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.
To assess the efficacy and safety of ATO in combination with ATRA for 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), 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.
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.
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.
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.