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. 2016 Dec 8;2016(12):CD008425. doi: 10.1002/14651858.CD008425.pub2

Arsenic trioxide for the treatment of acute promyelocytic leukaemia

ShuangNian Xu 1, JiePing Chen 1,✉, Jian Ping Liu 2, Yun Xia 3, Xi Li 1, Ya Tan 1
PMCID: PMC6463851

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the role of arsenic trioxide (ATO) for treating patients with acute promyelocytic leukaemia in comparison with regimens without ATO.

Background

Description of the condition

Acute promyelocytic leukaemia (APL) is an uncommon subtype of acute myeloid leukaemia (AML) which was initially described as a distinct clinical entity in 1957 (Hillestad 1957). It accounts for approximate 10 to 15% of all AML cases in most reports but can be as high as 32% in some area of china and 46% among AML patients of American‐Mexican descent(Chen 2003). Its clinical course and biology are distinct from other forms of AML. Morphologically, it is characterized by accumulation of abnormal promyelocytes in bone marrow and peripheral blood, and was classified as AML‐M3 by the French‐American‐British (FAB) classification in 1976 (Bennett 1976). Cytogenetically, it is commonly characterized by the presence of the PML/RARα fusion transcript which results from the unique t(15;17) translocation (Harris 1999). Other variant chromosomal translocations can be detected in no more than 2% of APL patients (Powell 2001). Clinically, its unique features include younger age at onset, frequent presentation with relatively low white blood cell counts, and severe consumptive coagulopathy with a high incidence of early fatal haemorrhages (Falanga 2001; Powell 2001; Wang 2008).

In the late 20th century, the introduction of all‐trans retinoic acid (ATRA) into the therapy of APL completely revolutionised the management and outcome of this disease. It also helped transform this once highly fatal subtype of APL into a curable condition. ATRA represents one of the most spectacular advances in the treatment of cancer, providing the first paradigm of molecule‐targeted differentiation therapy. Currently, the simultaneous administration of ATRA and anthracycline‐based chemotherapy is considered to be the standard induction regimen in newly diagnosed patients with APL. This combination results in extremely high antileukaemic efficacy; the complete remission (CR) rate could reach 90% to 95% and primary resistance has been reported in just a few anecdotal cases (Burnett 1999; Di Bona 2000; Fenaux 1999; Sanz 2004). However, approximately 20% to 30% of patients receiving ATRA‐based therapy will eventually relapse (Tallman 2002).

After the advent of ATRA came the introduction of arsenic trioxide (ATO), a form of inorganic arsenic and probably the most biologically active single agent in APL. This has provided another valuable addition to the therapeutic strategies and may contribute to further improving the clinical outcome of this disease (Douer 2005).

Description of the intervention

Brief history of arsenic as a drug

Arsenic is a naturally occurring substance that exists in organic and inorganic forms. In nature, it is rarely found in its pure elemental state. Instead, it exists as highly toxic, chemically unstable sulphides, oxides, and arsenates of potassium, sodium or calcium (Antman 2001; Waxman 2001). Although arsenic is a well‐known poison, it is also one of the oldest drugs in both Western medicine and traditional Chinese medicine (TCM). Indeed, inorganic arsenic that has been used as a drug is mainly constituted of three forms: red arsenic (As4S4, also known as realgar); yellow arsenic (As2S3, also known as orpiment); and white arsenic (As2O3, also known as ATO), which is produced by burning realgar and orpiment. The first mention of arsenic as a drug was made by Hippocrates (460 ‐ 370BC), who used realgar and orpiment to treat skin ulcers. As an ingredient of folk remedies in Central and Southern Asia, arsenic was firstly used for periodic fever, as described in Huang Di Nei‐Jing (Huangdi's Canon of Medicine, 263BC) (Zhu 2002). Later, the pharmacopedia of Shi‐Zhen Li in Chinese Ming Dynasty described the use of ATO to treat a variety of diseases (Li 1975). Although arsenic therapy was experimented with in the 16th and 17th centuries in Europe, it was seldom used because of its toxicity. In the late 18th century, Thomas Fowler created a potassium bicarbonate‐based solution of arsenic (also known as Fowler solution) that was originally used to treat periodic fever, and, later, chronic myelogenous leukaemia (CML) as well as many other diseases (Zhu 2002). However, since the early 20th century, arsenic has remained largely unused because of its toxicity and also due to the advent of radiation and cytotoxic chemotherapy (Douer 2005).

Arsenic trioxide in APL treatment

The use of arsenic trioxide in APL treatment was pioneered by Chinese investigators. In the early 1970s, a group from Harbin Medical University in Northeastern China identified ATO as an active ingredient from an old traditional Chinese recipe, and then used an arsenic compound to treat a variety of cancers with the principle of "taming an evil with a toxic agent". In 1992, Sun et al (Sun 1992) reported that, by intravenous infusion of Ailing‐1 (anti‐cancer 1), a crude solution of ATO composed of 1% ATO and trace amount of mercury chloride, 21 of 32 APL patients achieved CR with an impressive 30% survival rate after 10 years.

From 1994, clinical trials with pure ATO for the treatment of APL were conducted at the Shanghai Institute of Haematology (SIH) in Southern China. Fifteen APL patients at relapse after ATRA/chemotherapy received a dose of 0.16 mg/kg/day intravenously for 28 to 54 days. CR was obtained in 9 of 10 patients (90%) treated with ATO alone and in the remaining five treated by the combination of ATO and low‐dose chemotherapeutic drugs or ATRA (Shen 1997). These results were further confirmed by the same institution in a larger group of 47 relapsed and 11 newly diagnosed APL patients, with a CR rate of 85.1% and 72.7%, respectively (Niu 1999). Since then, similar results have been obtained in Western populations. A group from New York reported that of the 12 relapsed patients studied, 11 had CR after receiving pure ATO treatment, at doses ranging from 0.06 to 0.2 mg/kg/day, which lasted from 12 to 39 days (Soignet 1998).

Recently, the significant benefits of ATO in APL treatment have also been demonstrated by randomised controlled trials (RCT), mainly through comparing treatment including ATO versus treatment without ATO. Shen et al investigated the clinical application of ATO plus ATRA in comparison with ATRA alone. With the remaining high CR rate, the median time to achieve CR in patients treated with ATO plus ATRA was significantly shorter than those treated with ATRA alone (Shen 2004). The combination therapy showed a significant benefit on disease control of newly diagnosed APL. Similar results were obtained in a small RCT with similar trial design which included 26 cases of APL, but this clinical trial found that ATO plus ATRA may increase the incidence of adverse reactions such as renal and liver dysfunctions and oedema (Yang 2006).

The occurrence and severity of adverse reactions during ATO treatment is associated with body detoxification and excretion function of ATO, and also individual sensitivity to this drug. Several clinical trials have demonstrated that ATO treatment is only associated with mild adverse reactions, and myelosuppression and peripheral white blood cell (WBC) decrease is relatively rare. The common adverse reactions include gastrointestinal reactions such as anorexia, abdominal distension or discomfort, nausea, vomiting and diarrhoea, and skin reactions such as asteatosis cutis, rash and hyperpigmentation. Liver dysfunctions, such as elevation of aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ‐glutamyltransferase (GGT) and serum bilirubin, can also be observed in APL patients treated with ATO. Other possible adverse reactions include joint or muscle soreness, oedema, electrocardiogram abnormality, headache and increase of urea nitrogen (Harbin Medical University Pharmaceutical 2007).

How the intervention might work

APL is the clinical setting in which ATO has achieved notable success. The study of APL and the role of ATO in its treatment are among the most exciting stories in clinical oncology. A substantial body of evidence has accumulated during recent years suggesting the mechanisms by which the drug produces remissions in patients with APL. Arsenic trioxide facilitates profound cellular alterations via numerous pathways including induction of apoptosis, stimulation of differentiation, and inhibition of angiogenesis, which all take effect in APL treatment (Miller 2002; Waxman 2001). Many of the studies that show specific activities of ATO in APL have used NB4, a unique cell line derived from the bone marrow of an APL patient that carries the t(15;17) translocation juxtaposing the PML and RARα genes (Lanotte 1991).

Induction of apoptosis and stimulation of differentiation

ATO exerts dose‐dependent effects on APL cells. Under high concentration (1‐ 2 × 106 mol/L), ATO induces apoptosis, mainly through activating the mitochondria‐mediated intrinsic apoptotic pathway (Chen 1997). Under low concentration (0.25 ‐ 0.5 × 106 mol/L) and with a longer treatment course, ATO stimulates differentiation of APL cells, mainly through activating the mitogen‐activated protein kinase (MAPK) pathway or targeting PML/RARα (Chen 1996; Chen 1997; Hong 2001). Pharmacokinetic studies have shown that a range of ATO concentrations could exist in vivo.It is likely that both induction of apoptosis and stimulation of differentiation can make it possible cellular mechanisms of ATO function in a clinical setting. This point of view was then verified by examination of bone marrow of APL patients and APL mouse model under ATO treatment (Chen 2007).

Moreover, studies of the APL cell line NB4 have shown that ATO may also down‐regulate the bcl‐2 protein, inhibit glutathione peroxidase and increase cellular hydrogen peroxidase content, thereby enhancing apoptosis (Chen 1996; Dai 1999). Recently, the pro‐apoptotic ability and mechanism of ATO was further scrutinized at gene/protein level from other aspects, and a huge amount of information has been gathered. This includes histone H3 phosphoacetylation at the chromatin of CASPASE‐10 ( Li 2002), the involvement of JNK signalling, anion exchanger 2 and GSTP1‐1, up‐regulation of a set of genes responsible for reactive oxygen species production, intracellular oxidative DNA damage, suppression of human telomerase reverse transcriptase gene (hTERT), C17, and c‐Myc genes through Sp1 oxidation, repression of NFκB activation and down‐regulation of wt1 genes (Wang 2008).

The vast majority of clinical cases of APL are characterized by the t(15;17) translocation. This translocation generates a fusion between the PML gene and the RARα, which encodes a transcription factor. The resulting PML‐RARα blocks the expression of genes required for normal myeloid differentiation. The fact that ATO exerts selective therapeutic effects against APL rather than other subtypes of leukaemia suggests a crucial link between its action and PML/RARα fusion gene/protein. ATO stimulated leukaemic cell differentiation through PML/RARα has been demonstrated at a molecular level. Researchers observed that PML/RARα were induced to be degraded in APL cells upon ATO treatment in vitro and in vivo (Chen 1996; Chen 1997). This point of view was then supported by a leukaemic cell surface phenotypic transformation from CD33 to CD11b in serial immunophenotypic studies of peripheral blood and bone marrow samples from PML/RARα APL patients treated with ATO, which demonstrated that the leukaemic cells had undergone a maturation process (Soignet 1998). Studies also found that treatment of APL cells with ATO led to significant degree of sumoylation of PML‐RARα and subsequent recruitment of 11S proteasome, which is an essential process for the degradation of PML/RARα proteins (Chen 2007).

Inhibition of angiogenesis

Angiogenesis plays a critical role in the growth of solid tumours and may also be important for the expansion of leukaemic cell populations. Studies of human umbilical vein endothelial cells treated with ATO have revealed a series of events that may contribute to the ability of antileukaemia activity, including up‐regulation of endothelial cell adhesion of molecules, prevention of capillary tubule growth and branching, apoptosis of endothelial cells, and inhibition of vascular endothelial growth factor (VEGF) production. It is possible that release of VEGF by the leukaemic cells causes a positive feedback loop with the paracrine production of GM‐CSF, IL‐6, IL‐7, and IL‐10 by the stimulated, rapidly proliferating endothelial cells. These cytokines then provide additional growth signals to the leukaemic cell population, and a vicious cycle ensues. The ability of ATO to interrupt this loop may contribute to its efficacy (Roboz 2000).

Why it is important to do this review

Taken together, both basic and clinical studies have demonstrated that ATO is particularly effective in the treatment of both newly diagnosed and relapsed APL patients. As a single agent, it induces CR, causing few adverse effects and only minimal myelosuppression (Miller 2002). When used in combination with other drugs, it may shorten the time to achieve CR (Shen 2004). These results remind us that the advent of ATO is very likely to further improve the therapeutic outcomes of APL patients, especially the relapsed. Therefore, we are going to perform a systematic review concerning ATO for the treatment of APL to inform the current status of clinical practice and guide further clinical research in this area.

Objectives

To assess the role of arsenic trioxide (ATO) for treating patients with acute promyelocytic leukaemia in comparison with regimens without ATO.

Methods

Criteria for considering studies for this review

Types of studies

We considered only randomised controlled trials (RCT) as primary studies. Quasi‐randomised trials, crossover trials, cohort trials and case‐controlled studies were not included due to the risk of bias.

We included both full‐text and abstract publications.

Types of participants

Inclusion criteria are as follows:

  1. Patients with newly diagnosed or relapsed APL based on FAB morphological criteria or WHO classification, or both.

  2. Participants were included irrespective of age or gender.

For trials with mixed populations, we included the subgroup of the trial if it is reported for APL patients. Alternatively, if an APL subgroup is not reported separately, we included the whole trial providing the total sample consists of at least 90% of APL patients.

Types of interventions

Comparison of treatment including ATO versus treatment without ATO for the treatment of APL.

Specifically, we allowed any of the following comparisons:

  1. ATO versus placebo;

  2. ATO plus ATRA with or without chemotherapy versus same regimen without ATO;

  3. ATO plus chemotherapy versus same chemotherapy without ATO (both arms without ATRA).

We did not include studies which aimed to compare different ATO administration styles (continuous slow ATO intravenous infusion versus routine ATO infusion) on APL treatment.

We excluded trials that allow autologous or allogeneic stem cell transplantation in the control arm.

Types of outcome measures

Primary outcomes

We analysed overall survival (OS) and disease‐free survival (DFS) as primary outcomes. OS is defined as time from randomisation to death. DFS is defined as time from CR to relapse, death from any cause, or censoring of the data (Shen 2004).

Secondary outcomes

We analysed the following parameters as secondary endpoints:

  • CR rate;

  • relapse rate;

  • time to achieve CR: time from the start of treatment to the achievement of CR;

  • death during induction phase;

  • adverse reactions.

We also considered quality of life if it was analysed using a standardised validated questionnaire.

Search methods for identification of studies

We used search strategies based on those depicted in Chapter 6 of the Cochrane Handbook for Systematic Reviews of Interventions (Lefebvre 2009).

Electronic searches

We identified trials by electronic searches of the following databases of medical literature:

  1. MEDLINE (January 1950 to March 2010, see Appendix 1 for search strategy);

  2. EMBASE (January 1950 to March 2010, see Appendix 2 for search strategy);

  3. Chinese BioMedical Literature Database (CBM) (January 1978 to March 2010, see Appendix 3 for search strategy);

  4. The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 2, see Appendix 4 for search strategy).

We also searched the web site metaregister of clinical trials (available at: http://www.controlled‐trials.com/mrct/) for ongoing trials (see Appendix 5 for search strategy) and we saved the search results of each item for further screening.

In addition, we searched the following conference proceedings:

  1. Annual meeting of the American Society of Clinical Oncology (available at: http://www.asco.org/ASCOv2/Meetings/Abstracts) (2009);

  2. International Society for Hematology and Stem Cells (available at: http://www.exphem.org/search) (from 1999 to present).

Searching other resources

  • We inspected the reference lists of all identified trials and relevant review articles.

  • We electronically searched Conference Proceedings of the Chinese Society of Hematology (1980 to present).

We applied no language restrictions.

Data collection and analysis

Selection of studies

The primary review author (SX) conducted an initial screening of the titles and abstracts of the identified references in an attempt to determine if the references are of potential relevance. This first screening will discard studies that are clearly ineligible. We tried our best to obtain copies of full articles for references reporting a potentially eligible trial. For unpublished trials, we tried to obtain information from the trial protocol or other available sources. Two review authors(SX/YX) independently applied the following selection criteria on the methods sections of the selected trials and will independently decide on eligibility. The review authors will not be blinded to the trial author's name and institution. We resolved any disagreements through discussion (Higgins 2008a).

At every stage of literature searching and screening, we documented the overall number of trials identified, excluded and included, with reasons, in a Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) flow of information (Liberati 2009; Moher 2009).

Data extraction and management

Three groups of data were extracted.

  1. Details regarding the quality of the included studies, as is reflected in the section of "assessment of risk of bias in included studies".

  2. Study characteristics: language, date, place and authors of publication, date of publication, numbers of centres, detailed nature of participants, detailed nature of interventions and outcomes.

  3. Results of included studies as described in the section "type of outcome measures". If an included trial does not contribute data on a particular outcome, we will record its reason carefully and consider the possibility of selective reporting.

Two individual review authors (SX/YX) independently extracted data from the studies identified for inclusion. Any disagreement was resolved by consensus. All extracted information was entered into printed data‐extracting forms and finally entered into the latest Cochrane Review Manager software (Review Manager 5).

Assessment of risk of bias in included studies

Two review authors (SX/YX) independently reviewed each included study according to its design and how the trial was conducted to assess the possibility of bias. Assessment of risk of bias in included studies was based on the following criteria (Higgins 2009):

  • Was the allocation sequence adequately generated?

  • Was allocation adequately concealed?

  • Was knowledge of the allocated intervention adequately prevented during the study?

  • Were incomplete outcome data adequately addressed (for every outcome separately)?

  • Are reports of the study free of suggestion of selective outcome reporting?

  • Was the study apparently free of other problems that could put it at a high risk of bias?

We graded studies as low risk of bias, unclear risk of bias and high risk of bias according to the summary assessment of risk of bias as is suggested by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2009).

Measures of treatment effect

For time‐to‐event data including OS and DFS, we extracted hazard ratios with standard errors. If hazard ratios were not reported, we used the indirect estimating methods described by Tierney to calculate them (Tierney 2007). In reporting results, we adopted the hazard ratio (HR) as the measure of treatment effect with 95% confidence intervals as the measure of uncertainty.

For dichotomous data, such as CR rate, relapse rate, mortality and adverse reactions, we extracted or calculated events plus the total number of participants in each arm of every study. When reporting results, we adopted odds ratios (OR) as measures of treatment effect with 95% confidence intervals as measures of uncertainty.

For continuous data, such as quality of life and average time to achieve CR, we extracted or calculated the mean and its standard deviation plus the total amount in each arm of every study. From this we calculated the mean difference when the outcomes were measured in the same way across different studies. If the studies assessed the same outcome but measured it in a variety of ways, we used the standardized mean difference as a summary statistic (Higgins 2009). Either of the two measures selected were reported with its 95% confidence interval as the measure of uncertainty.

Unit of analysis issues

For parallel RCTs in which participants were individually randomised to one of two intervention groups, and a single measurement for each outcome from each participant was collected and analysed, we considered the individual participant as a unit of analysis.

For RCTs with multi‐intervention groups, firstly, we made a distinction between situations in which a study can contribute several independent comparisons (i.e. with no intervention group in common) and those in which several comparisons are correlated because they have intervention groups and participants in common. If the latter situation is encountered, we combined groups to create a single pair‐wise comparison to overcome a possible unit‐of‐analysis error.

Dealing with missing data

Missing data are very likely to be encountered during the data extraction process. At first, we distinguished 'missing at random' and 'missing not at random'. Then we sought missing or additional information from the authors when clarification or extra data are needed. If we still cannot obtain the necessary data, we made explicit the assumptions of any methods used to cope with missing data: for example, that the data are assumed missing at random, or that missing values were assumed to have a particular value such as a poor outcome.We also addressed the potential impact of missing data on the findings of the review in the discussion section (Higgins 2009).

Assessment of heterogeneity

We examined heterogeneity across studies qualitatively by inspecting the distribution of points estimates for the effect measure and the overlap in their confidence intervals on the forest plot. We also used the Chi2 statistic to check for heterogeneity and I2 statistic for inconsistency (Higgins 2002; Higgins 2003; Higgins 2008b). We used the following rough guide to interpret:

  • 0% to 40%: might not be important;

  • 30% to 60%: may represent moderate heterogeneity;

  • 50% to 90%: may represent substantial heterogeneity;

  • 75% to 100%: considerable heterogeneity.

Assessment of reporting biases

We made all necessary efforts to identify unpublished trials through comprehensively searching for studies that meet the eligibility criteria for this Cochrane review. For only 4 studies (less than 10) are included, we did not perform funnel plots to examine the likely presence of reporting bias in meta‐analysis since the power of the test is too low to distinguish chance from real asymmetry (Higgins 2009).

We carefully examined the author(s), institute(s) and other relevant information in order to avoid including duplicate publications.

We imposed no language or location restrictions, thus minimising language bias and location bias.

Data synthesis

We synthesized data with the latest Cochrane Review Manager software (Review Manager 5.0.24).

For dichotomous and continuous data, we used a fixed‐effect model with Mantel‐Haenszel method for the primary meta‐analysis, and repeat statistical analysis adopting a random‐effects model with DerSimonian Laird method in sensitivity analysis (Higgins 2009).

For time‐to‐event data, we only used a fixed‐effect model with 'O‐E and Variance' outcomes.

Subgroup analysis and investigation of heterogeneity

We took doses of ATO (0.16mg/(kg⁃d) and 10mg/d as reported in the primary literature) as indicators for subgroup analysis.

Sensitivity analysis

We did not perform sensitivity analysis based on results of "assessment of risk of bias" (excluding studies with high risk of bias if there are any) because all included studies are with moderate risk of bias. We did sensitivity analysis by repeating statistical analysis with a random‐effects model with DerSimonian Larid method for dichotomous and continuous data.

Acknowledgements

We are indebted to Ina Monsef, Trial Search Co‐ordinator of the CHMG, for her assistance with the search strategy. The authors wish to thank Nicole Skoetz (Managing Editor), the editors of the CHMG, the team of theeditorial base, as well as Céline Fournier, the consumer of the group for their valuable comments and corrections on this revieMany thanks to the copy editor for final corrections.

Appendices

Appendix 1. MEDLINE search strategy

#1 exp Leukemia, Myeloid, Acute/ #2 leukemia, myeloid/ #3 acute disease/ #4 2 and 3 #5 (acut$ or akut$ or agud$ or aigu$).tw,kf,ot. #6 ((myelo$ or mielo$ or nonlympho$ or granulocytic$) and (leuk?em$ or leuc$)).tw,kf,ot. #7 5 and 6 #8 aml.tw,kf,ot. #9 Leukemia, Promyelocytic, Acute/ #10 (acut$ or akut$ or agud$ or aigu$).tw,kf,ot. #11 ((promyelocyt$ or promielocitic$ or promyelozyt$ or progranulocyt$) and (leuk?em$ or leuc$)).tw,kf,ot. #12 10 and 11 #13 apl.tw,kf,ot. #14 FAB M3.tw,kf,ot. #15 1 or 4 or 7 or 8 or 9 or 12 or 13 or 14 #16 trisenox$.tw,kf,nm,ot. #17 arsenic$.tw,kf,ot,nm. #18 arsenic trioxide.tw,kf,nm,ot. #19 arsenit$.tw,kf,nm,ot. #20 As2o3.tw,kf,nm,ot. #21 or/16‐20 #22 15 and 21

Appendix 2. EMBASE search strategy

#1 exp ACUTE GRANULOCYTIC LEUKEMIA/ #2 MYELOID LEUKEMIA/ #3 ACUTE DISEASE/ #4 2 and 3 #5 (acut* or akut* or agud* or aigu*).tw. #6 (myelo* or mielo* or nonlympho* or granulocytic*).tw. #7 (leukem* or leukaem* or leuc*).tw. #8 5 and 6 and 7 #9 aml.tw. #10 PROMYELOCYTIC LEUKEMIA/ #11 (acut* or akut* or agud* or aigu*).tw. #12 (promyelocyt* or promielocitic* or promyelozyt* or progranulocyt*).tw. #13 (leukem* or leukaem* or leuc*).tw. #14 11 and 12 and 13 #15 FAB M3.tw. #16 1 or 4 or 8 or 9 or 10 or 14 or 15 #17 ARSENIC/ #18 ARSENIC TRIOXIDE/ #19 trisenox*.tw. #20 arsenic*.tw. #21 arsenic trioxide.tw. #22 arsenit*.tw. #23 As2O3.tw. #24 or/17‐23 #25 16 and 24

Appendix 3. CBM search strategy

1 promyelocytic leukaemia AND arsenic trioxide

2 myeloid leukaemia AND arsenic trioxide

3 promyelocytic leukaemia AND arsenical

4 myeloid leukaemia AND arsenical

Appendix 4. CENTRAL search strategy

#1 MeSH descriptor Leukemia, Myeloid, Acute explode all trees #2 MeSH descriptor Leukemia, Myeloid explode all trees #3 MeSH descriptor Acute Disease explode all trees #4 (#2 OR #3) #5 (acut* or akut* or agud* or aigu*) #6 ((myelo* or mielo* or nonlympho* or granulocytic*) and (leuk*em* or leuc*)) #7 (#5 AND #6) #8 aml #9 MeSH descriptor Leukemia, Promyelocytic, Acute explode all trees #10 (acut* or akut* or agud* or aigu*) #11 ((promyelocyt* or promielocitic* or promyelozyt* or progranulocyt*) and (leuk*em* or leuc*)) #12 (#10 AND #11) #13 apl #14 (#1 OR #4 OR #7 OR #8 OR #9 OR #12 OR #13) #15 (trisenox*) #16 (arsenic*) #17 (arsenic trioxide) #18 (arsenit*) #19 (As2O3) #20 (#15 OR #16 OR #17 OR #18 OR #19) #21 (#14 AND #20)

Appendix 5. metaRegister search strategy

1.promyelocytic leukemia AND arsenic

2.promyelocytic leukaemia AND arsenic

3.promyelocytic leukemia AND trisenox

4.promyelocytic leukaemia AND trisenox

5.promyelocytic leukemia AND arsenite

6.promyelocytic leukaemia AND arsenite

7.myeloid leukemia AND arsenic

8.myeloid leukaemia AND arsenic

9.myeloid leukemia AND trisenox

10.myeloid leukaemia AND trisenox

11.myeloid leukemia AND arsenite

12.myeloid leukaemia AND arsenite

What's new

Last assessed as up‐to‐date: 20 June 2010.

Date Event Description
8 December 2016 Amended withdrawn
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Contributions of authors

ShuangNian Xu: protocol development, studies identification, studies screening, data extracting, data analysis, report drafting.

Yun Xia: screening studies and extracting data.

Xi Li: studies identification, report drafting and revision.

Ya Tan: studies identification, report drafting and revision.

JianPing Liu: developing protocol, providing methodological perspectives and revise the protocol and the review.

JiePing Chen: protocol development, studies identification, studies screening, report drafting.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • National Key Basic Research and Development Plan (2006CB504602), China.

Declarations of interest

None known.

Notes

The completion of the last task is overdue for more than one year. New authors are being sought to take over this protocol.

Withdrawn from publication for reasons stated in the review

References

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