Maintenance therapy for acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) is a subtype of acute myelogenous leukemia (AML), comprising about 10% of AML cases. APL has a distinct therapeutic approach and is the most curable type of AML. It is characterized by a specific chromosome translocation, the t(15;17). The integrated effect of induction and consolidation in APL currently results in high long-term survival rates, reaching as high as 90% in some series. Contrary to the established role of initial treatment phases (termed induction and consolidation phases), in APL there is conflicting evidence regarding the place of a continued low-toxicity treatment (termed maintenance treatment) in these patients. This debate has become more intense after the introduction of all-trans retinoic acid (ATRA), which targets the PML-RARα fusion gene, and even more so with the recent addition of arsenic trioxide to the therapeutic options of APL.

We aimed to evaluate the effects of maintenance therapy on survival in APL patients as well as to assess its influence on other parameters, such as disease recurrence rate and adverse events. We also tried to establish the best maintenance regimen for these patients.

We therefore conducted a systematic review and meta-analysis of 10 randomized controlled trials including 2072 patients. Our main results showed that any maintenance treatment compared to observation prolongs the freedom from disease duration but not overall survival. Similarly, ATRA and chemotherapy compared to ATRA alone improves freedom from disease duration but not overall survival. Moreover, ATRA-based regimens compared to non-ATRA based regimens probably improves freedom from disease duration but not overall survival.

Finally, we showed that any maintenance treatment compared to observation as well as maintenance combining ATRA and chemotherapy compared to ATRA alone are more toxic, potentially limiting patient adherence to treatment. Our results imply that in patients with newly diagnosed APL, ATRA-based maintenance therapy may be added to the standard therapy in order to improve freedom from disease. Yet, one should bear in mind that this treatment does not improve overall survival and adds toxicity.

Our results are limited mainly by the diversity of trials in terms of maintenance regimens and treatments antedating maintenance administration. Additionally, quality of life (QOL) parameters were not reported, and therefore are worth evaluating in future trials since maintenance therapy has a direct impact on QOL.

Authors' conclusions: 

Maintenance therapy compared to observation in APL patients improved DFS but not OS. Similarly, ATRA and chemotherapy compared to ATRA and probably ATRA based regimens compared to non-ATRA based regimens improved DFS but not OS. The significance of these findings is limited due to clinical heterogeneity between studies.

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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.

Objectives: 

To examine the efficacy and safety of maintenance therapy in APL patients and to establish the optimal regimen for maintenance.

Search strategy: 

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.

Selection criteria: 

Randomized controlled trials assessing maintenance treatment in patients with newly diagnosed APL in first complete remission (CR) following induction or induction and consolidation therapy.

Data collection and analysis: 

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.

Main 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 probably improved with ATRA-based regimens compared to non-ATRA based regimens, but the effect did not reach statistical significance (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.

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