title: The role of maintenance therapy in acute promyelocytic leukemia in the first complete remission.
abstract: BACKGROUND
  Acute promyelocytic leukemia (APL) is the most curable type of leukemia. A consensus exists regarding the need for administration of both induction and consolidation treatments, albeit using different approaches. However, there is conflicting evidence for the role of maintenance treatment in APL patients.
  
  
  OBJECTIVE
  To examine the efficacy and safety of maintenance therapy in APL patients and to establish the optimal regimen for maintenance.
  
  
  METHODS
  We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 6), MEDLINE (January 1966 to July 2012), LILACS (1982 to July 2012), relevant conference proceedings (2000 to 2012) and databases of ongoing and unpublished trials.
  
  
  METHODS
  Randomized controlled trials assessing maintenance treatment in patients with newly diagnosed APL in first complete remission (CR) following induction or induction and consolidation therapy.
  
  
  METHODS
  Two review authors assessed the quality of trials and extracted data. We estimated and pooled hazard ratios (HR) and risk ratios (RR) with 95% confidence intervals (CI) using the fixed-effect model. If significant heterogeneity was present we explored potential causes for such heterogeneity and if not found we used also the random-effects model.
  
  
  RESULTS
  We included 10 randomized controlled trials enrolling 2072 patients in the systematic review, and conducted meta-analysis on nine of them. There was no statistically significant effect on overall survival (OS) in the three main comparisons (HR for any maintenance treatment versus observation 0.79, 95% CI 0.49 to 1.27; HR for all-trans retinoic acid (ATRA)-based maintenance versus non-ATRA based maintenance 1.21, 95% CI 0.73 to 1.98; HR for ATRA alone maintenance versus ATRA and chemotherapy 0.99, 95% CI 0.69 to 1.43). However, disease free survival (DFS) was improved with any maintenance therapy compared to observation (HR 0.59, 95% CI 0.48 to 0.74; 5 trials, 1209 patients) and with ATRA and chemotherapy compared to ATRA alone maintenance (HR for ATRA alone compared to ATRA and chemotherapy 1.38, 95% CI 1.09 to 1.76; 4 trials, 1028 patients). DFS was not improved with ATRA-based regimens compared to non-ATRA based regimens (HR 0.72, 95% CI 0.51 to 1.01; 4 trials, 670 patients). Analysis of clinically relevant adverse events could not be conducted due to paucity of data. Yet, increased reports of grade 3/4 adverse events were noted for any maintenance versus observation and for combined ATRA and chemotherapy versus ATRA alone treatment. The major limitation of this review lies in the variability between the included trials in both maintenance and pre-maintenance parameters. We tried to address this variability and to reduce its potential biases by conducting three separate main comparisons, as outlined above, leaving less statistical power to the presented results.
  
  
  CONCLUSIONS
  Maintenance therapy compared to observation in APL patients improved DFS but not OS. Similarly, ATRA and chemotherapy compared to ATRA improved DFS but not OS. In contrast, ATRA based regimens compared to non-ATRA based regimens did not demonstrate a survival benefit. The significance of these findings is limited due to clinical heterogeneity between studies.
authors.affiliation: Department of Medicine E, Beilinson Hospital, Rabin Medical Center, 39 Jabotinski Street, Petah Tikva, Israel, 49100.
authors.forename: Eli
authors.initials: E
authors.lastname: Muchtar
authors.forename: Liat
authors.initials: L
authors.lastname: Vidal
authors.forename: Ron
authors.initials: R
authors.lastname: Ram
authors.forename: Anat
authors.initials: A
authors.lastname: Gafter-Gvili
authors.forename: Ofer
authors.initials: O
authors.lastname: Shpilberg
authors.forename: Pia
authors.initials: P
authors.lastname: Raanani
mesh_terms: D018943:Anthracyclines / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018572:Disease-Free Survival; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000401:mortality; D060046:Maintenance Chemotherapy / Q000379:methods*; D016032:Randomized Controlled Trials as Topic; D014212:Tretinoin / Q000627:therapeutic use; D057832:Watchful Waiting
chemical_list: D018943:Anthracyclines; D000970:Antineoplastic Agents; D014212:Tretinoin
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