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The role of maintenance therapy in acute promyelocytic leukemia in the first complete remission

  1. Eli Muchtar1,*,
  2. Liat Vidal1,
  3. Ron Ram2,
  4. Anat Gafter-Gvili1,
  5. Ofer Shpilberg2,
  6. Pia Raanani2

Editorial Group: Cochrane Haematological Malignancies Group

Published Online: 28 MAR 2013

Assessed as up-to-date: 17 JUL 2012

DOI: 10.1002/14651858.CD009594.pub2


How to Cite

Muchtar E, Vidal L, Ram R, Gafter-Gvili A, Shpilberg O, Raanani P. The role of maintenance therapy in acute promyelocytic leukemia in the first complete remission. Cochrane Database of Systematic Reviews 2013, Issue 3. Art. No.: CD009594. DOI: 10.1002/14651858.CD009594.pub2.

Author Information

  1. 1

    Beilinson Hospital, Rabin Medical Center, Department of Medicine E, Petah Tikva, Israel

  2. 2

    Beilinson Hospital, Rabin Medical Center, Institute of Hematology, Davidoff Center, Petah Tikva, Israel

*Eli Muchtar, Department of Medicine E, Beilinson Hospital, Rabin Medical Center, 39 Jabotinski Street, Petah Tikva, 49100, Israel. muchtare@gmail.com. elim2@clalit.org.il.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 28 MAR 2013

SEARCH

 

Summary of findings    [Explanations]

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

 
Summary of findings for the main comparison.

Any maintenance compared with observation for patients with APL in first complete remission

Patient or population: patients with APL in first complete remission

Settings: Patients diagnosed with APL following induction and consolidation treatments

Intervention: any maintenance

Comparison: observation

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

Any maintenanceObservation

Overall survival

[range of median follow-up: 2 years to 10.1 years]
Study populationHR [1.07] ([0.23] to [4.86])[892]
([3])
⊕⊕⊝⊝

low
Moderate quality of evidence due to:

  • Relatively few events producing a wide confidence interval around the effect estimate
  • Heterogeneity among trials was significantly high


Disease-free survival

[range of median follow-up: 2 years to 10.1 years]
Study populationHR [0.63] ([0.41] to [0.97])[1209]
([5])
⊕⊕⊕⊕

high
High quality of evidence due to:

  • Heterogeneity among trials was significantly high
  • However, effect was large (HR < 0.5) in 3 out of 6 trials


Adverse events requiring discontinuation

[range of median follow-up: 6.2 years to 7.8 years]
Study populationRR [20.72] ([2.83] to [151.66])[906]
([3])
⊕⊕⊕⊝
moderate
Moderate quality of evidence due to:

  • Heterogeneity among trials was significantly high


  • Relatively few events producing a wide confidence interval around the effect estimate
  • However, effect was very large (RR > 5) in 2 trials.

[28] per 1000[0] per 1000

Relapse rate

[range of median follow-up: 6.2 years to 10.1 years]
study populationRR [0.74] ([0.50] to [1.11])[896]
([4])
⊕⊕⊕⊝
moderate
Moderate quality of evidence due to:

  • Heterogeneity among trials was significantly high

294 per 1000488 per 1000

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk Ratio;HR: Hazard Ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 Summary of findings 2

 Summary of findings 3

 

Background

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Description of the condition

Acute promyelocytic leukemia (APL) is a variant of acute myeloid leukemia (AML), which accounts for 5% to 10% of AML cases. As such, the disease is relatively uncommon, with an estimated annual incidence of 900 to 1000 new cases per year in the United States with equal male-to-female distribution. A higher incidence is reported among those of Latin American origin (Douer 2003). Further epidemiological data show that the incidence of APL increases during childhood until the age of 20 years and then plateaus. This observation, which stands in contrast to the increased incidence of AML with age, might be explained by the relatively few genetic mutations needed to induce this type of malignancy (Douer 2003). Indeed, one of the distinctive hallmarks of APL is a translocation involving the retinoic acid receptor-alpha (RAR-α) locus on chromosome 17 and the PML gene on chromosome 15 (Tallman 2009). This translocation, crucial but not sufficient to induce a leukemic phenotype, dysregulates differentiation and self-renewal of myeloid progenitor cells and confers resistance to apoptosis (de Thé 2010). An important clinical utility of this translocation is confirmation of the diagnosis of APL by cytogenetics (either karyotype or fluorescence in situ hybridization (FISH) or molecular reverse transcription-polymerase chain reaction (RT-PCR) methods demonstrating this translocation). Furthermore, this unique translocation enables the physician to confirm whether the patient has achieved remission following treatment. It may also enable the monitoring of high-risk patients for relapse during the follow-up period, after completion of all treatment phases.

Accordingly, the treatment scheme for APL is distinctively different from the standard treatment for AML in several aspects. One of the more significant differences is the use of two agents, all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), as part of the treatment plan at different phases. These two agents target the PML-RARα fusion gene and have revolutionized the treatment and prognosis of this type of leukemia, which is considered today the most curable type of AML.

Two treatment phases are well validated in APL, the:

  • remission induction phase which aims to achieve complete remission (CR);
  • consolidation (post-remission) phase directed at achieving a durable molecular remission and eventually cure. 

The vast majority of patients with newly diagnosed APL are given induction therapy that incorporates ATRA with anthracycline-based chemotherapy. This approach results in hematological complete remission rates of over 90% at the end of the induction phase. Despite the high complete remission rate at the end of induction, patients have a high chance of relapse if consolidation is not administered. Thus, with the integration of the induction remission and consolidation phases, the long-term survival rates for APL are now exceeding 70% in most clinical trials (Sanz 2005), reaching as high as 90% in some series (Hu 2009; Liu 2010).

A risk-assigned approach has been developed by some authors, stratifying the risk of relapse in accordance with clinical and biological features at presentation (Sanz 2003). The PETHEMA group suggests that a white cell count at presentation higher than 10 X 109/L is the strongest predictor for both hematological and molecular relapse (Sanz 2000).

 

Description of the intervention

Maintenance therapy, a treatment phase that follows the consolidation period and aims to prevent disease recurrence, is not an integral part of the standard treatment for AML. This fact might explain the scarce data regarding maintenance treatment in APL before the introduction of ATRA. In the pre-ATRA era, only two small retrospective studies (Kantarjian 1987; Marty 1984) addressed the issue of maintenance therapy in APL, showing a superior disease free survival (DFS) for patients with APL receiving low-dose 6-mercaptopurine (6-MP) and methotrexate (MTX) compared to no maintenance.

However, with the advent of ATRA as part of the treatment for APL, and the subsequently improved long-term survival, the issue of maintenance therapy in APL has been raised. This subject is particularly relevant for patients achieving complete molecular remission at the end of intensive consolidation chemotherapy with reverse transcription-PCR negativity for the PML-RARα transcript (Sanz 2009), who on the one hand might benefit from maintenance therapy but on the other hand might not need it since they are less prone to relapse (Grimwade 2002).

Maintenance therapy may include any combination of ATRA, chemotherapy and ATO for different time periods. Several randomized controlled trials have addressed the role of maintenance therapy in APL. These trials evaluated maintenance therapy (either ATRA-based, chemotherapy-based or a combination of both) compared to observation. While some trials have shown superiority of maintenance therapy, either ATRA or chemotherapy-based (Adès 2010; Tallman 2002), in terms of either DFS or overall survival (OS), others could not shown a statistically significant effect (Avvisati 2002; Avvisati 2011) or even demonstrated a negative impact of maintenance (Asou 2007) on OS.

The type of anthracycline used during the induction and consolidation phases might also influence the need for maintenance. For example, trials applying daunorubicin as the anthracycline showed superiority for the incorporation of maintenance, while those using idarubicin could not prove it. These differences in the need for maintenance based on the anthracycline used contributed to the confusion regarding the role of maintenance treatment in APL (Park 2011).

 

How the intervention might work

On a molecular basis, ATRA exerts its anti-leukemic effect through differentiation of the leukemic cells upon exposure to this agent (Tallman 2009). Moreover, ATRA is potentially responsible for induction of caspase-like activity that degrades the PML-RARα fusion transcript (Douer 2000). Similarly, ATO exerts its action on the leukemic cells by direct degradation of the PML-RARα fusion transcript, inducing predominantly apoptosis but also differentiation of the leukemic cells (Tallman 2009). Therefore, the anti-leukemic effect of each of these agents if administrated as maintenance in remission, and given separately or in combination with conventional chemotherapy, may prevent re-expansion of the quiescent APL leukemic clone and as a consequence prevent a clinical relapse. A trial which followed 33 out of 100 APL patients throughout the maintenance phase demonstrated a PML-RARα transcript reduction starting during the induction phase, continuing throughout the consolidation phase and becoming undetectable during the maintenance phase (Yao 2008), suggesting a biological  effect of maintenance. 

On clinical grounds, as maintenance therapy might preserve clinical (and even molecular) remission, the consequences of omitting maintenance therapy could eventually be translated into disease relapse, necessitating salvage therapy with high-dose chemotherapy with or without autologous or allogeneic hematopoietic cell transplantation. Thus, omitting maintenance therapy might eventually result in a negative effect on OS for patients with APL.

 

Why it is important to do this review

With the advent of differentiating agents (that is ATRA, ATO) APL has become the most curable subtype of AML. A consensus exists regarding the administration of both induction and consolidation treatments, albeit using different approaches. However, there is conflicting evidence for the effect of maintenance treatment on survival and on DFS in APL patients, making it a controversial treatment. We have decided to conduct a systematic review and meta-analysis to establish the role of maintenance therapy in APL patients achieving complete remission. Furthermore, as the disease is highly curable and disease relapse risk depends on patients' individual risk score at presentation, it seems necessary to define which subgroups of patients might benefit most from maintenance therapy.

 

Objectives

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 
Primary objective:

to examine the efficacy and safety of maintenance therapy in terms of overall survival (OS), disease-free survival (DFS) and adverse effects for patients with APL.

 
Secondary objective:

to compare different protocols for maintenance therapy in APL and to establish the optimal protocol in terms of efficacy and safety.

 

Methods

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Criteria for considering studies for this review

 

Types of studies

Randomized controlled trials, irrespective of publication status, year of publication and language. We excluded from the review quasi-randomized trials and cross-over trials.

 

Types of participants

Patients with newly diagnosed APL in complete remission (hematological or molecular) following either induction or induction and consolidation therapy. Randomization to maintenance could be performed before induction or after the achievement of complete remission, either after induction or induction and consolidation treatments. Both pediatric and adult patients were included.

 

Types of interventions

We evaluated three main comparisons, as follows.

 
Comparison I

  • Investigational intervention arm: any maintenance (ATRA, chemotherapy, ATO or combination of any of the above)
  • Control arm: observation, i.e. no maintenance

We evaluated different maintenance strategies as follows.

 
Comparison II

  • Investigational intervention arm: ATRA-based maintenance
  • Control arm: non-ATRA based maintenance

 
Comparison III

  • Investigational intervention arm: ATRA alone maintenance
  • Control arm: ATRA in combination with any chemotherapy maintenance

 

Types of outcome measures

We based definitions of measured outcomes on the revised recommendations of the National Cancer Institute (NCI) for diagnosis, response criteria and treatment outcome in AML (Cheson 2003).

 

Primary outcomes

  • Overall survival (OS), defined as the time from enrollment to maintenance till death from any cause. If a trial reported on OS from study entry or from any time point after the diagnosis of APL, and not from randomization to maintenance, we did not exclude it from the meta-analysis.
  • Disease-free survival (DFS), defined as the time from enrollment to maintenance until relapse or death.

 

Secondary outcomes

  • Treatment-related mortality.
  • Hematological relapse.
  • Molecular relapse.
  • Central nervous system (CNS) relapse.
  • Rate of patients undergoing hematopoietic cell transplantation.
  • Quality of life.
  • Adverse events (a comparison was done only between two active treatment arms):
    • adverse events requiring discontinuation of therapy,
    • grade 3/4 adverse events,
    • grade 3/4 hematologic toxicity,
    • APL differentiation syndrome (formerly ATRA syndrome).

 

Search methods for identification of studies

 

Electronic searches

We searched the following databases in accordance with the search strategy outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Lefebvre 2011):

  • Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 6) (see Appendix 1);                       
  • MEDLINE (1966 to 8 July 2012) (through PubMed) (see Appendix 2);                      
  • LILACS (1982 to 8 July 2012) (see Appendix 3).

We crossed the term 'acute promyelocytic leukemia' and similar OR 'APL' and similar with the term 'maintenance' and similar (see Appendix 1; Appendix 2; Appendix 3 for the detailed search strategies).

We combined the search terms with the highly sensitive search strategy for identifying reports of randomized controlled trials (Robinson 2002) in the MEDLINE search.

 

Searching other resources

We searched the conference proceedings of the American Society of Hematology (2000 to 2011), American Society of Clinical Oncology Annual Meeting (2000 to 2011) and the European Hematology Association (2000 to 2011) for relevant abstracts.

We searched databases of ongoing and unpublished trials: http://www.controlled-trials.com; http://www.clinicaltrials.gov/ct; http://clinicaltrials.nci.nih.gov.

We contacted the first or corresponding author of each included study and the researchers active in the field for information regarding unpublished trials or complementary information on their own trial.

We checked the citations of included trials and major reviews for additional studies.

 

Data collection and analysis

 

Selection of studies

We performed selection of studies in accordance with the guidelines in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). Two review authors (LV, EM) inspected the title and, when available, the abstract of each reference identified in the search and applied the inclusion criteria. Where relevant articles were identified, we obtained the full article and the two review authors inspected it independently.

We included trials regardless of publication status, date of publication and language.

We used a PRISMA flow diagram to report the numbers of identified records, excluded records and articles and included studies (Moher 2009).

 

Data extraction and management

We conducted data extraction according to the guidelines proposed in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011c), with two review authors (LV, EM) independently extracting the data from included trials. We discussed any disagreement between the two review authors. If the disagreement remained unresolved a third review author (AG) independently extracted the data. We discussed the data extraction, documented disagreements and their resolution and, where necessary, contacted the authors of the studies for clarification. If this was unsuccessful, we reported disagreements.

We documented the justification for excluding studies from the review. We collected all data on an intention-to-treat basis, where possible.

We extracted, checked and recorded the following data.

 
1.   Characteristics of trials

  • Author, title, source, publication date, country, language, duplicate publications
  • Publication status: published, published as abstract, unpublished
  • Year (defined as recruitment initiation year) and country or countries of study
  • Trial sponsor (academic, industrial)
  • Intention-to-treat analysis: performed, possible to extract, efficacy analysis
  • Design and possible sources of bias (method of allocation generation and concealment, blinding (participants personnel, outcome assessors), incomplete outcome data, selective outcome reporting, other sources of bias)
  • Duration of study follow-up
  • Response definition, event definitions
  • Case definitions used (inclusion and exclusion criteria)
  • Assessment of mortality (primary outcome, secondary outcome, safety)
  • Study endpoints as reported in the methods section of each trial

 
2.   Characteristics of patients

  • Number of participants in each group
  • Age (mean and standard deviation)
  • Gender
  • Ethnicity
  • Participants lost to follow-up
  • Histological subtype, classical M3, microgranular variant (vM3)
  • Additional diagnoses
  • Type of remission confirmation (molecular, morphological)
  • Number and type of previous induction and consolidation cycles
  • Risk stratification group according to white blood cell count at presentation: below or equal to 10 X 109/L, above 10 X 109/L
  • Performance status

 
3. Characteristics of interventions

  • Experimental intervention:
    • dose, number of administered doses and total duration of therapy,
    • additional drugs (combination).
  • Treatment of control group:
    • observation.
  • Maintenance: regimen, dose, number of administered doses and total duration of therapy.

 
4. Characteristics of outcome measures (extracted for each group and total events)

  • Overall survival (OS):

    • number of patients available for survival analysis at the end of follow-up,
    • hazard ratio (HR) of OS and its standard error (SE), confidence interval (CI) or P value,
    • crude mortality at the end of follow-up (used for dichotomous all-cause morality analysis if over 50% of the included trials lacked sufficient time-to-event data),
    • Kaplan-Meier curve (yes or no).
  • Disease-free survival (DFS).
  • Number of patients with relapsed disease.
  • HR of progression-free survival and its SE, CI or P value.
  • Number of patients achieving complete response.
  • Adverse effects (grade 3 and 4, requiring discontinuation of treatment, infection-related).
  • Number of patients excluded from outcome assessment after randomization and the reasons for their exclusion.
  • Quality of life (scale and score).

The following parameters for OS, DFS and grade 3 or 4 adverse events are described in the ' Summary of findings for the main comparison'.

  • Point estimate and 95% CI.
  • Number of participants and trials.
  • Risk of event in control and experimental groups.
  • Quality of evidence (GRADE), reasons for downgrading and upgrading.

 

Assessment of risk of bias in included studies

Two review authors (LV, EM) independently and individually assessed the trials for methodological quality. Allocation concealment, sequence generation, blinding, incomplete outcome data and selective outcome reporting according to The Cochrane Collaboration's tool for assessing bias (Higgins 2011) were described and assessed. We resolved any disagreement by discussion. If disagreement persisted, a third review author (AG) extracted the data independently. We discussed data extraction, document disagreements and their resolution and, where necessary, we contacted the authors of the studies for clarification.

 

Measures of treatment effect

We measured risk ratio (RR) for dichotomous data and hazard ratio (HR) for time-to-event outcomes. We estimated standardized mean difference (SMD) for quality of life assessment.

 

Unit of analysis issues

For dichotomous outcomes, the unit of analysis was the number of participants assigned to the investigational arm and the number of participants assigned to the control arm. For continuous outcomes, the mean, standard deviation and the number of participants in the investigational and control arms were the unit of analysis.

For time-to-event outcomes we used log HR and the standard error of log HR as the unit of analysis (Deeks 2011).

 

Dealing with missing data

We used methods to deal with missing data as outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). Briefly, we contacted authors of the included trials in order to obtain additional information not reported in the publications of the trials.

If not all randomized patients were analyzed we made assumptions on the missing data as to whether they were randomly or non-randomly missing or could not be categorized. We made assumptions based on the reports of the reasons for missing data and the distribution between allocated groups. If such data were not provided we categorized the missing data as unclear. We performed sensitivity analysis of the primary outcome based on these assumptions to detect the impact of assumption modifications on the results.

For dichotomous parameters we imputed missing data for patients who were lost to follow-up after randomization, assuming a poor outcome (worst-case scenario) for missing individuals. We performed sensitivity analysis of the primary outcome, without trials with above 20% of participants lost to follow-up.

In addition, we addressed the effect of missing data on outcomes in the Discussion section of the review.

 

Assessment of heterogeneity

We assessed the heterogeneity of the trials' results with the Chi2 test of heterogeneity and the I2 statistic of inconsistency. Statistically significant heterogeneity was defined as a P value of less than 0.1 or an I2 statistic greater than 40%. We explored potential sources of heterogeneity through subgroup stratification by age, type of induction treatment, disease-risk groups, allocation concealment, blinding and size of studies (Deeks 2011).

 

Assessment of reporting biases

We aimed to inspect the funnel plot of the treatment effect against the precision of trials (plot of the log of the RR for efficacy against the standard error) in order to estimate potential asymmetry that may indicate selection bias (the selective publication of trials with positive findings) or methodological flaws in the small studies (Sterne 2011). However, due to low numbers of trials included in each comparison, this methodology evaluation was not performed as the test is underpowered in these circumstances.

 

Data synthesis

We entered data into the Cochrane statistical package Review Manager 5 (RevMan 5) (RevMan 2011). For dichotomous data, we estimated risk ratios (RR) and their CIs using the Mantel-Haenszel method. We pooled log HR for time-to-event outcomes using an inverse variance method. If the HR and its SE (or CI) were not reported, we estimated ‘O – E’ and ‘V’ statistics indirectly using the methods described by Parmar 1998 and Tierney 2007.

In order to better deal with the heterogeneity between the included trials in both pre-maintenance and maintenance therapies, we created three main comparisons, as stated above, to group trials as similarly as possible.

In all comparisons, we used the fixed-effect model. However, in the case of significant heterogeneity (I2 > 40%) we tried to explore heterogeneity by subgroup and sensitivity analyses as outlined in the subsequent paragraphs. If we could not explain the reasons for heterogeneity we also used the random-effects model and reported results accordingly.

 

Subgroup analysis and investigation of heterogeneity

We explored potential sources of heterogeneity through stratifying the patient subgroups given below; allocation concealment; blinding and size of studies.

For the primary analysis, we performed subgroup analysis according to:

  • age (younger adults, age < 60 years; older adults, age ≥ 60 years);
  • pediatric patients (age < 15 years) versus adult patients (age ≥ 15 years);
  • risk stratification group according to white blood cell count at presentation (low risk, below or equal to 10 X 109/L; high risk, above 10 X 109/L);
  • type of prior induction and consolidation therapy (ATRA-containing treatment, daunorubicin versus idarubicin-containing treatment, cytarabine-containing treatment);
  • type of maintenance (ATRA alone, ATRA-containing regimen, ATO-containing regimen) compared with no maintenance.

We formally assessed differences between subgroups using the Chi2 test for differences between subgroups (Deeks 2001).

 

Sensitivity analysis

We performed sensitivity analyses using the method of allocation concealment (Schulz 1995); blinding (patients, caregivers and assessors); allocation generation; incomplete outcome data (adequately, inadequately addressed); selective reporting (Higgins 2011); time definition for OS and DFS measures (randomization to maintenance, other time point) and the type of publication (full paper, abstract, unpublished).

 

Results

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Description of studies

 

Results of the search

A total of 1273 potentially relevant titles and abstracts were screened. At initial screening, 1193 references were excluded. Eighty full text articles were retrieved for a detailed evaluation. We retrieved an additional six abstracts from conference proceedings. Three ongoing trials were identified; none have currently reported results (Figure 1).

 FigureFigure 1. Flow diagram.

 

Included studies

Ten trials (42 publications) enrolling 2072 patients, recruited between the years 1989 to 2005, were eligible for this systematic review. Meta-analysis was conducted on nine of them. Nine trials were published as full text and one trial was published as abstract only (Feusner 2010).

Each trial randomized between 60 and 586 patients. All but two trials (Lin 2007; Shen 2004) were multicenter trials. The median follow-up period ranged from to 1.5 to 10 years (as specified in Characteristics of included studies).

 

Type of patients

All trials evaluated patients with newly diagnosed APL. Two trials excluded children (Asou 2007; Powell 2010). Median age at study entry ranged between 33 and 48 years (range 1 to 81 years). In all trials APL was confirmed by the demonstration of t(15;17) or by the presence of the PML-RARA transcript, or both. Major organ dysfunction (that is heart, lung, kidney, liver) was an exclusion criterion in four trials (Asou 2007; Avvisati 2002; Avvisati 2011; Tallman 2002).

 

Study design

The treatment scheme in all included trials consisted of induction, consolidation and maintenance phases according to the various protocols (see in 'Additional tables':  Table 1 for maintenance protocols;  Table 2 for pre-maintenance treatment scheme). Detailed protocols are given in the Characteristics of included studies section). In six trials (Asou 2007; Avvisati 2002; Avvisati 2011; Feusner 2010; Lin 2007; Parovichnikova 2004) randomization to maintenance treatment of patients in complete remission was done after completion of the induction and consolidation phases. In three trials (Adès 2010; Powell 2010; Tallman 2002) two randomizations were carried out, the first one before the induction or consolidation phases and the second one before maintenance. In one trial (Shen 2004) randomization was carried out before induction initiation and patients were randomized to three different induction and maintenance treatments hitherto receiving the same consolidation treatment.

In six trials (Adès 2010; Avvisati 2002; Feusner 2010; Powell 2010; Shen 2004; Tallman 2002) assessment of remission achievement was done morphologically, while in four trials (Asou 2007; Avvisati 2011; Lin 2007; Parovichnikova 2004) assessment of remission was done either molecularly or by morphology.

 

Intervention

 
Maintenance protocols

Seven trials compared two arms of maintenance (Asou 2007; Avvisati 2002; Feusner 2010; Lin 2007; Parovichnikova 2004; Powell 2010; Tallman 2002), one trial compared three arms (Shen 2004) and two trials compared four arms (Adès 2010; Avvisati 2011) ( Table 1).

Types of maintenance protocols varied among trials and the following comparisons were included:

 
Type of anthracycline used during induction and consolidation

All included trials employed anthracycline at the induction or consolidation, or both, phases of treatment. Daunorubicin (Adès 2010; Feusner 2010; Lin 2007; Parovichnikova 2004; Powell 2010; Shen 2004; Tallman 2002) and idarubicin (Asou 2007; Avvisati 2002; Avvisati 2011) were usually administered. Mitoxantrone was given in three trials (Asou 2007; Avvisati 2002; Avvisati 2011) and aclarubicin was used in one trial (Lin 2007). For the purpose of comparing the anthracycline dose intensity prior to maintenance treatment, we converted the cumulative dose of anthracyclines in each trial into doxorubicin dose equivalents. The type of anthracycline used during the induction and consolidation phases and the cumulative dose in each trial, expressed in daunorubicin equivalents, are described in  Table 3. We used anthracycline equivalents as described previously (Mandelli 2009).

 
Duration of intervention

The duration of the maintenance period varied between trials. In three trials (Feusner 2010; Powell 2010; Tallman 2002) maintenance was given for one year. In four trials (Adès 2010; Avvisati 2002; Avvisati 2011; Parovichnikova 2004) maintenance was given for two years. In one trial (Asou 2007) the duration of maintenance was reported as six cycles of treatment, with six weeks between each cycle. In Shen 2004 maintenance was measured as five cycles, each cycle lasting around two months. In Lin 2007 maintenance was reported as continued for two to three years or more.

 
Dosing of intervention

  • ATRA: the daily dose of ATRA was 45 mg/m2 in most trials, except for two trials (Lin 2007; Shen 2004) where the dose was 25 mg/m2 daily. In one trial (Tallman 2002) ATRA was given on a daily basis for one year. In all other trials ATRA was administered intermittently according to various schedules ( Table 1).

  • Chemotherapy: dosing and schedules of chemotherapy varied between trials ( Table 1).

 
Duration of follow-up

Follow-up in trials varied. It ranged between 1.5 to 10 years (see Characteristics of included studies).

 Table 1 summarizes the maintenance protocols of the included trials.

 

Outcome assessment

 
Primary outcome measure

Overall survival data were available from six trials (Adès 2010; Asou 2007; Avvisati 2011; Feusner 2010; Parovichnikova 2004; Powell 2010). For three trials (Adès 2010; Asou 2007; Avvisati 2011) OS measurement was from randomization to maintenance. For two trials (Feusner 2010; Powell 2010) OS data were from enrollment to induction treatment, and in one trial (Parovichnikova 2004) data were missing for the starting point of OS measurement. DFS was defined as the time from attainment of complete remission (CR) or randomization to maintenance till relapse or death. DFS data were available from nine trials (Adès 2010; Asou 2007; Avvisati 2002; Avvisati 2011; Feusner 2010; Parovichnikova 2004; Powell 2010; Tallman 2002) and were calculated for all but one trial (Shen 2004) following CR achievement after the last consolidation cycle. The outcomes and their definitions for each trial included are described in the table 'Characteristics of included studies'.

 

Excluded studies

Forty-six articles were excluded after evaluation of full text publications for the following reasons (see table 'Characteristics of excluded studies'):

 

Risk of bias in included studies

Figure 2 summarizes the risk of bias of the included trials.

 FigureFigure 2. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

 

Other potential sources of bias  

 

Allocation

Allocation was adequately concealed in seven out of 10 included trials (Adès 2010; Asou 2007; Avvisati 2002; Avvisati 2011; Feusner 2010; Powell 2010; Tallman 2002) and was not reported in three trials (Lin 2007; Parovichnikova 2004; Shen 2004). The sequence was adequately generated in six trials (Adès 2010; Asou 2007; Avvisati 2002; Avvisati 2011; Feusner 2010; Powell 2010) and was centrally performed. In four trials the method of sequence generation was not reported (Lin 2007; Parovichnikova 2004; Shen 2004; Tallman 2002). We judged the quality of these trials as unclear risk of bias.

 

Blinding

In all trials, blinding of patients and caregivers was not applied since prolonged blinded maintenance treatment was difficult to carry out, especially since most comparators included active treatment. We reported the quality of these trials as unclear risk of bias. Blinding of outcome assessors was not reported in all trials. We judged the quality of these trials as unclear risk of bias.

 

Incomplete outcome data

For the primary outcome analysis, three trials reported missing outcome data (Asou 2007; Avvisati 2002; Powell 2010). In all three trials the percentage of drop-outs was less than 10% of randomized patients. Reasons for missing data and treatment allocation were given in two trials (Asou 2007; Avvisati 2002). We reported the quality of these trials as low risk of bias. In another six trials there was no report on missing data (Adès 2010; Avvisati 2011; Feusner 2010; Lin 2007; Shen 2004; Tallman 2002) and all randomized patients were included in the analysis. We judged the quality of these trials as low risk of bias. One trial (Parovichnikova 2004) did not report missing data and we were not able to determine whether all randomized patients were included in the analysis. We judged this trial's quality as unclear risk of bias.

 

Selective reporting

The protocols of four trials (Adès 2010; Avvisati 2011; Feusner 2010; Powell 2010) were available for assessment. In these trials, all pre-planned outcomes were addressed in the trial publications. We reported those trials as low risk for reporting bias. For six trials the study's protocol was not available for assessment. However, in four of these trials (Asou 2007; Avvisati 2002; Lin 2007; Tallman 2002) survival and toxicity outcomes were reported. Therefore, we reported these trials as low risk for reporting bias. In two trials (Parovichnikova 2004; Shen 2004) the outcome reporting was incomplete (toxicity was missing in Parovichnikova 2004; overall survival reporting was missing in Shen 2004) and we reported these trials as high risk for reporting bias.

 

Other potential sources of bias

We focused on four other potential sources of bias in each of the included trials, as detailed below.

# Funding: while seven trials reported grants awarded from non-pharmaceutical organizations, either academic or governmental, three trials (Avvisati 2002; Lin 2007; Parovichnikova 2004) did not report on financial support.

# Intention-to-treat (ITT) analysis: all included trials except for one (Parovichnikova 2004) reported analysis based on ITT.

# Sample size calculation: sample size calculations were reported in four out of 10 included trials (Adès 2010; Avvisati 2002; Avvisati 2011; Powell 2010). In all these trials the designed sample size was reached.

# Early termination of trial: one trial (Shen 2004) was stopped early due to superior outcome in the combined ATRA-ATO-6-MP-MTX group. As this trial's termination was not pre-defined in its protocol we reported this trial as high risk of bias.

 

Effects of interventions

See:  Summary of findings for the main comparison;  Summary of findings 2;  Summary of findings 3

We defined three main comparisons for the effects of interventions in our protocol, as outlined in the 'Methods' section above (Types of interventions). Definitions of the primary outcomes were given in the 'Included studies' section above and specifically for each trial in the 'Characteristics of included studies' section. Briefly, OS was measured from randomization to maintenance (most trials) or from enrollment to induction. DFS was measured from attainment of CR or randomization to maintenance until relapse or death.

 

Any maintenance compared to observation

Five trials were included in this comparison (Adès 2010; Asou 2007; Avvisati 2002; Avvisati 2011; Tallman 2002). Three trials reported on the OS outcome (Adès 2010; Asou 2007; Avvisati 2011), and all five trials reported on the DFS outcome.

 

Primary outcome measures

 
Overall survival (OS)

Three trials (892 patients) reported on this outcome (Adès 2010; Asou 2007; Avvisati 2011). We found no effect on OS for any maintenance treatment compared to observation (HR 0.79, 95% CI 0.49 to 1.27, fixed-effect model; I2 for heterogeneity = 89%; Figure 3). Exploration for the significant heterogeneity was unsuccessful, probably reflecting the small number of participating trials in this comparison as well as the differences in both the maintenance and pre-maintenance treatments. Using the random-effects model for this comparison the HR for maintenance treatment compared to observation was 1.07 (95% CI 0.23 to 4.86).

 FigureFigure 3. Forest plot of comparison: 1 any maintenance compared to observation, outcome: 1.1 Overall survival.

 
Disease-free survival (DFS)

Five trials (1209 patients) were included in this comparison (Adès 2010; Asou 2007; Avvisati 2002; Avvisati 2011; Tallman 2002). Any maintenance given to APL patients in the first complete remission was associated with improved DFS compared to observation (HR 0.59, 95% CI 0.48 to 0.74, fixed-effect model; I2 for heterogeneity = 72%; Figure 4). Heterogeneity in this comparison was mainly explained by the trial that used intensive chemotherapy in the maintenance phase (Asou 2007). As appears in the subgroup analysis below (low intensity maintenance versus observation), by excluding this trial heterogeneity was reduced to 31% with negligible impact on the point estimate and CI for this comparison.

 FigureFigure 4. Forest plot of comparison: 1 any maintenance compared to observation, outcome: 1.2 Disease-free survival.

 

Secondary outcome measures

 
Treatment-related mortality

Treatment-related mortality was reported in two trials. In one trial (Asou 2007) there was no treatment-related mortality in both arms. In the other trial (Avvisati 2011) treatment-related mortality was similar between the active maintenance arm and the observation arm (1.6% in any maintenance versus 1.3% in observation arm). Due to the paucity of data, a meta-analysis could not be conducted.

 
Relapse rate

The risk of relapse was reduced in the maintenance arm compared to observation (RR 0.69, 95% CI 0.58 to 0.81, fixed-effect model; 4 trials, 896 patients; I2 for heterogeneity = 82%) (Adès 2010; Asou 2007; Avvisati 2002; Tallman 2002). The reasons for heterogeneity in this comparison probably stem from the different treatments in the comparator arms, but we failed to demonstrate reduced heterogeneity by subgroup analysis. Using the random-effects model, the relapse rate was found to be similar between any maintenance and observation (HR 0.74, 95% CI 0.50 to 1.11).

 
Adverse events
 
Adverse events requiring discontinuation of therapy

Adverse events requiring discontinuation of therapy were reported in three trials. In two trials the rate was 8.6% and 14.1% in the active treatment arm (Avvisati 2002; Tallman 2002), respectively. In Avvisati 2011 a discontinuation of treatment was not registered.

 
Grade 3 and 4 adverse events

Only one trial (Tallman 2002) reported on grade 3 to 4 adverse events for ATRA maintenance as compared to observation. An increased risk for this outcome in the treatment arm (ATRA alone) was noted (34% of patients versus 2.9% of patients in the control arm).

 
Grade 3 and 4 hematologic toxicity

None of the trials reported on grade 3 or 4 hematologic toxicity.

 
Infection-related adverse events

Only two studies reported on this adverse effect. In one trial (Adès 2010) the rate of infections related to the 'any maintenance arm' was 3.7% (12 patients, of whom six died of sepsis) compared to none in the observation arm. Similarly, in Tallman 2002 seven patients experienced infectious complications during the maintenance phase (ATRA alone) compared to none in the observation arm. Due to the paucity of trials providing data on this outcome, a meta-analysis was not feasible for this outcome.       

 
APL differentiation syndrome (formerly ATRA syndrome)

None of the trials reported on APL differentiation syndrome during maintenance treatment.

 

Subgroup analysis for overall survival (OS) and disease-free survival (DFS)

 
Low intensity maintenance versus observation

As the maintenance regimen employed in Asou 2007 was intensive chemotherapy-based and very different from the other trials included in this comparison (Adès 2010; Avvisati 2002; Avvisati 2011; Tallman 2002), which used either ATRA, low dose chemotherapy or both, we performed a subgroup analysis with the exclusion of the above exceptional trial.

The effect on OS for any maintenance treatment compared to observation remained similar, although borderline significance in favor of any maintenance was achieved (HR 0.60, 95% CI 0.36 to 1.01, fixed-effect model; I2 for heterogeneity = 91%) (Adès 2010; Avvisati 2011).

For the DFS outcome, by the exclusion of Asou 2007 any maintenance given to APL patients in the first complete remission remained associated with statistically significant improved DFS compared to observation as in the main analysis (HR 0.52, 95% CI 0.41 to 0.66, fixed-effect model) but with reduced statistical heterogeneity (I2 for heterogeneity = 31%). Finally, the relapse rate in this subgroup analysis was reduced with any maintenance compared to observation (HR 0.39, 95% CI 0.28 to 0.55, fixed-effect model) but with reduced heterogeneity compared to the main comparison, albeit remaining high (I2 for heterogeneity = 64% versus 82% in the main comparison).

 
Elderly patients (age > 60 years)

No data were available for subgroup analysis of the primary outcomes regarding elderly patients.

 
Pediatric patients (age < 15 years)

Only one trial (Tallman 2002), enrolling 36 pediatric patients, reported on the primary outcomes among children. This trial demonstrated that maintenance with ATRA alone did not improve OS compared to observation alone (5-year OS 83% in the treatment arm versus 55% in the observation arm, P = 0.13). However, maintenance with ATRA alone had a superior effect on DFS compared to observation alone (5-year DFS 61% in the treatment arm versus 15% in the observation arm, P = 0.0002).

 
Risk group stratification

There were not enough data to analyze the primary outcomes according to risk group stratification.

 
Type of remission confirmation

Maintenance therapy compared to observation did not have a statistically significant effect on OS in trials that defined remission only by morphology as well as in those that defined it morphologically or molecularly, or both. Conversely, DFS was improved by maintenance as compared to observation in trials where remission was defined morphologically (HR 0.52, 95% CI 0.41 to 0.67, fixed-effect model; 3 trials, 721 patients; I2 for heterogeneity = 54%) (Adès 2010; Avvisati 2002; Tallman 2002) but not in those where it was defined according to molecular criteria (HR 0.90, 95% CI 0.57 to 1.44, random effect model; 2 trials, 488 patients; I2 for heterogeneity = 82%) (Asou 2007; Avvisati 2011). The difference in this outcome between these two subgroups was statistically significant (P = 0.04).

 
Type of prior induction and consolidation therapy
 
Type of prior anthracycline use:

Analysis of trials that used idarubicin for induction or consolidation demonstrated a marginally statistically significant negative effect of maintenance therapy on OS compared to observation (HR 1.86, 95% CI 0.99 to 3.48, fixed-effect model; 2 trials, 491 patients; I2 for heterogeneity = 48%) (Asou 2007; Avvisati 2011). Only one trial that used daunorubicin for induction or consolidation reported on OS and showed superiority of any maintenance compared to observation (HR 0.25, 95% CI 0.12 to 0.52) (Adès 2010). The difference between these two subgroups was statistically significant (P < 0.0001).

Analysis of DFS in trials that used idarubicin for induction or consolidation did not demonstrate a statistically significant effect of maintenance therapy compared to observation (HR 0.85, 95% CI 0.61 to 1.18, fixed-effect model; 3 trials, 604 patients; I2 for heterogeneity = 65%) (Asou 2007; Avvisati 2002; Avvisati 2011). Conversely, when daunorubicin was used for induction or consolidation maintenance was associated with improved DFS compared to no maintenance (HR 0.44, 95% CI 0.33 to 0.60, fixed-effect model; 2 trials, 605 patients; I2 for heterogeneity = 0%) (Adès 2010; Tallman 2002). The difference between these two subgroups was statistically significant (P = 0.004).

 
Subtypes of maintenance comparisons

  • Chemotherapy alone versus observation: four trials were eligible for this comparison (Adès 2010; Asou 2007; Avvisati 2002; Avvisati 2011). Data on OS could be retrieved from two trials. Chemotherapy alone compared to observation for maintenance did not improve OS (HR 0.60, 95% CI 0.29 to 1.23, fixed-effect model; 2 trials, 369 patients; I2 for heterogeneity = 92%) (Adès 2010; Asou 2007). Similarly, DFS was not improved with chemotherapy alone compared to observation (HR 0.94, 95% CI 0.68 to 1.30, fixed-effect model; 3 trials, 369 patients; I2 for heterogeneity = 34%) (Asou 2007; Avvisati 2002; Avvisati 2011).
  • ATRA alone versus observation: three trials were eligible for this subgroup analysis (Adès 2010; Avvisati 2011; Tallman 2002). Only one trial with 155 patients (Adès 2010) reported on OS for this comparison, demonstrating a similar effect for ATRA alone compared to observation (HR 0.53, 95% CI 0.24 to 1.15). However, maintenance with ATRA alone improved DFS compared to observation (HR 0.47, 95% CI 0.33 to 0.66; 2 trials, 204 patients; I2 for heterogeneity = 0%) (Avvisati 2011; Tallman 2002).
  • ATRA-containing regimens versus observation: two trials were eligible for  this subgroup analysis (Avvisati 2011; Tallman 2002). Only one trial with 240 patients (Avvisati 2011) reported on OS for this comparison, demonstrating a similar effect for ATRA alone compared to observation (HR 1.40, 95% CI 0.67 to 2.96). However, ATRA-containing regimens (that is ATRA alone or ATRA combined with chemotherapy) compared to observation achieved a statistically significant improved DFS (HR 0.48, 95% CI 0.35 to 0.66; 2 trials, 444 patients; I2 for heterogeneity = 0%) (Avvisati 2011; Tallman 2002).

 

ATRA-based maintenance compared to non-ATRA based maintenance

Four trials were included in this comparison (Adès 2010; Avvisati 2011; Parovichnikova 2004; Shen 2004). Three trials reported on OS (Adès 2010; Avvisati 2011; Parovichnikova 2004) and all four trials reported on DFS.

 

Primary outcome measures

 
Overall survival (OS)

There was no statistically significant effect on OS for patients treated with ATRA-based maintenance compared to non-ATRA based maintenance (HR 0.98, 95% CI 0.64 to 1.51, fixed-effect model; three trials, 632 patients; I2 for heterogeneity = 0%) (Adès 2010; Avvisati 2011; Parovichnikova 2004) (Figure 5).

 FigureFigure 5. Forest plot of comparison: 2 ATRA-based maintenance compared to non-ATRA based maintenance, outcome: 2.1 Overall survival.

 
Disease-free survival (DFS)

ATRA-based maintenance was probably associated with improved DFS compared to non-ATRA based maintenance, but result did not reach statistical significance (HR 0.72, 95% CI 0.51 to 1.01, fixed-effect model; 4 trials, 670 patients; I2 for heterogeneity = 0%) (Adès 2010; Avvisati 2011; Parovichnikova 2004; Shen 2004) (Figure 6).

 FigureFigure 6. Forest plot of comparison: 2 ATRA-based maintenance compared to non-ATRA based maintenance, outcome: 2.2 Disease-free survival.

 

Secondary outcome measures

 
Treatment-related mortality

Only one study assessed this outcome (Avvisati 2011). Treatment-related mortality was not affected by ATRA-based maintenance compared to non-ATRA based maintenance (3.7% in ATRA based arm versus 2.6% in non-ATRA based arm).

 
Relapse rate

Risk of relapse was similar between patients who received ATRA-based maintenance and those who received non-ATRA based maintenance (RR 0.88, 95% CI 0.59 to 1.30, fixed-effect model; 3 trials, 425 patients; ; I2 for heterogeneity = 19%) (Adès 2010; Parovichnikova 2004; Shen 2004).

 
Adverse events
 
Adverse events requiring discontinuation of therapy

None of the trials reported on adverse events requiring discontinuation of therapy.

 
Grade 3 and 4 adverse events

None of the trials reported on grade 3 and 4 adverse events.

 
Grade 3 and 4 hematologic toxicity

None of the trials reported on grade 3 and 4 hematologic adverse events.

 
Infection-related adverse events

None of the trials reported on infection-related adverse events.

 
APL differentiation syndrome (formerly ATRA syndrome)

None of the trials reported on APL differentiation syndrome during maintenance.

 

Subgroup analysis for overall survival (OS) and disease-free survival (DFS)

 
Elderly patients (age > 60 years)

None of the trials in this comparison reported on elderly patients.

 
Pediatric patients (age < 15 years)

None of the trials in this comparison reported on pediatric patients.

 
Risk group stratification

There were not enough data to analyze primary outcomes according to risk group stratification.

 
Type of remission confirmation

No statistically significant effect on OS nor DFS was noted between patients allocated to ATRA-based maintenance compared to non-ATRA based maintenance by stratifying trials according to the type of remission confirmation, that is molecular versus hematological.

 
Type of prior induction and consolidation therapy
 
Type of prior anthracycline

OS was not affected by the allocated treatments in patients with APL who received daunorubicin during induction or consolidation, or both (Adès 2010; Parovichnikova 2004) (HR 1.31, 95% CI 0.64 to 2.70, fixed-effect model; 2 trials, 390 patients; I2 for heterogeneity = 0%). Only one trial used idarubicin, with no effect on OS with ATRA-based maintenance compared to non-ATRA based maintenance (HR 1.12, 95% CI 0.56 to 2.22) (Avvisati 2011). The difference between the subgroups was not statistically significant (P = 0.64).

DFS was not improved with the use of ATRA-based maintenance compared to non-ATRA based maintenance for APL patients receiving daunorubicin prior to maintenance treatment (HR 0.81, 95% CI 0.53 to 1.22, fixed-effect model; 3 trials, 428 patients; I2 for heterogeneity = 2%) (Adès 2010; Parovichnikova 2004; Shen 2004). Only one trial used idarubicin (Avvisati 2011), with no advantage for ATRA-based maintenance compared to non-ATRA based maintenance with regards to DFS (HR 0.56, 95% CI 0.30 to 1.03). The difference between the subgroups was not statistically significant (P = 0.33).

 

ATRA alone maintenance compared to ATRA and chemotherapy maintenance

Four trials were included in this comparison, all of them reported on OS and DFS (Adès 2010; Avvisati 2011; Feusner 2010; Powell 2010).

 

Primary outcome measures

 
Overall survival (OS)

There was no difference in the HR for OS between ATRA alone or ATRA and chemotherapy maintenance (HR 0.99, 95% CI 0.69 to 1.43, fixed-effect model; 4 trials, 1033 patients; I2 for heterogeneity = 51%) (Adès 2010; Avvisati 2011; Feusner 2010; Powell 2010) (Figure 7). Heterogeneity could be explained by the use of different anthracyclines in the pre-maintenance treatments, as described in the subgroup analysis below.

 FigureFigure 7. Forest plot of comparison: 3 Maintenance with ATRA alone compared to maintenance with ATRA and chemotherapy, outcome: 3.1 Overall survival.

 
Disease-free survival (DFS)

ATRA alone maintenance was statistically significantly inferior to combined ATRA and chemotherapy maintenance in terms of DFS (HR 1.38, 95% CI 1.09 to 1.76, fixed-effect model; 4 trials, 1028 patients; I2 for heterogeneity = 46%) (Adès 2010; Avvisati 2011; Feusner 2010; Powell 2010) (Figure 8). Again, heterogeneity could be explained by the different anthracyclines used prior to maintenance treatment and also by the different types of remission confirmation (see subgroup analysis below).

 FigureFigure 8. Forest plot of comparison: 3 Maintenance with ATRA alone compared to maintenance with ATRA and chemotherapy, outcome: 3.2 Disease-free survival.

 

Secondary outcome measures

 
Treatment-related mortality

Only one trial (Avvisati 2011) enrolling 432 patients reported on this outcome. In this trial, no difference in treatment-related mortality was demonstrated between ATRA alone and ATRA and chemotherapy maintenance (0.9% in ATRA alone arm versus 1.9% in the combination arm).

 
Relapse rate

Only one trial (Adès 2010) enrolling 205 patients reported the relapse rate for ATRA alone compared to ATRA and chemotherapy, demonstrating an increased relapse rate for ATRA alone (34% in ATRA alone arm versus 14% in the combination arm).

 
Adverse events
 
Adverse events requiring discontinuation of therapy

No data were available for this analysis.

 
Grade 3 and 4 adverse events

Only one trial (Powell 2010) including 331 patients reported grade 3 to 4 adverse events. This trial reported a reduced risk for grade 3 to 4 adverse events in the ATRA alone maintenance arm compared to the ATRA and chemotherapy maintenance arm (25% in the ATRA alone maintenance arm versus 36% in the combination arm, P = 0.033).

 
Grade 3 and 4 hematologic toxicity

Only one trial (Powell 2010) including 331 patients reported grade 3 to 4 hematological adverse events. This trial reported a reduced risk for grade 3 to 4 hematological adverse events in the ATRA alone maintenance arm as compared to the ATRA and chemotherapy maintenance arm (4% in the ATRA alone maintenance versus 18% in the combination arm, P < 0.0001).

 
Infection-related adverse events

No data were available for this analysis.

 
APL differentiation syndrome (formerly ATRA syndrome)

No data were available for this analysis.

 

Subgroup analysis for overall survival (OS) and disease-free survival (DFS)

 
Adults patients (excluding pediatric patients)

No data were available for this analysis.

 
Elderly patients (age > 60 years)

No data were available for this analysis.

 
Pediatric patients (age < 15 years)

Two trials reported on a pediatric population (Avvisati 2011; Feusner 2010). Overall, ATRA alone maintenance had an effect on OS similar to ATRA and chemotherapy maintenance (HR 2.05, 95% CI 0.47 to 8.82, fixed-effect model; 2 trials, 133 patients; I2 for heterogeneity = 0%).

For DFS, the overall effect of ATRA maintenance alone was statistically significantly inferior to ATRA and chemotherapy maintenance (HR 2.17, 95% CI 1.09 to 4.31, fixed-effect model; 2 trials, 127 patients; I2 for heterogeneity = 40%).

 
Risk group stratification

There were not enough data to analyze the primary outcomes according to risk group stratification.

 
Type of remission confirmation

ATRA alone maintenance had no statistically significant effect on OS compared to ATRA and chemotherapy maintenance in trials which applied hematological remission confirmation prior to maintenance initiation (HR 1.55, 95% CI 0.92 to 2.63, fixed-effect model; three trials, 606 patients; I2 for heterogeneity = 0%) (Adès 2010; Feusner 2010; Powell 2010). Only one trial using molecular remission confirmation was available for this comparison (Avvisati 2011). This trial did not demonstrate a difference in OS between the two allocated maintenance arms (HR 0.65, 95% CI 0.39 to 1.08). However, the difference between the subgroups was statistically significant (P = 0.02) due to different points of estimate.

Trials which used hematological remission confirmation demonstrated a negative effect on DFS for patients allocated to ATRA alone maintenance compared to ATRA and chemotherapy maintenance (HR 1.72, 95% CI 1.23 to 2.41, fixed effect model; 3 trials, 596 patients; I2 for heterogeneity = 3%) (Adès 2010; Feusner 2010; Powell 2010). Only one trial using molecular remission confirmation was available for this comparison (Avvisati 2011), showing no effect on DFS with ATRA alone maintenance compared to ATRA and chemotherapy maintenance (HR 1.08, 95% CI 0.76 to 1.54). The difference between the subgroups was not statistically significant (P = 0.06).

 
Type of prior induction and consolidation therapy
 
Type of prior anthracycline used

Trials which used daunorubicin demonstrated a similar effect on OS for ATRA alone maintenance compared to ATRA and chemotherapy maintenance (HR 1.55, 95% CI 0.92 to 2.63, fixed-effect model; 3 trials, 606 patients; I2 for heterogeneity = 0%) (Adès 2010; Feusner 2010; Powell 2010). Only one trial reporting OS in this comparison used idarubicin (Avvisati 2011), with a similar OS for patients treated with ATRA alone for maintenance and those treated with ATRA and chemotherapy as maintenance (HR 0.65, 95% CI 0.39 to 1.08). The difference between the subgroups was statistically significant (P = 0.02) due to different points of estimate.

In terms of DFS, there was a negative impact for ATRA alone maintenance compared to ATRA and chemotherapy maintenance when daunorubicin was used, namely patients previously treated with daunorubicin faired less well when maintenance consisted of ATRA alone compared to ATRA and chemotherapy (HR 1.72, 95% CI 1.23 to 2.41, fixed-effect model; 3 trials, 596 patients; I2 for heterogeneity = 3%) (Adès 2010; Feusner 2010; Powell 2010). Only one trial used idarubicin in this comparison (Avvisati 2011), with similar DFS rates for patients treated with ATRA alone and those treated with ATRA and chemotherapy maintenance (HR 1.08, 95% CI 0.76 to 1.54). The difference between the subgroups was not statistically significant (P = 0.06).

 

Sensitivity analysis

 
Sensitivity analysis by allocation concealment and allocation generation

Three trials reported neither allocation generation nor the allocation concealment method (Lin 2007; Parovichnikova 2004; Shen 2004). One trial (Lin 2007) did not include an outcome report that could be used for primary outcome meta-analysis. The remaining two trials were included under the same comparison; therefore this type of sensitivity analysis was only available for the comparison of ATRA-based maintenance and non-ATRA based maintenance. No difference in OS was noted between the two trials reporting adequate methods of allocation concealment and generation (Adès 2010; Avvisati 2011) and the single trial (Parovichnikova 2004) which did not report it. As for DFS, trials with adequate methods of allocation concealment and generation did not demonstrate improved DFS with ATRA-based maintenance compared to non-ATRA based maintenance (HR 0.73, 95% CI 0.51 to 1.03, fixed-effect model; 2 trials, 564 patients; I2 for heterogeneity = 5%) (Adès 2010; Avvisati 2011). The two trials with unclear methods of allocation concealment and generation did not differ in terms of DFS regarding ATRA-based maintenance and non-ATRA based maintenance as well. The difference between the two subgroups was not statistically significant (P = 0.83).

 
Sensitivity analysis by duration of follow-up

Six trials had a follow-up duration of over five years (Adès 2010; Asou 2007; Avvisati 2002; Avvisati 2011; Powell 2010; Tallman 2002), whereas three trials had a follow-up duration of five years or less (Feusner 2010; Parovichnikova 2004; Shen 2004). Since all five trials included in the comparison of any maintenance compared to observation had longer than five years follow-up, sensitivity analysis was not applicable for this comparison. Stratifying follow-up duration into two subgroups according to this cutoff did not demonstrate improved OS in the other two main comparisons. However, among these two comparisons, DFS was improved in trials with follow-up longer than five years in all three main comparisons. In contrast, no effect on DFS was noted in trials where the follow-up duration was five years or less.   

 
Sensitivity analysis by measure of OS

Among the six trials reporting OS data, three trials reported OS data from the time of randomization to maintenance till death from any cause (Adès 2010; Asou 2007; Avvisati 2011), whereas three trials reported either OS data from study entry (Feusner 2010; Powell 2010) or from an undetermined time point (Parovichnikova 2004). Sensitivity analysis by stratifying trials on the basis of the survival duration measurement method was applicable for two main comparisons (comparison 2: ATRA-based maintenance versus non-ATRA based maintenance; and comparison 3: ATRA alone maintenance versus ATRA and chemotherapy maintenance) and did not result in a different OS effect between subgroups.

 
Sensitivity analysis by measure of DFS

One trial (Shen 2004) had only one randomization for both the induction and maintenance treatments. This randomization was conducted before induction initiation. Moreover, DFS in this trial was measured differently (after achieving CR following induction and prior to consolidation), in contrast to all other included trials where randomization was carried out after the consolidation phase. Therefore, we performed sensitivity analysis, excluding the DFS data from this trial. The results of this sensitivity analysis were similar to the main comparison, reflecting the negligible effect of this small-sized trial.

 

Discussion

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Summary of main results

Ten randomized controlled trials enrolling a total of 2072 patients were compatible with the inclusion criteria and were therefore included in our systematic review. Nine of them (2012 patients enrolled) were included in the meta-analysis.

There was no evidence that any maintenance therapy improved OS compared to observation. DFS was improved with any maintenance compared to observation. When comparing the two active arms, ATRA and chemotherapy showed improved DFS but not OS compared to ATRA alone. For ATRA-based regimens compared to non-ATRA based regimens, DFS was probably improved, but OS was not. There was a major statistical and clinical heterogeneity between the trials included in our meta-analysis, reflecting the differences in both pre-maintenance treatments, namely induction and consolidation regimens, as well as in the maintenance protocols and disease monitoring.

Subgroup analysis suggested that DFS benefit may depend on pre-maintenance treatment parameters including the type of anthracycline used and the intensity of treatment as well as the definitions of the type of remission.

There was increased toxicity with any maintenance compared to observation and with combined maintenance protocols compared to monotherapy. This might negatively balance the improved disease control achieved with the use of maintenance.

 

Overall completeness and applicability of evidence

The objectives of this review were to examine the efficacy and safety of maintenance therapy for patients with APL, and to establish the optimal maintenance regimen. Our results show that according to the three main comparisons, maintenance therapy does not improve OS but improves DFS. This was shown according two main comparisons, that is any maintenance compared to observation, and ATRA alone compared to ATRA and chemotherapy (with statistically marginal proof of benefit in the second comparison of ATRA-based maintenance compared to non-ATRA based maintenance). It is perplexing that according to our review, DFS was prolonged in the maintenance arm while OS, treatment-related mortality and relapse rates were not different. As CR rates by the end of consolidation were between 70% and 90% and the relapse rates ranged between 20% and 30% in most trials ( Table 4), it might be difficult to demonstrate an OS benefit for maintenance therapy as most patients might have been already cured prior to the maintenance phase. Therefore, the possibility of an underpowered meta-analysis for the OS measure should be considered.

The improved DFS with no effect on OS may also stem from the toxicity of maintenance therapy that consequently negatively balanced the improved disease control, from the extended time to relapse with maintenance therapy which ultimately occurs and from the availability of a very effective salvage therapy upon relapse. Yet, even in the ATO salvage therapy era, survival following relapse in APL is reduced (50% to 81% at 2 years) (Lengfelder 2012). Moreover, most trials included in our review were performed in the pre-ATO era with a 2-year survival of 50% or less following relapse (Lo coco 1999). Therefore, the last explanation is less plausible for the discrepancy between DFS and OS.

Yet, improved DFS with no OS benefit, albeit all the limitations mentioned above, may be important for both treating physicians and patients as it may imply better disease control and save additional treatments upon relapse. Thus, although no clear survival advantage is demonstrated for maintenance therapy, this type of treatment may indirectly impact the quality of life of patients by reducing treatment burden with a better disease control. Still, as we do not have quality of life data from the included trials and as maintenance therapy by itself has a direct impact on patients' quality of life, this hypothesis should be appropriately evaluated in future trials.

Another interesting point is that although there was no difference in the relapse rate according to the random-effects model, DFS was better with maintenance. This finding may be due to the fact that relapse rate was not reported by all trials. Moreover, due to differences in the follow-up periods between the included trials, there might have been an impact on the time to relapse influencing DFS, which is a time to event variable. Furthermore, the relapse rate becomes statistically significant between maintenance and observation when the intensive chemotherapeutic maintenance versus observation trial published by Asou et al is excluded (Asou 2007). This observation highlights both the clinical and statistical complexity of this review and might imply that in APL patients achieving CR, a more intensive maintenance regimen does not translate necessarily into improved disease control.   

We found a positive interaction between certain maintenance regimens and DFS advantage when daunorubicin rather than idarubicin was used as the anthracycline in the induction and consolidation phases. Moreover, most trials used similar cumulative doses of anthracyclines for the induction or consolidation phases, or both ( Table 3). This could be used as a surrogate to eliminate dose response differences between trials. Still, this interaction may be the consequence of a bystander effect, especially in light of the low number of included trials.Therefore, until a direct comparison is made between the various types of anthracyclines, there is no advantage for one anthracycline over the other with respect to the issue of maintenance.

The method of remission confirmation varied between trials. Some trials confirmed remission by molecular methods (Asou 2007; Avvisati 2011; Parovichnikova 2004) whereas others used morphological assessment (Adès 2010; Avvisati 2002; Feusner 2010; Lin 2007; Powell 2010; Shen 2004; Tallman 2002). Detection of molecular relapse is highly predictive for hematological relapse (Diverio 1998). There are reports of improved outcome if pre-emptive treatment is given at the time of molecular relapse rather than waiting for hematological relapse (Lo coco 1999). In trials where remission confirmation was based on morphology and not on molecular grounds, 2% to 8% of patients might be positive for the PML-RARa transcript if screened by molecular methods and are therefore at a higher risk for relapse while on maintenance treatment (Grimwade 2002). Yet, one has to bear in mind that 30% of patients who test negative on RT-PCR might still relapse. Although PCR-based remission confirmation and disease monitoring are superior to morphological confirmation and monitoring only, the true impact of this difference in remission assessment on the maintenance outcome is still uncertain.

We were not able to perform analysis by risk group stratification as only one trial (Powell 2010) reported survival data for maintenance according to the risk groups used in the PETHEMA trial (Sanz 2000). This issue needs to be addressed in future trials.

Due to a lack of detailed information concerning the elderly group, we could not conduct a meta-analysis for this group. One of the two trials (Adès 2010; Avvisati 2011) describing the outcome of maintenance among elderly patients reported a poorer survival in this group, not because of an increased relapse rate but due to death in CR during the maintenance period (Adès 2010). This data, albeit restricted to one trial, demonstrates the complexity of APL treatment among the elderly, which might discourage the use of maintenance treatment in this age group.

With regard to pediatric patients, four trials addressed the issue of maintenance in children (Adès 2010; Avvisati 2011; Feusner 2010; Tallman 2002). However, due to the range of comparisons and the low number of pediatric patients (reflecting the rarity of the disease among children), a meta-analysis (of two trials only) could be conducted only for the comparison of ATRA alone versus ATRA and chemotherapy. Thus, the role of maintenance in pediatric patients needs further investigation.

Extramedullary relapse occurs in nearly 3% to 5% of APL patients, manifested usually in the central nervous system and even more so since the introduction of ATRA (Raanani 2007). This type of relapse is associated with high white blood cell (WBC) count at presentation and carries a poor prognosis (de Botton 2006). We did not have enough data to evaluate the influence of maintenance treatment on the occurrence or prevention of extramedullary relapse.

 

Quality of the evidence

All trials that were included were randomized controlled trials. Allocation generation and concealment were adequate in seven out of 10 trials. None of the trials reported blinding of participants and personnel, and probably also outcome assessors. This might introduce both selection bias (mainly for trials with an observation control arm) and detection bias for all trials.

All trials but one reported analysis on the basis of intention to treat, and the drop-out rates were low. The risk of attrition bias is therefore low. The primary outcomes measures in this review are given as time-to-event measures. This type of outcome measure minimizes risk of bias when compared to outcome measures given by specified time points (that is 5-year survival).

Although included trials are of adequate methodological quality and their results are valid, it is difficult to draw robust conclusions due to the clinical and statistical heterogeneity. Using the GRADE scoring system, quality of evidence was graded for most measured primary outcomes as moderate or low quality. The main reasons for quality faults in the included trials were lack of blinding, low numbers of patients and events producing a wide confidence interval (i.e., imprecision) and high heterogeneity between trials. However, few outcome measures were upgraded with a large effect. This emphasizes the major limitations, as described above, and stresses the need for further randomized trials.

 

Potential biases in the review process

The major limitation of the present review is the clinical variability among the trials included stemming from the variability in the maintenance protocols, in the treatments prior to maintenance and in the definitions of outcomes. This variability led us to conduct three main comparisons to evaluate the effect of maintenance therapy, thus leaving less power for each comparison compared to conducting only one main comparison. Comparing any maintenance to observation demonstrates best this clinical heterogeneity, as it is well reflected in the significant statistical heterogeneity of the results of this comparison. However, analysis of subgroups of patients by the type of treatment arm (that is ATRA alone, ATRA-containing regimen, chemotherapy alone) in order to explore the reasons for this heterogeneity demonstrated improved DFS with no effect on OS only for ATRA-containing regimens (either ATRA alone or ATRA plus chemotherapy) compared to observation, without statistical heterogeneity between trials. However, the limitation of this subgroup analysis is underlined by the low number of trials available for each subgroup.

We conducted two subgroup analyses for each comparison to explore heterogeneity and to assess the effect of different factors on outcome measures. However, only very few trials were included in these subgroup analyses and thus a reliable conclusion cannot be drawn. Furthermore, with respect to the two subgroup analyses conducted, namely the type of anthracycline used in the remission induction and consolidation phase and the type of remission confirmation, it was difficult to separate the effect of anthracycline type from that of remission type since remission was confirmed morphologically in trials that used daunorubicin for induction or consolidation, while it was established molecularly in those using idarubicin as the anthracycline.

We also compared several outcome measures of trials which randomized patients before induction ( Table 4). Complete response rate was similar between these trials and reached 90% or more, except for two (Avvisati 2002; Tallman 2002) reporting on a complete remission rate of 70%. As response endpoints achieved before the initiation of maintenance were similar among trials, it can be assumed that no attrition bias was introduced by prior induction and consolidation treatments.

Differences in duration of follow-up between trials might affect survival outcomes. The median duration of follow-up varied between 1.5 and 10 years among the included trials. Of note, in six trials the duration of follow-up was longer than five years. We therefore conducted a sensitivity analysis on the primary outcomes according to follow-up duration (over five years versus five years or less) with no significant influence on the results.

As for the availability of data from the included trials, most trials have reported satisfactory data. Whenever important data were missing we contacted the primary investigators for more detailed information, usually successfully.

 

Agreements and disagreements with other studies or reviews

To our knowledge this is the first systematic review and meta-analysis assessing the role of maintenance therapy in APL. Three meta-analyses recently conducted addressed the role of ATO in APL (Wang 2011; Xu 2009; Xu 2009a). These reviews did not assess its role for maintenance and included newly diagnosed patients as well as relapsed patients.

Maintenance therapy, despite being controversial, is part of many APL protocols worldwide. The Spanish PETHEMA group protocols LPA 99 and LPA 96 incorporated maintenance treatment consisting of ATRA and low dose methotrexate and mercaptopurine for two years in APL patients (Sanz 2004a). The German AML Cooperative Group (AMLCG) incorporated monthly maintenance chemotherapy for three years as part of their protocol for APL (Lengfelder 2009).

Clinical guidelines addressing APL treatment are few and are usually given as part of AML clinical guidelines (Milligan 2006; NCCN 2001). The National Comprehensive Cancer Network (NCCN) updated guidelines (NCCN 2001) on AML favor the use of maintenance therapy in APL but underline the unclear effect of maintenance therapy, particularly among low risk patients who achieve molecular remission at the end of consolidation. The British guidelines (Milligan 2006) are even less conclusive on the role of maintenance treatment in APL. Additionally, an expert panel on behalf of the European LeukemiaNet (Sanz 2009) stressed the relative benefit of maintenance in accordance with the prior induction and consolidation therapy. Therefore, the panel suggested using maintenance in conjunction with protocols in which a benefit for maintenance was demonstrated.

The Australian Leukaemia and Lymphoma Group (ALLG) has recently published the results of a prospective study conducted between the years 1997 and 2002 (Iland 2012) where APL patients were given two induction cycles based on the AIDA 0493 protocol (Avvisati 2011) and consolidation consisted of intermittent doses of ATRA only followed by an observational period. However, after an interim analysis, the protocol was amended and all the following patients received maintenance treatment consisting of a combination of ATRA and chemotherapy (6-MP+MTX) for two years. The investigators reported improved DFS, remission duration and failure-free survival with maintenance compared to observation, but like us they could not show advantage in terms of OS.

 

Authors' conclusions

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

 

Implications for practice

Maintenance treatment in APL does not affect OS according to existing data. However, mainly if ATRA-based, it prolongs DFS. With the growing use of ATO in APL for induction and consolidation as well as for relapse, the role of maintenance treatment might become even more obscure. Therefore, the current approach should be individually based, taking into consideration patient preferences as well as disease and patient biological parameters such as age, prognostic risk group, pre-maintenance treatment and type of remission status.

 
Implications for research

As survival data are incomplete and as there is considerable variability among included trials for both pre-maintenance and maintenance treatments, we recommend an individualized patient data meta-analysis as a measure that can validate the results of this review and answer some of the unsolved issues of maintenance therapy in APL.

As appears from the current review, the major gaps in the field of maintenance in APL that should be the focus of future research are as follows.

  • The characterization of the patients who might benefit most from maintenance and those who do not need it, by using validated risk group stratification.
  • The significance of the intensity of the pre-maintenance treatment with regard to the role of maintenance treatment.
  • The effect of different anthracyclines used in the pre-maintenance treatment on the role of maintenance.
  • The significance of type of remission and relapse definition (hematological versus molecular) and the effect on maintenance efficacy.
  • The optimal duration of maintenance.
  • The best maintenance regimen.
  • The effect of maintenance treatment among certain groups of patients, such as the elderly and pediatric patients.   

 

Acknowledgements

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

We would like to acknowledge the following researchers for providing us valuable and updated data from their trials: Prof Martin Tallman; Prof Giuseppe Avvisati; Dr Francesca Paola Paoloni; Prof Lionel Adès; Prof Pierre Fenaux; Prof Sylvie Chevret; Prof Bayard Powell; Prof James H Feusner; Prof Norio Asou; Dr Masako Iwanaga; and Dr Marco Vignetti.

We would like to thank also Dr Nicole Skoetz and Ms Bettina Schmidtke from the Cochrane Haematological Malignancies Group for reviewing this protocol and Ms Ina Monsef for her help in constructing the search strategy.

 

Data and analyses

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
Download statistical data

 
Comparison 1. Any maintenance compared to observation

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Overall survival3892Hazard Ratio (Fixed, 95% CI)0.79 [0.49, 1.27]

 2 Disease-free survival51209Hazard Ratio (Fixed, 95% CI)0.59 [0.48, 0.74]

 3 Relapse rate4896Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.58, 0.81]

 4 Low intensity maintenance vs. observation: Overall survival2719Odds Ratio (Fixed, 95% CI)0.60 [0.36, 1.01]

 5 Low intensity maintenance vs. observation: Disease-free survival41039Odds Ratio (Fixed, 95% CI)0.52 [0.41, 0.66]

 6 Low intensity maintenance vs. observation: Relapse rate3721Odds Ratio (M-H, Fixed, 95% CI)0.39 [0.28, 0.55]

 
Comparison 2. ATRA-based maintenance compared to non-ATRA based maintenance

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Overall survival3632Hazard Ratio (Fixed, 95% CI)1.21 [0.73, 1.98]

 2 Disease-free survival4670Hazard Ratio (Fixed, 95% CI)0.72 [0.51, 1.01]

 3 Relapse rate3425Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.59, 1.30]

 
Comparison 3. Maintenance with ATRA alone compared to maintenance with ATRA and chemotherapy

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Overall survival41033Hazard Ratio (Fixed, 95% CI)0.99 [0.69, 1.43]

 2 Disease-free survival41028Hazard Ratio (Fixed, 95% CI)1.38 [1.09, 1.76]

 
Comparison 4. ATRA alone maintenance compared to ATRA and chemotherapy maintenance in pediatric patients

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Overall survival2133Hazard Ratio (Fixed, 95% CI)2.05 [0.47, 8.82]

 2 Disease-free survival2127Hazard Ratio (Fixed, 95% CI)2.17 [1.09, 4.31]

 
Comparison 5. Subgroup analysis: overall survival by type of remission confirmation

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Any maintenance compare to observation3892Hazard Ratio (Fixed, 95% CI)0.79 [0.49, 1.27]

    1.1 Molecular confirmation
2491Hazard Ratio (Fixed, 95% CI)1.86 [0.99, 3.48]

    1.2 Hemtological confirmation
1401Hazard Ratio (Fixed, 95% CI)0.25 [0.12, 0.52]

 2 ATRA based maintenance compare to non-ATRA based maintenance3632Hazard Ratio (Fixed, 95% CI)1.21 [0.73, 1.98]

    2.1 Molecular confirmation
2310Hazard Ratio (Fixed, 95% CI)1.24 [0.67, 2.29]

    2.2 Hemtological confirmation
1322Hazard Ratio (Fixed, 95% CI)1.15 [0.50, 2.67]

 3 ATRA alone maintenance compare to ATRA and chemotherapy maintenance41033Hazard Ratio (Fixed, 95% CI)0.99 [0.69, 1.43]

    3.1 Molecular confirmation
1427Hazard Ratio (Fixed, 95% CI)0.65 [0.39, 1.08]

    3.2 Hemtological confirmation
3606Hazard Ratio (Fixed, 95% CI)1.55 [0.92, 2.63]

 
Comparison 6. Subgroup analysis: disease-free survival by type of remission confirmation

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Any maintenance compare to observation51209Hazard Ratio (Fixed, 95% CI)0.59 [0.48, 0.74]

    1.1 Molecular confirmation
2488Hazard Ratio (Fixed, 95% CI)0.90 [0.57, 1.44]

    1.2 Hemtological confirmation
3721Hazard Ratio (Fixed, 95% CI)0.52 [0.41, 0.67]

 2 ATRA based maintenance compare to non-ATRA based maintenance4670Hazard Ratio (Fixed, 95% CI)0.72 [0.51, 1.01]

    2.1 Molecular confirmation
2310Hazard Ratio (Fixed, 95% CI)0.61 [0.35, 1.07]

    2.2 Hematological confirmation
2360Hazard Ratio (Fixed, 95% CI)0.79 [0.52, 1.21]

 3 ATRA alone maintenance compare to ATRA and chemotherapy maintenance41028Hazard Ratio (Fixed, 95% CI)1.38 [1.09, 1.76]

    3.1 Molecular confirmation
1432Hazard Ratio (Fixed, 95% CI)1.08 [0.76, 1.54]

    3.2 Hemtological confirmation
3596Hazard Ratio (Fixed, 95% CI)1.72 [1.23, 2.41]

 
Comparison 7. Subgroup analysis: overall survival by type of prior anthracycline use

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Any maintenance compare to observation3892Hazard Ratio (Fixed, 95% CI)0.79 [0.49, 1.27]

    1.1 Daunorubicin use
1401Hazard Ratio (Fixed, 95% CI)0.25 [0.12, 0.52]

    1.2 Idarubicin use
2491Hazard Ratio (Fixed, 95% CI)1.86 [0.99, 3.48]

 2 ATRA based maintenance compare to non-ATRA based maintenance3554Hazard Ratio (Fixed, 95% CI)1.21 [0.73, 1.98]

    2.1 Daunorubicin use
2390Hazard Ratio (Fixed, 95% CI)1.31 [0.64, 2.70]

    2.2 Idarubicin use
1164Hazard Ratio (Fixed, 95% CI)1.12 [0.56, 2.22]

 3 ATRA alone maintenance compare to ATRA and chemotherapy maintenance41033Hazard Ratio (Fixed, 95% CI)0.99 [0.69, 1.43]

    3.1 Daunorubicin use
3606Hazard Ratio (Fixed, 95% CI)1.55 [0.92, 2.63]

    3.2 Idarubicin use
1427Hazard Ratio (Fixed, 95% CI)0.65 [0.39, 1.08]

 
Comparison 8. Subgroup analysis: disease-free survival by type of prior anthracycline use

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Any maintenance compare to observation51209Hazard Ratio (Fixed, 95% CI)0.59 [0.48, 0.74]

    1.1 Daunorubicin use
2605Hazard Ratio (Fixed, 95% CI)0.44 [0.33, 0.60]

    1.2 Idarubicin use
3604Hazard Ratio (Fixed, 95% CI)0.85 [0.61, 1.18]

 2 ATRA based maintenance compare to non-ATRA based maintenance4592Hazard Ratio (Fixed, 95% CI)0.72 [0.51, 1.01]

    2.1 Daunorubicin use
3428Hazard Ratio (Fixed, 95% CI)0.81 [0.53, 1.22]

    2.2 Idarubicin use
1164Hazard Ratio (Fixed, 95% CI)0.56 [0.30, 1.03]

 3 ATRA alone maintenance compare to ATRA and chemotherapy maintenance41028Hazard Ratio (Fixed, 95% CI)1.38 [1.09, 1.76]

    3.1 Daunorubicn use
3596Hazard Ratio (Fixed, 95% CI)1.72 [1.23, 2.41]

    3.2 Idarubicin use
1432Hazard Ratio (Fixed, 95% CI)1.08 [0.76, 1.54]

 
Comparison 9. Sensitivity analysis: overall survival by method of allocation concealment, allocation generation

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 ATRA based maintenance compare to non-ATRA based maintenance3632Hazard Ratio (Fixed, 95% CI)1.21 [0.73, 1.98]

    1.1 adequate allocation generation and concealment
2564Hazard Ratio (Fixed, 95% CI)1.13 [0.66, 1.92]

    1.2 unclear
168Hazard Ratio (Fixed, 95% CI)1.88 [0.47, 7.55]

 
Comparison 10. Sensitivity analysis: disease-free survival by method of allocation concealment, allocation generation

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 ATRA based maintenance compare to non-ATRA based maintenance4670Hazard Ratio (Fixed, 95% CI)0.72 [0.51, 1.01]

    1.1 adequate allocation generation and concealment
2564Hazard Ratio (Fixed, 95% CI)0.73 [0.51, 1.03]

    1.2 unclear
2106Hazard Ratio (Fixed, 95% CI)0.62 [0.16, 2.41]

 
Comparison 11. Sensitivity analysis: overall survival by duration of follow-up

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Any maintenance compare to observation3892Hazard Ratio (Fixed, 95% CI)0.79 [0.49, 1.27]

    1.1 over 5 years
3892Hazard Ratio (Fixed, 95% CI)0.79 [0.49, 1.27]

   1.2 5 years or less
00Hazard Ratio (Fixed, 95% CI)0.0 [0.0, 0.0]

 2 ATRA based maintenance compare to non-ATRA based maintenance3711Hazard Ratio (Fixed, 95% CI)0.98 [0.64, 1.51]

    2.1 over 5 years
2643Hazard Ratio (Fixed, 95% CI)0.92 [0.58, 1.45]

    2.2 5 years or less
168Hazard Ratio (Fixed, 95% CI)1.88 [0.47, 7.55]

 3 ATRA alone maintenance compare to ATRA and chemotherapy maintenance41033Hazard Ratio (Fixed, 95% CI)0.99 [0.69, 1.43]

    3.1 over 5 years
3963Hazard Ratio (Fixed, 95% CI)0.99 [0.68, 1.43]

    3.2 5 years or less
170Hazard Ratio (Fixed, 95% CI)1.14 [0.16, 8.08]

 
Comparison 12. Sensitivity analysis: disease-free survival by duration of follow-up

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Any maintenance compare to observation51209Hazard Ratio (Fixed, 95% CI)0.59 [0.48, 0.74]

    1.1 over 5 years
51209Hazard Ratio (Fixed, 95% CI)0.59 [0.48, 0.74]

   1.2 5 years or less
00Hazard Ratio (Fixed, 95% CI)0.0 [0.0, 0.0]

 2 ATRA based maintenance compare to non-ATRA based maintenance4749Hazard Ratio (Fixed, 95% CI)0.61 [0.46, 0.83]

    2.1 over 5 years
2643Hazard Ratio (Fixed, 95% CI)0.61 [0.45, 0.83]

    2.2 5 years or less
2106Hazard Ratio (Fixed, 95% CI)0.62 [0.16, 2.41]

 3 ATRA alone maintenance compare to ATRA and chemotherapy maintenance41028Hazard Ratio (Fixed, 95% CI)1.38 [1.09, 1.76]

    3.1 over 5 years
3964Hazard Ratio (Fixed, 95% CI)1.37 [1.07, 1.77]

    3.2 5 years or less
164Hazard Ratio (Fixed, 95% CI)1.54 [0.65, 3.64]

 
Comparison 13. Sensitivity analysis by overall survival (OS) measure method

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 ATRA based maintenance compare to non-ATRA based maintenance3632Hazard Ratio (Fixed, 95% CI)1.21 [0.73, 1.98]

    1.1 OS measure from time of randomization to maintenance
2564Hazard Ratio (Fixed, 95% CI)1.13 [0.66, 1.92]

    1.2 Unknown time measure for OS data
168Hazard Ratio (Fixed, 95% CI)1.88 [0.47, 7.55]

 2 ATRA alone maintenance compare to ATRA and chemotherapy maintenance41033Hazard Ratio (Fixed, 95% CI)0.99 [0.69, 1.43]

    2.1 OS measure from time of randomization to maintenance
2632Hazard Ratio (Fixed, 95% CI)0.84 [0.53, 1.32]

    2.2 OS measure from study entry
2401Hazard Ratio (Fixed, 95% CI)1.35 [0.73, 2.50]

 
Comparison 14. Sensitivity analysis by disease-free survival (DFS) measure method

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 ATRA based maintenance compare to non-ATRA based maintenance4670Hazard Ratio (Fixed, 95% CI)0.72 [0.51, 1.01]

    1.1 DFS measure from randomization to maintenance
3632Hazard Ratio (Fixed, 95% CI)0.74 [0.52, 1.04]

    1.2 DFS measure prior to maintenance initiation
138Hazard Ratio (Fixed, 95% CI)0.12 [0.01, 1.83]

 
Comparison 15. Subgroup analysis: survival by subtype of maintenance compared to observation

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Overall survival3679Hazard Ratio (Fixed, 95% CI)0.55 [0.36, 0.86]

    1.1 Chemotherapy alone maintenance compared to observation
2369Hazard Ratio (Fixed, 95% CI)0.60 [0.29, 1.23]

    1.2 ATRA alone maintenance compared to observation
1155Hazard Ratio (Fixed, 95% CI)0.53 [0.24, 1.15]

    1.3 ATRA containing regimen compared to observation
1155Hazard Ratio (Fixed, 95% CI)0.53 [0.24, 1.15]

 2 Disease-free survival41088Hazard Ratio (Fixed, 95% CI)0.60 [0.50, 0.72]

    2.1 Chemotherapy alone maintenance compared to observation
3440Hazard Ratio (Fixed, 95% CI)0.94 [0.68, 1.30]

    2.2 ATRA alone maintenance compared to observation
2204Hazard Ratio (Fixed, 95% CI)0.47 [0.33, 0.66]

    2.3 ATRA containing regimen maintenance compared to observation
2444Hazard Ratio (Fixed, 95% CI)0.48 [0.35, 0.66]

 

Appendices

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Appendix 1. Search strategy (CENTRAL)

 

Appendix 2. Search strategy (Ovid MEDLINE)


#Searches

1exp LEUKEMIA, MYELOID, ACUTE/

2LEUKEMIA, MYELOID/

3ACUTE DISEASE/

42 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.

75 and 6

8aml.tw,kf,ot.

9LEUKEMIA, 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.

1210 and 11

13apl.tw,kf,ot.

141 or 4 or 7 or 8 or 9 or 12 or 13

15exp MAINTENANCE/

16maintenanc$.tw,kf,ot.

17((post-remission$ or postremission$) adj2 therap$).tw,kf,ot.

18or/15-17

1914 and 18

20randomized controlled trial.pt.

21controlled clinical trial.pt.

22randomized.ab.

23placebo.ab.

24drug therapy.fs.

25randomly.ab.

26trial.ab.

27groups.ab.

28or/20-27

29humans.sh.

3028 and 29

3119 and 30



 

Appendix 3. Search strategy (LILACS)

We searched the following terms:

acute promyelocytic leukemia

APL

 

What's new

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Last assessed as up-to-date: 17 July 2012.


DateEventDescription

10 June 2013AmendedMinor changes due to external feedback.



 

Contributions of authors

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Eli Muchtar: conception and design, provision of study material, protocol development, search for trials, data extraction, analysis and data interpretation, writing of the review and final approval of the review.

Liat Vidal: conception and design, provision of study material, protocol development, search for trials, data extraction, analysis and data interpretation, final approval of the review.

Ron Ram: conception, protocol development, analysis and data interpretation, final approval of the review.

Anat Gafter-Gvili: protocol development, search for trials, analysis and data interpretation, final approval of the review.

Ofer Shpilberg: protocol development and design, analysis and data interpretation, final approval of the review, clinical and scientific advice.

Pia Raanani: conception and design, provision of study material, protocol development, analysis and data interpretation, final approval of the review, clinical and scientific advice.

 

Declarations of interest

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

None known to declare.

 

Sources of support

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Internal sources

  • Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

 

External sources

  • No sources of support supplied

 

Differences between protocol and review

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

# We used the most updated available results for data analysis. In the case where more updated data were provided by the authors, different from the published data, we used the updated data.

# For both dichotomous data and time-to-event outcomes we used the fixed-effect model. Where significant heterogeneity was noted we explored reasons for heterogeneity and if not found we also used the random-effects model for the pooled data analysis.

# For sensitivity analysis we also applied the median follow-up period, stratifying for trials with a follow-up period over five years and for trials with a median follow-up of five years or less.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to ongoing studies
  22. Additional references
Adès 2010 {published and unpublished data}
  • Ades L, Chevret S, De Botton S, Thomas X, Dombert H, Sanz M, et al. Outcome of acute promyelocytic leukemia (APL) treated with all trans retinoic acid (ATRA) and chemotherapy (CT) in elderly patients (>60 years): the European group experience. Blood. 2003; Vol. 102:619a, abstract 2286.
  • Adès L, Chevret S, de Botton S, Thomas X, Dombret H, Beve B, et al. Outcome of acute promyelocytic leukemia treated with all trans retinoic acid and chemotherapy in elderly patients: the European group experience. Leukemia 2005;19(2):230-3.
  • Adès L, Guerci A, Raffoux E, Chevallier P, Lapusan S, Recher C, et al. Very long-term outcome of acute promyelocytic leukemia after treatment with all-trans retinoic acid and chemotherapy: the European APL Group experience. Blood 2010;115(9):1690-6.
  • Adès L, Guerci A, Raffoux E, Sanz M, Chevallier P, Lapusan S, et al. Very long term outcome of acute promyelocytic leukemia after treatment with all trans retinoic acid and chemotherapy: the European APL group experience. Blood (ASH Annual Meeting Abstracts). 2009; Vol. 114:abstract 2088.
  • Bourgeois L, Chevret S, Sanz M, Dombert H, Thomas X, Ryon C, et al. long term follow up of APL treated with ATRA and chemotherapy (CT) including incidence of late relapse and overall toxicity. Blood. 2003; Vol. 102:140a, abstract 483.
  • Fenaux P, Chevret S, Sanz M, Thomas X, Dombert H, Fey M, et al. ATRA followed by chemotherapy (CT) vs ATRA plus CT and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia (APL): long term follow up of APL 93 trial. Blood. 2001; Vol. 98:766a, abstract 3190.
  • Kelaidi C, Chevret S, de Botton S, Raffoux E, Guerci A, Thomas X, et al. Improved outcome of acute promyelocytic leukemia with high WBC counts over the last 15 years: the European APL Group experience. Journal of Clinical Oncology 2009;27(16):2668-76.
  • Kelaidi C, Chevret S, de Botton S, Raffoux E, Guerci A, Thomas X, et al. Outcome of acute promyelocytic leukemia (APL) with very high WBC counts treated with ATRA and chemotherapy (CT): The European group experience. Blood. 2007; Vol. 110:1845.
  • de Botton S, Coiteux V, Chevret S, Rayon C, Vilmer E, Sanz M, et al. Outcome of childhood acute promyelocytic leukemia with all-trans-retinoic acid and chemotherapy. Journal of Clinical Oncology 2004;22(8):1404-12.
Asou 2007 {published and unpublished data}
  • Asou N, Kishimoto Y, Kiyoi H, Okada M, Kawai Y, Tsuzuki M, et al. A Randomized study with or without intensified maintenance chemotherapy in patients with acute promyelocytic leukemia who had become negative for PML-RAR transcript after consolidation therapy: The Japan adult leukemia study group (JALSG) APL97 study [abstract]. Blood. 2006; Vol. 108:569.
  • Asou N, Kishimoto Y, Kiyoi H, Okada M, Kawai Y, Tsuzuki M, et al. A randomized study with or without intensified maintenance chemotherapy in patients with acute promyelocytic leukemia who have become negative for PML-RARalpha transcript after consolidation therapy: the Japan Adult Leukemia Study Group (JALSG) APL97 study. Blood 2007;110(1):59-66.
  • Ono T, Takeshita A, Kishimoto Y, Kiyoi H, Okada M, Kawai Y, et al. Clinical features and outcomes of elderly patients with acute promyelocytic leukemia (APL) - the Japan adult leukemia study group APL97 study. Blood. 2010; Vol. 116:abstract 1077.
Avvisati 2002 {published data only}
  • Avvisati G, Petti MC, Lo-Coco F, Vegna ML, Amadori S, Baccarani M, et al. Induction therapy with idarubicin alone significantly influences event-free survival duration in patients with newly diagnosed hypergranular acute promyelocytic leukemia: final results of the GIMEMA randomized study LAP 0389 with 7 years of minimal follow-up. Blood 2002;100(9):3141-6.
Avvisati 2011 {published data only}
  • Avvisati G, Lo-Coco F, Paoloni FP, Petti MC, Diverio D, Vignetti M, et al. GIMEMA, AIEOP, and EORTC Cooperative Groups. AIDA 0493 protocol for newly diagnosed acute promyelocytic leukemia: very long-term results and role of maintenance. Blood 2011;117(18):4716-25.
  • Avvisati G, Petti MC, Lo Coco F, Testi AM, Fazi P, Specchia G, et al. AIDA; The Italian way of treating acute promyelocytic leukemia (APL), final act. Blood. 2003; Vol. 102:142a, abstract 487.
  • Mandelli F, Latagliata R, Avvisati G, Fazi P, Rodeghiero F, Leoniet F, et al. Treatment of elderly patients (> or = 60 years) with newly diagnosed acute promyelocytic leukemia. Results of the Italian multicenter group GIMEMA with ATRA and idarubicin (AIDA) protocols. Leukemia 2003;17(6):1085-90.
  • Testi AM, Biondi A, Lo Coco F, Moleti ML, Giona F, Vignetti M, et al. GIMEMA-AIEOPAIDA protocol for the treatment of newly diagnosed acute promyelocytic leukemia (APL) in children. Blood 2005;106(2):447-53.
  • Testi AM, Foa R, Tomei G, Lo Coco F, Biondi A, Pession A, et al. GIMEMA-AIEOP AIDA protocols for the treatment of newly diagnosed acute promyelocytic leukemia (APL) In children: Analysis of 247 patients enrolled In two sequential Italian multicenter trials. Blood. 2010; Vol. 116:abstract 871.
  • Testi AM, Lo Coco F, Biondi A, et al. GIMEMA-AIEOP AIDA protocol for the treatment of newly diagnosed acute promyelocytic leukemia (APL) in children. Blood. 2003; Vol. 102:141a, abstract 485.
Feusner 2010 {published and unpublished data}
  • Feusner JH, Gregory J, Moser BK, Hars V, Willman CL, Powell BL, et al. Dose-intensified daunorubicin induction and consolidation plus combined modality maintenance therapy for children with newly diagnosed acute promyelocytic leukemia (APL): North American Intergroup Study C9710. Journal of Clinical Oncology. 2010; Vol. 15s:abstract 9510.
Lin 2007 {published data only}
  • Lin QD, Wei XD, Wang P, Liu YY, Zhang LN, Li YF, et al. Application of all-trans retinoic acid combining chemotherapy and As4S4 in the maintenance treatment of patients with acute promyelocytic leukemia] [Chinese]. Chung-Hua Hsueh Yeh Hsueh Tsa Chin: Chinese Journal of Hematology 2007;28(1):19-21.
Parovichnikova 2004 {published data only}
  • Parovichnikova EN, Savchenko VG, Demidova IA, Isaev VG, Shuravina EN, Ustinova EN, et al. [Preliminary results of a multicenter randomized study on the treatment of acute promyelocytic leukemias] [Predvaritel'nye rezul'taty mnogotsentrovogo randomizirovannogo issledovaniia po lecheniiu ostrykh promielotsitarnykh leikozov]. Terapevticheskii Arkhiv 2004;76(7):11-8. [PUBMED: 15379121]
  • Parovichnikova EN, Savchenko VG, Isaev VG, Shuravina EN, Demidova IA, Olshankaya JV, et al. Addition of ATRA to the maintenance protocol did not improve disease-free survival: Results of the Russian APL trial. Blood 2007;110:161b-2b.
Powell 2010 {published and unpublished data}
  • Powell BL, Moser B, Stock W, Gallagher RE, Willman C, Coutre S, et al. Effect of consolidation with arsenic trioxide (As2O3) on event-free survival (EFS) and overall survival (OS) among patients with newly diagnosed acute promyelocytic leukemia (APL): North American Intergroup Protocol C9710. Journal of Clinical Oncology. 2007; Vol. ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S:2.
  • Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM. Adding mercaptopurine and methotrexate to alternate week ATRA maintenance therapy does not improve the outcome for adults with acute promyelocytic leukemia (APL) in first remission: Results from North American leukemia intergroup trial C9710. Blood. 2011; Vol. 118, issue 21:abstract 258.
  • Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, et al. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood 2010;116(19):3751-7.
  • Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, et al. Preliminary results from the North American acute promyelocytic leukemia (APL) study C9710. Blood. 2006; Vol. 108:abstract 566.
  • Stock W, Harvey R, Moser B, Sher D, Schachter-Tokarz E, Myers M, et al. Minimal residual disease (MRD) and risk of relapse in acute promyelocytic leukemia (APL): Insights from the north American intergroup phase III trial C9710. Blood. 2006; Vol. 108:abstract 494.
  • Stock W, Moser B, Powell BL, Appelbaum FR, Tallman MS, Larson RA, et al. Prognostic significance of initial clinical and molecular genetic features of acute promyelocytic leukemia (APL): Results from the North American Intergroup Trial C9710. Journal of Clinical Oncology. 2007; Vol. ASCO Annual Meeting Proceedings Part I.Vol 25, No. 18S:abstract 7016.
Shen 2004 {published data only}
  • Shen ZX, Shi ZZ, Fang J, et al. All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proceedings of the National Academy of Sciences of the United States of America 2004;101(15):5328-35.
  • Shi Z, Shen Z, Fang J, Gu B, Zhu Y, Chen Y, et al. Induction/maintenance with ATRA/A2O3 combination yields a high quality clinical/molecular remission and disease-free survival in newly diagnosed patients with acute promyelocytic leukemia under evaluation. Blood 2003;102:141a.
Tallman 2002 {published data only}
  • Douer D, Zickl L, Schiffer CA, Appelbaum FR, Feusner JH, Shepherd LE, et al. Late relapses following all-trans retinoic acid for acute promyelocytic leukemia are uncommon, respond well to salvage therapy and occur independently of prognostic factors at diagnosis:  Long-term follow-up of North American intergroup study I0129. Blood. 2011; Vol. 118, issue 21:abstract 83.
  • Gallagher RE, Willman CL, Slack JL, Andersen JW, Li YP, Viswanatha D, et al. Association of PML-RAR alpha fusion mRNA type with pretreatment hematologic characteristics but not treatment outcome in acute promyelocytic leukemia: an intergroup molecular study. Blood 1997;90(4):1656-63.
  • Gregory J, Kim H, Alonzo T, Gerbing R, Woods W, Weinstein H, et al. Treatment of children with acute promyelocytic leukemia: results of the first North American Intergroup trial INT0129. Pediatric Blood & Cancer 2009;53(6):1005-10.
  • Tallman MS. All-trans retinoic acid (ATRA) maintenance for acute promyelotic leukemia (APL). Annals of Hematology. 1999; Vol. 78 Suppl 1:S15, abstract 58.
  • Tallman MS, Andersen JW, Schiffer CA, Appelbaum FR, Feusner JH, Ogden A, et al. All-trans retinoic acid in acute promyelocytic leukemia: long term outcome results and prognostic factor analysis from Intergroup protocol 0129. Blood. 1999; Vol. 94:698a, abstract 3086.
  • Tallman MS, Andersen JW, Schiffer CA, Appelbaum FR, Feusner JH, Ogden A, et al. All-trans-retinoic acid in acute promyelocytic leukemia. New England Journal of Medicine 1997;337(15):1021-8.
  • Tallman MS, Andersen JW, Schiffer CA, Appelbaum FR, Feusner JH, Woods WG, et al. All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol. Blood 2002;100(13):4298-302.
  • Tallman MS, Andersen JW, Schiffer CA, Appelbaum FR, Feusner JH, Woods WG, et al. Phase III randomized study of All-Trans Retinoic Acid (ATRA) vs daunorubicin (D) and cytosine arabinose (A) as induction therapy and ATRA VS observation as maintenance therapy for patients with previously untreated acute promyelocyric leukemia (APL). Blood. 1995; Vol. 86:125a, abstract 488.

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to ongoing studies
  22. Additional references
Adès 2010a {published data only}
  • Adès L, Raffoux E, Chevret S, Pigneux A, Thomas X, Bordessoule D, et al. Arsenic trioxide (ATO) in the consolidation treatment of newly diagnosed APL - first interim analysis of a randomized trial (APL 2006) by the French Belgian Swiss APL group. Blood. 2010; Vol. 116, issue 21:Abstract No. 505.
Asou 1998 {published data only}
  • Asou N, Adachi K, Tamura J, Kanamaru A, Kageyama S, Hiraoka A, et al. Analysis of prognostic factors in newly diagnosed acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy. Japan Adult Leukemia Study Group. Journal of Clinical Oncology 1998;16(1):78-85.
Asou 2001 {published data only}
  • Asou N, Adachi K, Tamura U, Kanamaru A, Kageyama S, Hiraoka A, et al. Analysis of prognostic factors in newly diagnosed patients with acute promyelocytic leukemia: the APL92 study of the Japan Adult Leukemia Study Group (JALSG). Cancer Chemotherapy & Pharmacology 2001;48:Suppl 65-71.
Bapna 1998 {published data only}
  • Bapna A, Nair R, Tapan KS, Nair CN, Kadam P, Gladstone B, et al. All-trans-retinoic acid (ATRA): pediatric acute promyelocytic leukemia. Pediatric Hematology and Oncology 1998;15(3):243-8.
Burnett 1999 {published data only}
  • Burnett AK, Grimwade D, Solomon E, Wheatley K, Goldstone AH. Presenting white blood cell count and kinetics of molecular remission predict prognosis in acute promyelocytic leukemia treated with all-trans retinoic acid: result of the Randomized MRC Trial. Blood 1999;93(12):4131-43. [PUBMED: 10361110]
Burnett 2007 {published and unpublished data}
  • Burnett AK, Hills RK, Grimwade D, Goldstone AH, Hunter A, Milligan D, et al. Idarubicin and ATRA is as effective as MRC chemotherapy in patients with acute promyelocytic leukaemia with lower toxicity and resource usage: preliminary results of the MRC AML15 trial. Blood 2007;110(11):abstract 589.
Castaigne 1990 {published data only}
  • Castaigne S, Chomienne C, Daniel MT, Ballerini P, Berger R, Fenaux P, et al. All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia: Clinical results. Blood 1990;76(9):1704-9.
Dai 2009 {published data only}
  • Dai CW, Zhang GS, Shen JK, Zheng WL, Pei MF, Xu YX, et al. Use of all-trans retinoic acid in combination with arsenic trioxide for remission induction in patients with newly diagnosed acute promyelocytic leukemia and for consolidation/maintenance in CR patients. Acta Haematologica 2009;121(1):1-8.
Estey 2001 {published data only}
  • Estey E, Koller C, Cortes J, Reed P, Freireich E, Giles F, et al. Treatment of newly diagnosed acute promyelocytic leukemia with liposomal all-trans retinoic acid. Leukemia & Lymphoma 2001;42(3):309-16.
Estey 2005 {published data only}
  • Estey E, Koller C, Tsimberidou AM, O'Brien S, Beran M, Cortes J, et al. Potential curability of newly diagnosed acute promyelocytic leukemia without use of chemotherapy: the example of liposomal all-trans retinoic acid. Blood 2005;105(3):1366-7. [PUBMED: 15659618]
Fenaux 1991 {published data only}
  • Fenaux P, Tertian G, Castaigne S, Tilly H, Leverger G, Guy H, et al. A randomized trial of amsacrine and rubidazone in 39 patients with acute promyelocytic leukemia. Journal of Clinical Oncology 1991;9(9):1556-61.
Fenaux 1992 {published data only}
  • Fenaux P, Castaigne S, Dombret H, Archimbaud E, Duarte M, Morel P, et al. All-transretinoic acid followed by intensive chemotherapy gives a high complete remission rate and may prolong remissions in newly diagnosed acute promyelocytic leukemia: a pilot study on 26 cases. Blood 1992;80(9):2176-81.
Fenaux 2000 {published data only}
  • Fenaux P, Chevret S, Guerci A, Fegueux N, Dombret H, Thomas X, et al. Long-term follow-up confirms the benefit of all-trans retinoic acid in acute promyelocytic leukemia. European APL group. Leukemia 2000;14(8):1371-7. [PUBMED: 10942231]
  • Fenaux P, Le Deley MC, Castaigne S, Archimbaud E, Chomienne C, Link H, et al. Effect of all transretinoic acid in newly diagnosed acute promyelocytic leukemia. Results of a multicenter randomized trial. European APL 91 Group. Blood 1993;82(11):3241-9. [PUBMED: 8241496]
Frankel 1994 {published data only}
  • Frankel SR, Eardley A, Heller G, Berman E, Miller WH, Dmitrovsky E, et al. All-trans retinoic acid for acute promyelocytic leukemia. Results of the New York Study. Annals of Internal Medicine 1994;120(4):278-86.
Gore 2010 {published data only}
  • Gore SD, Gojo I, Sekeres MA, Morris L, Devetten M, Jamieson K, et al. Single cycle of arsenic trioxide-based consolidation chemotherapy spares anthracycline exposure in the primary management of acute promyelocytic leukemia. Journal of Clinical Oncology 2010;28(6):1047-53.
Head 1995 {published data only}
  • Head D, Kopecky K J, Weick J, Files J C, Ryan D, Foucar K, et al. Effect of aggressive daunomycin therapy on survival in acute promyelocytic leukemia. Blood 1995;86(5):1717-28.
Hu 2000 {published data only}
Iland 2012 {published data only}
  • Iland HJ, Bradstock K, Seymour J, Hertzberg M, Grigg A, Taylor K, et al. Results of the APML3 trial incorporating all-trans-retinoic acid andidarubicin in both induction and consolidation as initial therapy forpatients with acute promyelocytic leukemia. Haematologica 2012;97(2):227-34.
Jurcic 2000 {published data only}
  • Jurcic JG, De blasio T, Dumont L, Yao TJ, Scheinberg DA. Molecular remission induction with retinoic acid and anti-CD33 monoclonal antibody HuM195 in acute promyelocytic leukemia. Clinical Cancer Research 2000;6(2):372-80.
Kantarjian 1987 {published data only}
Kobayashi 2010 {published data only}
  • Kobayashi Y, Hatta Y, Ishizuka H, Hirabayashi Y, Tanaka T, Takei K, et al. Successful post-remission therapy with a combination of all-trans retinoic acid and arsenic trioxide in an elderly Japanese patient newly diagnosed with acute promyelocytic leukemia. International Journal of Hematology 2010;91(1):152-3.
Koh 2001 {published data only}
  • Koh L P, Goh YT, Teoh G, Tan P. Treatment of acute promyelocytic leukaemia using a combination of all-trans retinoic acid and chemotherapy. Annals of the Academy of Medicine, Singapore 2001;30(4):401-8.
Lengfelder 2000 {published data only}
  • Lengfelder E, Reichert A, Schoch C, Haase D, Haferlach T, Löffler H, et al. Double induction strategy including high dose cytarabine in combination with all-trans retinoic acid: effects in patients with newly diagnosed acute promyelocytic leukemia. German AML Cooperative Group. Leukemia 2000;14(8):1362-70.
Lengfelder 2009 {published data only}
  • Lengfelder E, Haferlach C, Saussele S, Haferlach T, Schultheis B, Schnittger S, et al. High dose ara-C in the treatment of newly diagnosed acute promyelocytic leukemia: long-term results of the German AMLCG. Leukemia 2009;23(12):2248-58.
Lu 2002 {published data only}
  • Lu DP, Wang Q. Current study of APL treatment in China. International Journal of Hematology 2002;76 Suppl:8.
Martinelli 1998 {published data only}
  • Martinelli G, Ottaviani E, Testoni N, Visani G, Diverio D, D'Elia G, et al. Disappearance of PML/RAR alpha acute promyelocytic leukemia-associated transcript during consolidation chemotherapy. Haematologica 1998;83(11):985-8.
Marty 1984 {published data only}
  • Marty M, Ganem G, Fischer J, Flandrin G, Berger R, Schaison G, et al. Acute promyelocytic leukemia: retrospective study of 119 patients treated with daunorubicin. Nouvelle Revue Francaise d'Hematologie 1984;26(6):371-8.
Mathews 2009 {published data only}
  • Mathews V, George B, Jijina F, Ross C, Nair R, Apt S, et al. Single agent arsenic trioxide regimen for the treatment of newly diagnosed acute promyelocytic leukemia: Initial results of a multicenter randomized controlled study from India to study the optimal duration of arsenic trioxide maintenance therapy (IAPLSG04). Blood. 2009; Vol. 114, issue 22:Abstract 2082.
McMullin 2005 {published data only}
  • McMullin MF, Nugent E, Thompson A, Hull D, Jones FG, Grimwade D. Prolonged molecular remission in PML-RARalpha-positive acute promyelocytic leukemia treated with minimal chemotherapy followed by maintenance including the histone deacetylase inhibitor sodium valproate. Leukemia 2005;19(9):1676-7.
Ortega 2005 {published data only}
  • Ortega JJ, Madero L, Martín G, Verdeguer A, García P, Parody R, et al. Treatment with all-trans retinoic acid and anthracycline monochemotherapy for children with acute promyelocytic leukemia: a multicenter study by the PETHEMA Group. Journal of Clinical Oncology 2005;23(30):7632-40.
Santamaria 2007 {published data only}
  • Santamaria C, Chillon MC, Fernandez C, Martin-Jimenez P, Balanzategui A, Garcia Sanz R, et al. Using quantification of the PML-RARalpha transcript to stratify the risk of relapse in patients with acute promyelocytic leukemia. Haematologica 2007;92(3):315-22.
Sanz 1999 {published data only}
  • Sanz MA, Martín G, Rayón C, Esteve J, González M, Díaz-Mediavilla J, et al. A modified AIDA protocol with anthracycline-based consolidation results in high antileukemic efficacy and reduced toxicity in newly diagnosed PML/RARalpha-positive acute promyelocytic leukemia. PETHEMA group. Blood 1999;94(9):3015-21.
Sanz 2004 {published data only}
  • Sanz MA, Vellenga E, Rayón C, Díaz-Mediavilla J, Rivas C, Amutio E, et al. All-trans retinoic acid and anthracycline monochemotherapy for the treatment of elderly patients with acute promyelocytic leukemia. Blood 2004;104(12):3490-3.
Sanz 2004a {published data only}
  • Sanz MA, Martín G, González M, León A, Rayón C, Rivas C, et al. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood 2004;103(4):1237-43.
Seiter 1995 {published data only}
  • Seiter K, Miller WH, Feldman EJ, Ahmed T, Arlin Z. Pilot study of all-trans retinoic acid as post-remission therapy in patients with acute promyelocytic leukemia. Leukemia 1995;9(1):15-8.
Sun 1993 {published data only}
  • Sun GL, Ouyang RR, Chen SJ, Gu YZ, Huang LA, Lu JX, et al. Treatment of acute promyelocytic leukemia with all-trans retinoic acid. A five-year experience. Chinese Medical Journal 1993;106(10):743-8. [PUBMED: 8033606]
Warrell 1994 {published data only}
  • Warrell RP, Maslak P, Eardley A, Heller G, Miller WH, Frankel SR. Treatment of acute promyelocytic leukemia with all-trans retinoic acid: an update of the New York experience. Leukemia 1994;8(6):929-33.
Willemze 1994 {published data only}
  • Willemze R, Suciu S, Mandelli F, De Witte T, Cadiou M, Castoldi GL, et al. Treatment of patients with acute promyelocytic leukemia. The EORTC-LCG experience. EORTC Leukemia Cooperative Group. Leukemia 1994;8(Suppl 2):S48-55.
Xu 2007 {published data only}
  • Xu XJ, Shi SW, Tang YM, Song H, Yang SL, Wei J, et al. Long-term follow-up of treatment outcome and prognosis on 46 children with acute promyelocytic leukemia [Chinese]. Zhongguo Dangdai Erke Zazhi 2007;9(1):28-33.
Zhang 2000 {published data only}
  • Zhang P, Wang S, Hu L, Qiu F, Yang H, Xiao Y, et al. Seven years' summary report on the treatment of acute promyelocytic leukemia with arsenic trioxide:an analysis of 242 cases [Chinese]. Chung-Hua Hsueh Yeh Hsueh Tsa Chih: Chinese Journal of Hematology 2000;21(2):67-70.
Zhang 2011 {published data only}
  • Zhang L, Zhu X, Zou Y, Chen Y, Chen X. Effect of arsenic trioxide on the treatment of children with newly diagnosed acute promyelocytic leukemia in China. International Journal of Hematology 2011;93(2):199-205.
Zheng 2010 {published data only}
Zubizarreta 2000 {published data only}
  • Zubizarreta PA, Rose AB, Felice MS, Alfaro E, Delfino S, Cygler AM, et al. Childhood acute promyelocytic leukemia: no benefit of all-trans-retinoic acid administered in a short-course schedule. Pediatric Hematology and Oncology 2000;17(2):155-62. [PUBMED: 10734658]

References to ongoing studies

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to ongoing studies
  22. Additional references
0903X-101128 {published data only}
  • not available. Comparison of two treatments in intermediate and high-risk acute promyelocytic leukemia (APL) patients to assess efficacy in 1st hematological complete remission and molecular remission. ClinicalTrials.gov Last Updated on August 19, 2009.
CDR0000064499 {published data only}
  • Muus P, Mandelli F. Combination chemotherapy with or without bone marrow transplantation in treating patients with acute promyelocytic leukemia. ClinicalTrials.gov Last Updated on February 6, 2009.
CDR0000553210 {published data only}
  • Coutre SE. Combination chemotherapy with or without gemtuzumab followed by tretinoin, mercaptopurine, and methotrexate or observation in treating patients with acute promyelocytic leukemia. ClinicalTrials.gov Last updated: January 2, 2013.

Additional references

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to ongoing studies
  22. Additional references
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