Abstract: 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. 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.

Plain-language summary: 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.