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Journal of Chinese Integrative Medicine ›› 2009, Vol. 7 ›› Issue (11): 1023-1034.doi: 10.3736/jcim20091102

• Systematic Review • Previous Articles     Next Articles

Arsenic trioxide in combination with all-trans retinoic acid 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:2009-08-13 Online:2009-11-20 Published:2009-11-15
  • Contact: Jie-ping Chen,Jian-ping Liu E-mail:chenjpxn@yahoo.com.cn;jianping_l@hotmail.com

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Background

The studies have demonstrated that arsenic trioxide (ATO) in combination with all-trans retinoic acid (ATRA) takes effects in treatment of acute promyelocytic leukemia (APL) through different underlying mechanisms. This has established the molecular foundation of ATO plus ATRA therapy. Currently, ATO plus ATRA has also been widely used in clinical practice.
Objective

To assess the efficacy and safety of ATO in combination with ATRA for APL.
Search strategy

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), CNKI (from 1994 to December 2008), 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 authors also hand-searched Chinese periodicals potentially related to the question including Chinese Journal of Hematology, Journal of Experimental Hematology and Journal of Clinical Hematology.
Inclusion criteria

All randomized controlled trials comparing ATO plus ATRA with other regimens for the treatment of APL were included. Intervention and comparison regimens include: 1) ATO plus ATRA vs ATO monotherapy; 2) ATO plus ATRA vs ATRA monotherapy; 3) ATO plus ATRA vs ATRA plus chemotherapy; 4) ATO plus ATRA vs ATO+ATRA+chemotherapy.
Data extraction and analysis

Related data concerning complete remission rate, overall survival rate, and disease free survival rate, time to complete remission, relapse rate, mortality and adverse reactions were extracted independently by two reviewers. The different statistical methods were applied according to different data type with RevMan 5.0 software.
Results

After merging of the included trials, seven eligible randomized controlled trials with 392 cases were analyzed, among which 6 RCTs were methodologically graded as middle and one as of high risk of bias. The control therapies included ATO monotherapy, ATRA monotherapy and chemotherapy with ATO plus ATRA. Compared with ATO monotherapy, ATO plus ATRA could improve time to complete remission and relapse rate of newly diagnosed APL, but could not improve the complete remission rate, disease free survival rate, mortality and liver dysfunction of relapsed APL patients based on meta-analysis and sensitivity analysis. Compared with ATRA monotherapy, ATO plus ATRA shortened the time to complete remission, improved the disease free survival rate and relapse rate, but increased the incidence of edema during the treatment. Compared with chemotherapy with ATO plus ATRA, ATO plus ATRA could improve the complete remission rate, relapse rate, mortality and adverse reactions.
Conclusion

For newly diagnosed APL, ATO plus ATRA is superior to ATO monotherapy, ATRA monotherapy and chemotherapy with ATO plus ATRA, but due to the lack of data about comparison with the current standard treatment regimen (ATRA plus chemotherapy), it is not enough to recommend ATO plus ATRA as a frontline therapy. For relapsed APL, ATO plus ATRA is not superior to ATO monotherapy, and ATRA plus ATO is not a supportive therapy. Due to limitation of sample size and risk of bias from the included trials, the effects of ATO plus ATRA need to be confirmed by large and high-quality randomized controlled trials.

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"

Basic characteristics Dombret et al[14] Raffoux et al[15] Ren et al[16] Yang et al[17]
ATO plus ATRA ATO ATO plus ATRA ATO ATO plus ATRA ATO ATO plus ATRA ATO
Cases NA NA 10 10 43 52 15 11
Male/Female 6/4 6/4 6/4 23/20 30/22 5/10 4/7
Median age (years) 47 NA NA 34 32 39 41
Mean white blood cell count
($\bar{x}$±s , ×109/L)		 NA NA NA NA 13.6±23.9 11.9±21.5 NA NA
Disease condition Relapsed Relapsed Newly diagnosed Newly diagnosed
Basic characteristics Shen et al[18] Su et al[19] Zhong et al[20,21,22]
ATO plus ATRA ATO ATRA ATO plus
ATRA		 ATO ATRA ATO plus
ATRA		 ATO
Cases 21 20 20 40 30 36 38 36
Male/Female 12/9 12/8 9/11 19/21 12/18 18/18 23/15 22/14
Median age (years) 34 39 30.5 37.2 31 33.3 23 22
Mean white blood cell count
($\bar{x}$±s×109/L)		 NA NA NA 15.7±20.6 13.6±23.9 11.9±21.5 26.3±19.2 27.4±18.3
Disease condition Newly diagnosed Newly diagnosed Newly diagnosed

Table 2

Intervention regimens of the included studies"

Study ATO ATRA ATO plus ATRA ATO, ATRA, and
chemotherapy
Dombret et al[14] 0.15 mg/（kg·d） NA ATO 0.15 mg/(kg·d)+
ATRA 45 mg/(m2·d)		 NA
Raffoux et al[15] 0.15 mg/(kg·d) NA ATO 0.15 mg/(kg·d)+
ATRA 45 mg/(m2·d)		 NA
Ren et al[16] NA 25 mg/(m2·d) ATO 10 mg/d+
ATRA 25 mg/(m2·d)		 NA
Yang et al[17] NA 30-60 mg/d ATO 10 mg/d+
ATRA 30-60 mg/d		 NA
Su et al[18] 0.16 mg/(kg·d) 25 mg/(m2·d) ATO 0.16 mg/(kg·d)+
ATRA 30-40 mg/d		 NA
Shen et al[19] 0.16 mg/(kg·d) 25 mg/(m2·d) ATO 0.16 mg/(kg·d)+
ATRA 25 mg/(m2·d)		 NA
Zhong et al [20,21,22] NA NA ATO 10 mg/d+
ATRA 45 mg/(m2·d)		 ATO 10 mg/d+ATRA 45 mg/(m2·d)+DA/MA

Figure 2

Risk of bias from the included trials"

Figure 3

Summary of the risk of bias from the included trials"

Figure 4

Meta-analysis of relapse rate between ATO plus ATRA and ATO monotherapy"

Figure 5

Meta-analysis of relapse rate between ATO plus ATRA and ATRA monotherapy"

Figure 6

Meta-analysis of incidence of edema between ATO plus ATRA and ATO monotherapy"

Table 3

Sensitivity analysis of different outcomes between ATO plus ATRA and ATO monotherapy according to disease conditions"

Outcome Newly diagnosed APL patients
(result of sensitivity analysis and 95% CI)		 Relapsed APL patients
(result of sensitivity analysis and 95% CI)
Complete remission rate 1.67 [0.61, 4.59] 1.18 [0.20, 7.08]
Disease free survival rate 0.12 [0.01, 1.83] 2.36 [0.55, 10.07]
Mortality 0.64 [0.21, 1.93] 1.33 [0.21, 8.35]
Liver dysfunction 1.33 [0.38, 4.62] 1.00 [0.17, 5.98]
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