白血病的临床观察和随访[J]. 中华医学杂志, 2004,84(5):405-408
doi: 10.3760/j:issn:0376-2491.2004.05.015
[10] Zhou J, Meng R, Yang BF . Comparing two arsenic trioxide administration methods in APL therapy[J]. Chin Med J (Engl), 2004,117(9):1411-1413
[11] Zhou J, Meng R, Sui XH, Meng L, Jia J, Yang BF . Effects of administration styles of arsenic trioxide on intracellular arsenic concentration, cell differentiation and apoptosis[J]. Haematologica, 2005,90(9):1277-1279
[12] Zhou J, Meng R, Sui XH, Meng L, Yang BF . Effects of arsenic trioxide administration styles on leukocytosis[J]. Chin Med Sci J, 2006,21(2):111-114
pmid: 16845799
[13] Zhou J, Meng R, Yang BF . Clinical effects of arsenic trioxide by slowing-intravenous infusion on acute promyelocyte leukemia[J]. Chin Med Sci J, 2005,20(2):137
[14] Shen ZX, Shi ZZ, Fang J, Gu BW, Li JM, Zhu YM, Shi JY, Zheng PZ, Yan H, Liu YF, Chen Y, Shen Y, Wu W, Tang W, Waxman S, De Thé H, Wang ZY, Chen SJ, Chen Z . All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia[J]. Natl Acad Sci U S A, 2004,101(15):5328-5335
doi: 10.1073/pnas.0400053101
[15] Su XL, Xia WL . Clinical observation of all-trans retinoic acid and arsenic trioxide in treatment of newly diagnosed acute promyelocytic leukemia[J]. Ji Ceng Yi Xue Lun Tan, 2006,10(4):338-339
doi: 10.3969/j.issn.1672-1721.2006.07.030
苏秀连, 夏维林 . 维甲酸联合砷剂治疗初发APL的临床疗效观察[J]. 基层医学论坛, 2006,10(4):338-339
doi: 10.3969/j.issn.1672-1721.2006.07.030
[16] Ren JH, Lin FR, Guo XN, Wang Y, Zhang JN, Wang Y, Dong ZR . Clinical observation of all-trans retinoic acid, arsenic trioxide and chemotherapy in treating acute promyelocytic leukemia[J]. Zhonghua Xue Ye Xue Za Zhi, 2004,25(7):437-438
doi: 10.3760/j:issn:0253-2727.2004.07.016
任金海, 林凤茹, 郭晓楠, 王颖, 张静楠, 王艳, 董作仁 . 全反式维甲酸、三氧化二砷及联合化疗治疗急性早幼粒细胞白血病临床观察[J]. 中华血液学杂志, 2004,25(7):437-438
doi: 10.3760/j:issn:0253-2727.2004.07.016
[17] Yang EQ, Liu ZM, He C . Efficacy of all-trans retinoic acid and arsenic trioxide in treatment of newly diagnosed acute promyelocytic leukemia[J]. Bai Xue Bing Lin Ba Liu, 2006,15(3):216-217
杨恩芹, 刘志梅, 贺春 . 维a酸与亚砷酸联合治疗初发的急性早幼粒细胞白血病疗效分析[J]. 白血病·淋巴瘤, 2006,15(3):216-217
[18] Chen Z, Zhao WL, Shen ZX, Li JM, Chen SJ, Zhu J, Lallemand BV, Zhou J, Guillemin MC, Vitoux D, de The H. Arsenic trioxide and acute promyelocytic leukemia: clinical and biological[J]. Curr Top Microbiol Immunol, 2007, 313: 129-144
doi: 10.1007/978-3-540-34594-7_8 pmid: 17217042
[19] Chen GQ, Shi XG, Tang W, Xiong SM, Zhu J, Cai X, Han ZG, Ni JH, Shi GY, Jia PM, Liu MM, He KL, Niu C, Ma J, Zhang P, Zhang TD, Paul P, Naoe T, Kitamura K, Miller W, Waxman S , Wang ZY, de The H, Chen SJ, Chen Z. Use of arsenic trioxide(As2O3) in the treatment of acute promyelocytic leukemia(APL): Ⅰ. As2O3 exerts dose-dependent dual effects on APL cells[J]. Blood, 1997,89(9):3345-3353
[20] Douer D, Tallman M . Arsenic trioxide: new clinical experience with an old medication in hematologic malignancies[J]. J Clin Oncol, 2005,23(10):2396-2410
doi: 10.1200/JCO.2005.10.217 pmid: 15800332
[1] Chiung-Hui Huang, Mei-Ling Yeh, Fang-Pey Chen, Daphne Wu. Low-level laser acupuncture reduces postoperative pain and morphine consumption in older patients with total knee arthroplasty: A randomized placebo-controlled trial. Journal of Integrative Medicine, 2022, 20(4): 321-328.
[2] Ming-min Xu, Pei Guo, Qing-yu Ma, Xuan Zhou, Yu-long Wei, Lu Wang, Yue Chen, Yu Guo. Can acupuncture enhance therapeutic effectiveness of antidepressants and reduce adverse drug reactions in patients with depression? A systematic review and meta-analysis. Journal of Integrative Medicine, 2022, 20(4): 305-320.
[3] Jia-yi Zhao, Jin Pu, Jian Fan, Xin-yu Feng, Jian-wen Xu, Rong Zhang, Yan Shang. Tanshinone IIA prevents acute lung injury by regulating macrophage polarization. Journal of Integrative Medicine, 2022, 20(3): 274-280.
[4] Ting-ting Lu, Cun-cun Lu, Mei-xuan Li, Li-xin Ke, Hui Cai, Ke-hu Yang. Reporting and methodological quality of meta-analyses of acupuncture for patients with migraine: A methodological investigation with evidence map. Journal of Integrative Medicine, 2022, 20(3): 213-220.
[5] Maryam Azimi, Hanieh Niayesh, Mahboobeh Raeiszadeh, Sedigheh Khodabandeh-shahraki. Efficacy of the herbal formula of Foeniculum vulgare and Rosa damascena on elderly patients with functional constipation: A double-blind randomized controlled tria. Journal of Integrative Medicine, 2022, 20(3): 230-236.
[6] Ubiratan Cardinalli Adler, Maristela Schiabel Adler, Ana Elisa Madureira Padula, Livia Mitchiguian Hotta, Amarilysde Toledo Cesar, José Nelson Martins Diniz, Helen de Freitas Santos, Edson Zangiacomi Martinez. Homeopathy for COVID-19 in primary care: A randomized, double-blind, placebo-controlled trial (COVID-Simile study). Journal of Integrative Medicine, 2022, 20(3): 221-229.
[7] Xin Wang, Wen-juan Song, Yi Ruan, Bing-chu Li, Can Lü, Nian Huang, Fan-fu Fang, Wei Gu. Core muscle functional strength training for reducing the risk of low-back pain in military recruits: An open-label randomized controlled trial. Journal of Integrative Medicine, 2022, 20(2): 145-152.
[8] Witoo Dilokthornsakul, Ramanya Kosiyaporn, Rattanamanee Wuttipongwaragon, Piyameth Dilokthornsakul. Potential effects of propolis and honey in COVID-19 prevention and treatment: A systematic review of in silico and clinical studies. Journal of Integrative Medicine, 2022, 20(2): 114-125.
[9] Deng-chao Wang, Miao Yu, Wen-xian Xie, Li-yan Huang, Jian Wei, Yue-hua Lei. Meta-analysis on the effect of combining Lianhua Qingwen with Western medicine to treat coronavirus disease 2019. Journal of Integrative Medicine, 2022, 20(1): 26-33.
[10] Jun-peng Yao, Li-ping Chen, Xian-jun Xiao, Ting-hui Hou, Si-yuan Zhou, Ming-min Xu, Kai Wang, Yu-jun Hou, Lin Zhang, Ying Li. Effectiveness and safety of acupuncture for treating functional constipation: An overview of systematic reviews. Journal of Integrative Medicine, 2022, 20(1): 13-25.
[11] Yang-hao-tian Wu, Wen-bo He, Yin-yan Gao, Xue-mei Han. Effects of traditional Chinese exercises and general aerobic exercises on older adults with sleep disorders: A systematic review and meta-analysis. Journal of Integrative Medicine, 2021, 19(6): 493-502.
[12] Yi Yuan, Rui-Ting Wang, Jun Xia, Hui-Juan Cao. Interventions for preventing influenza: an overview of Cochrane systematic reviews and a Bayesian network meta-analysis. Journal of Integrative Medicine, 2021, 19(6): 503-514.
[13] Meng-zhu Zhao, Chen Zhao, Shuang-shuang Tu, Xu-xu Wei, Hong-cai Shang. Evaluating the methodology of studies conducted during the global COVID-19 pandemic: A systematic review of randomized controlled trials. Journal of Integrative Medicine, 2021, 19(4): 317-326.
[14] Si-chun Gu, Jie Zhou, Qing Ye, Can-xing Yuan. Pingchan granule for depressive symptoms in Parkinson’s disease: A randomized, double-blind, placebo-controlled trial. Journal of Integrative Medicine, 2021, 19(2): 120-128.
[15] Jie Wu, Shu-wei Duan, Hong-tao Yang, Yue-yi Deng, Wei Li, Ya-ni He, Zhao-hui Ni, Yong-li Zhan, Shan Lin, Zhi-yong Guo, Jun Zhu, Jing-ai Fang, Xu-sheng Liu, Li-hua Wang, Rong Wang, Nian-song Wang, Xiao-hong Cheng, Li-qun He, Ping Luo, Shi-ren Sun s, Ji-feng Sun, Ai-ping Yin, Geng-ru Jiang, Hong-yu Chen, Wen-hu Liu, Hong-li Lin, Meng Liang, Lu Ma, Ming Chen, Li-qun Song, Jian Chen, Qing Zhu, Chang-ying Xing, Yun Li, Ji-ning Gao, Rong-shan Li, Ying Li, Hao Zhang, Ying Lu, Qiao-ling Zhou, Jun-zhou Fu, Qiang He, Guang-yan Cai, Xiang-mei Chen. Efficacy and safety of Shenyankangfu Tablet, a Chinese patent medicine, for primary glomerulonephritis: A multicenter randomized controlled trial. Journal of Integrative Medicine, 2021, 19(2): 111-119.
Full text



[1] Jin-rong Fu. Establishment of multivariate diagnosis and treatment system of modern gynecology of traditional Chinese medicine. Journal of Chinese Integrative Medicine, 2008, 6(1): 22-24
[2] Hao Li, Ming-jiang Yao, Wen-ming Zhao, Jie Guan, Lin-lin Cai, Ling Cui. A randomized, controlled, double-blind trial of Huannao Yicong capsule in senile patients with mild cognitive impairment. Journal of Chinese Integrative Medicine, 2008, 6(1): 25-31
[3] Zhi-chun Jin. Problems in establishing clinical guideline for integrated traditional Chinese and Western medicine. Journal of Chinese Integrative Medicine, 2008, 6(1): 5-8
[4] SUN Ming-yu, ZUO Jian, DUAN Ji-feng, HAN Jun, FAN Shi-ming, ZHANG Wei, ZHU Li-fang, YAO Ming-hui. Antitumor activities of kushen flavonoids in vivo and in vitro. Journal of Chinese Integrative Medicine, 2008, 6(1): 51-59
[5] Min Cheng, Qiong Feng, Shu-wen Qian, Hui Gao, Cui-qing Zhu. Preliminary assay of p-amyloid binding elements in heart-beneficial recipe. Journal of Chinese Integrative Medicine, 2008, 6(1): 68-72
[6] Ning-qun Wang, Liang-duo Jiang, Zong-xing Li. Research progress in asthma-related quality of life. Journal of Chinese Integrative Medicine, 2008, 6(1): 93-97
[7] Jing-yuan Mao, Chang-xiao Liu, Heng-he Wang, Guang-li Wei , Zhen-peng Zhang, Jie Xing, Wang Xian liang , Ying-fei Bi . Effects of Shenmai Injection on serum concentration and pharmacokinetics of digoxin in dogs with heart failure. Journal of Chinese Integrative Medicine, 2010, 8(11): 1070-1074
[8] Zhi-mei Wang, Bin Zhang. A study on translation of ellipses in Huangdi Neijing from perspective of hermeneutic theory. Journal of Chinese Integrative Medicine, 2010, 8(11): 1097-1100
[9] Gui Yu, Jie Wang. Thinking on building the network cardiovasology of Chinese medicine. Journal of Chinese Integrative Medicine, 2012, 10(11): 1206-1210
[10] Pedro Saganha João, Doenitz Christoph, Greten Tobias, Efferth Thomas, J. Greten Henry. Qigong therapy for physiotherapists suffering from burnout: a preliminary study. Journal of Chinese Integrative Medicine, 2012, 10(11): 1233-1239