{'fraction_non_alphanumeric': 0.03530318885278405, 'fraction_numerical': 0.025444732059260892, 'mean_word_length': 5.038576654472896, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 3, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 1, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Maintenance therapy with all-trans retinoic acid and arsenic trioxide improves relapse-free survival in adults with low- to intermediate-risk acute promyelocytic leukemia who have achieved complete remission after consolidation therapy

Background Currently, the optimal maintenance therapy for patients with acute promyelocytic leukemia (APL) who have achieved complete remission (CR) after completing consolidation chemotherapy remains controversial. The comparative effectiveness of the all-trans retinoic acid (ATRA) plus arsenic trioxide (As2O3) maintenance strategy with classic ATRA plus chemotherapy has not been evaluated. In this study, we compared the efficacy and toxicity of maintenance therapy with ATRA plus As2O3 and classic ATRA plus chemotherapy in low- to intermediate-risk APL patients reaching the first CR after induction and consolidation therapy. Methods A retrospective review of 58 adult patients diagnosed with APL was conducted. After receiving consolidation therapy and achieving CR, 30 patients were administered maintenance therapy with an ATRA plus As2O3 regimen (ATRA+As2O3 group), whereas 28 patients were administered 3-monthly cycles of an ATRA plus chemotherapy regimen (ATRA+chemotherapy group). Results Grade 3–4 neutropenia was significantly more frequent in the ATRA+chemotherapy group (N=9, 32.1%) than in the ATRA+As2O3 group (N=0) (P=0.001). At a median follow-up of 49.1 months (range: 9.7–97.4 months) from the completion of consolidation, no relapses were observed in the ATRA+As2O3 group, whereas seven relapses occurred in the ATRA+chemotherapy group. The risk of relapse in the patients administered ATRA+As2O3 maintenance was significantly lower than that in those administered ATRA+chemotherapy maintenance (P=0.004). Based on log-rank analysis, only maintenance therapy with ATRA and As2O3 was associated with a significantly higher relapse-free survival (P=0.0159). Conclusion Maintenance therapy with ATRA and As2O3 was beneficial in low- to intermediate-risk APL patients who were effectively treated to achieve CR. Further clinical trials with reliable designs are needed to confirm these observations.


Introduction
Acute promyelocytic leukemia (APL) is a distinct clinical and pathologic entity associated with fusion of the promyelocytic leukemia (PML) gene with the retinoic acid receptor α (RARA) gene (PML-RARA), formed by the t(15;17)(q22;q21) chromosomal translocation. 1 The use of differentiation induction therapy with all-trans retinoic acid The combination of ATRA and anthracycline-based chemotherapy that is currently considered the standard of care for newly diagnosed APL 2 yields complete remission (CR) rates of approximately 80%-95% and long-term disease-free survival (DFS) rates exceeding 80%. 3,4 Therefore, much focus has been placed on the prevention of relapse for APL patients in CR.
In addition to ATRA, arsenic trioxide (As 2 O 3 ) has been shown to induce sustained molecular remission in APL patients who relapse after treatment with ATRA-containing regimens. [5][6][7] Of greater relevance, several studies have shown that the early addition of As 2 O 3 to induction and/or consolidation regimens might provide another approach to improve the outcome of APL. [8][9][10][11][12] However, for APL patients who have achieved CR after completing consolidation therapy, the role of maintenance therapy remains a matter of discussion, especially for the low-to intermediate-risk category. Maintenance with different combinations of ATRA, chemotherapy, and As 2 O 3 has been used over different time periods. Two previous randomized studies reported the benefit of maintenance therapy with ATRA and/or low-dose chemotherapy (6-mercaptopurine  and methotrexate [MTX]), 13,14 and this was later confirmed by the analysis of long-term outcomes. 15,16 However, the Italian GIMEMA group demonstrated no significant benefits in 12-year DFS in patients administered maintenance therapy with any of those three options (6-MP plus MTX, ATRA, and both), compared with observation in APL patients achieving molecular CR by the AIDA 0493 protocol (ATRA plus idarubicin [IDA]). 17 Thus, for patients achieving molecular CR after intensive induction and consolidation therapy, the benefit of maintenance therapy has been questioned. Until recently, a meta-analysis conducted by Muchtar et al that included nine randomized controlled trials suggested that maintenance therapy improves DFS. As for the type of maintenance regimen, ATRA and chemotherapy compared with ATRA alone improves DFS. 18 However, incorporation of As 2 O 3 into an effective therapeutic arsenal against APL further confounds the effects of maintenance therapy. The results of several of the latest trials have demonstrated the efficacy and safety of ATRA plus As 2 O 3 -based maintenance therapy in newly diagnosed APL patients. 19,20 Furthermore, to our knowledge, the comparative efficacy of the ATRA plus As 2 O 3 maintenance strategy with classic ATRA plus chemotherapy has not been evaluated.
In this study, a retrospective analysis was conducted to compare the efficacy and toxicity of maintenance therapy with ATRA plus As 2 O 3 and classic ATRA plus chemotherapy in low-to intermediate-risk APL patients reaching the first CR (CR1) after induction and consolidation therapy.

Molecular monitoring
Regular real-time quantitative polymerase chain reaction assays for the PML-RARA fusion transcript were performed on the bone marrow sample obtained at diagnosis, after induction and each consolidation cycle, and subsequently, OncoTargets and Therapy 2017:10 submit your manuscript | www.dovepress.com

2307
Maintenance with aTra and as 2 O 3 improves survival in patients with aPl every 3 months for 3 years. Molecular relapse was defined as the reappearance of PML-RARA positivity after achievement of molecular remission at the end of consolidation that could be verified in a subsequent consecutive sample taken 2 weeks later. Frank relapses were confirmed by morphological and molecular analyses.

statistical analysis
All data were censored on November 1, 2016. Relapse-free survival (RFS) was measured from the completion of consolidation until relapse of any kind. The probability of RFS was calculated using the Kaplan-Meier method. Differences in RFS were tested using log-rank analysis. Categorical variables were compared using the Fisher's exact test or chi-square test. Numerical variables were compared using the Wilcoxon rank-sum test. A two-tailed P-value of ,0.05 was considered statistically significant. All statistical analyses were performed using the Stata version 12 software (StataCorp LP, College Station, TX, USA).

Patient characteristics
In total, 58 eligible patients reaching CR1 after induction and consolidation therapy received maintenance therapy with either ATRA plus As 2 O 3 (ATRA+As 2 O 3 group, N=30) or ATRA plus chemotherapy containing 6-MP and MTX (ATRA+chemotherapy group, N=28). The median age of the participants was 41 years (range: 15-70 years), and six were older than 60 years. Characteristics of the 58 patients according to the type of maintenance regimen are presented in Table 1. Significant differences were noted between the two maintenance groups in terms of sex and WBC count at diagnosis. The percentage of male patients in the ATRA+chemotherapy group (67.9%) was significantly higher than that in the ATRA+As 2 O 3 group (40.0%) (P=0.034), while the percentage of patients with a WBC count at diagnosis ,5×10 9 /L was significantly lower in the ATRA+chemotherapy group (71.4%) than in the ATRA+As 2 O 3 group (93.3%) (P=0.027).

adverse events observed during maintenance
All 58 patients receiving maintenance therapy were reviewed, to evaluate the incidence of toxicity during maintenance (graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03). 21 A total of 24 adverse events (seven in the ATRA+As 2 O 3 group vs 17 in the ATRA+chemotherapy group) were reported in

nonhematologic toxicity
Three out of 30 patients (10.0%) in the ATRA+As 2 O 3 group and four out of 28 patients (14.3%) in the ATRA+chemo therapy group had reversible liver function derangements during maintenance (P=0.701). Prolongation of the QT interval, defined as a corrected QT interval $450 ms in men and $460 ms in women calculated using the Framingham formula, 22 was observed in two patients (6.7%) in the ATRA+As 2 O 3 group, and was not observed in the ATRA+chemotherapy group (P=0.492). There were no reports of life-threatening cardiac arrhythmias. Dyspepsia was reported in one patient (3.3%) in the ATRA+As 2 O 3 group and in three patients (10.7%) in the ATRA+chemotherapy group (P=0.344). Two out of 58 patients experienced other adverse events, including herpes zoster reactivation (one in the ATRA+chemotherapy group) and hemolysis (one in the ATRA+As 2 O 3 group). All clinical signs improved after symptomatic treatment only or observation, with the exception of hemolysis that was resolved with temporary discontinuation of As 2 O 3 and symptomatic treatment.

relapse and survival
At a median follow-up of 49.1 months (range: 9.7-97.4 months) from the completion of consolidation, no relapses were observed in the ATRA+As 2 O 3 group, whereas seven relapses were observed in the ATRA+chemotherapy group. Of the seven relapsed patients, five presented with

2309
Maintenance with aTra and as 2 O 3 improves survival in patients with aPl frank relapse (bone marrow, N=4; CNS, N=1), and two presented with molecular relapse. Death occurred in one patient, 8.8 months after relapse. The other six patients who relapsed received salvage therapy with As 2 O 3 , and all achieved molecular CR and remained alive at the final follow-up.
To define the risk of relapse in patients during maintenance, the impacts of sex, age (#40 years vs .40 years), WBC count at diagnosis (#5×10 9 /L vs .5×10 9 /L), platelet count at diagnosis (#40×10 9 /L vs .40×10 9 /L), hemoglobin level at diagnosis (,100 g/L vs $100 g/L), and types of induction regimen (ATRA+As 2 O 3 +IDA vs ATRA+IDA) and maintenance regimen (ATRA+As 2 O 3 vs ATRA+chemotherapy) on relapse were all analyzed. The risk of relapse in patients administered ATRA+As 2 O 3 maintenance was significantly lower than that in those administered ATRA+chemotherapy maintenance (P=0.004). Other parameters analyzed showed no significant effects on the rate of relapse (Table 3).
Furthermore, the impacts of sex, age, WBC count at diagnosis, platelet count at diagnosis, hemoglobin level at diagnosis, and types of induction and maintenance regimens on RFS were analyzed. Maintenance with ATRA and As 2 O 3 was associated with a significantly higher RFS (P=0.0159, log-rank; Table 4). The RFS according to the type of maintenance regimen administered is shown in Figure 2. However, no relapse was observed in the ATRA+As 2 O 3 group, hampering the multivariate analysis to test whether maintenance with ATRA and As 2 O 3 was an independent factor for RFS.
Due to the relatively high number of patients in our cohort receiving the ATRA+IDA protocol during the induction phase, we further analyzed the impacts of clinicopathologic features on relapse and RFS during maintenance therapy in 47 APL patients receiving ATRA+IDA as the induction regimen. The risk of relapse in the patients who received   19,20,23 Altogether, these findings show that As 2 O 3 -based maintenance therapy might be another approach to improve the outcome in APL patients achieving CR. In contrast to ATRA that targets the RARA moiety of PML-RARA, As 2 O 3 exerts its therapeutic effects by targeting the PML moiety, thereby inducing differentiation and apoptosis of leukemic promyelocytes, as well as the inhibition of leukemic progenitor self-replication and antiangiogenic effects. [24][25][26][27] The synergistic effects between ATRA and As 2 O 3 have been demonstrated at both the biological 28,29 and clinical levels. For example, recent studies report that the combination of ATRA with As 2 O 3 administered for initial induction and consolidation therapy improves outcomes compared with standard ATRA plus chemotherapy, particularly in low-to intermediate-risk APL patients. 30,31 Therefore, based on our observations regarding the benefit of maintenance therapy with ATRA and As 2 O 3 , the best timing for the use of As 2 O 3 in APL, whether during initial remission induction, consolidation, or maintenance, should be further investigated.
In addition to efficacy, safety is another major concern regarding the treatment of low-to intermediate-risk APL patients. In our study, we alternated As 2 O 3 with conventional  ATRA+As 2 O 3 maintenance therapy was significantly lower than that in those who received the ATRA+chemotherapy maintenance (P=0.007; Table 5). In addition, Kaplan-Meier analysis showed that maintenance with ATRA and As 2 O 3 was associated with a significantly higher RFS (P=0.0264, log-rank; Table 6). Similarly, a multivariate analysis to test whether maintenance with ATRA and As 2 O 3 was an independent factor for RFS was hampered by the absence of relapse in the ATRA+As 2 O 3 group. Futhermore, there were too few APL patients (N=11) receiving ATRA+As 2 O 3 +IDA as the induction regimen to make a similar analysis.

Discussion
In the present study, we retrospectively compared the efficacy and toxicity of ATRA

2311
Maintenance with aTra and as 2 O 3 improves survival in patients with aPl chemotherapy. Myelosuppression was observed significantly less frequently in patients administered maintenance therapy with ATRA and As 2 O 3 than in those administered chemotherapy. The commonly observed adverse effects during maintenance with ATRA and As 2 O 3 included hepatotoxicity, gastrointestinal reactions, and prolongation of the QT interval, all of which were manageable. Of note, one patient developed hemolysis during maintenance with ATRA plus As 2 O 3 , and the exact reason for this is unknown. Although the druginduced immune hemolysis was anticipated, a negative direct antiglobulin test result was observed. Another major concern after long-term exposure to inorganic arsenic compounds is the increased risk of secondary tumors. 32,33 No instances of secondary tumors were observed in the present study. In fact, the average total dosage of As 2 O 3 for maintenance was 26.9 mg/kg in the present study, which is similar to that in the Shanghai trial (28.3 mg/kg). 34 Thus, APL patients could benefit from As 2 O 3 -based maintenance without overtreatment.
One of the limitations of our study is the retrospective nature; thus, heterogeneity of the data was difficult to be ruled out. Therefore, caution should be taken when interpreting the results of the present study, as they might not be applicable to other populations. Another limitation of the present study is the fact that a greater number of patients received the ATRA plus IDA protocol during the induction phase. Two pilot studies have proven the high efficacy of chemotherapy-free regimens based on As 2 O 3 in newly diagnosed APL. 35,36 Subsequently, several recent reports provide evidence of the efficacy and safety of ATRA plus As 2 O 3 , with or without a chemotherapy protocol, for firstline therapy in patients with newly diagnosed APL. [37][38][39] Furthermore, a recent meta-analysis by Ma et al showed significant benefits of the ATRA plus As 2 O 3 protocol, compared with the standard ATRA plus chemotherapy protocol, particularly in low-to intermediate-risk APL patients. 30 In line with results of these pilot studies, the final results of the randomized Italian-German APL0406 trial demonstrated the advantages of ATRA plus As 2 O 3 over ATRA plus chemotherapy for induction and consolidation therapy in low-to intermediate-risk APL. 31 These data suggest that the standard first-line treatment for newly diagnosed APL is now shifting towards induction and consolidation regimens that include ATRA and arsenic. Thus, the variables associated with frontline induction and consolidation therapies in the present study might work against future outcomes. For example, a recent randomized non-inferiority study demonstrated that DFS was not significantly different among low-to intermediate-risk APL patients who were reaching molecular CR after consolidation therapy including As 2 O 3 and received ATRA+chemotherapy maintenance therapy vs those who received no maintenance therapy, and suggested that maintenance therapy may not be needed if patients are treated with an intensive post-remission regimen including As 2 O 3 . 40 The question of whether maintenance with ATRA and As 2 O 3 benefits low-to intermediate-risk APL patients in whom As 2 O 3 has been incorporated in induction and consolidation will need to be addressed in future studies.
In conclusion, the present study, conducted in a welldefined cohort, albeit a retrospective single-center analysis of a relatively small number of subjects, showed that maintenance therapy with ATRA and As 2 O 3 was beneficial for low-to intermediate-risk APL patients who were effectively treated to achieve CR. In addition, the use of As 2 O 3 in maintenance precluded the need for myelosuppressive chemotherapy. However, further clinical trials with reliable designs are needed to confirm the results of the present study.

OncoTargets and Therapy
Publish your work in this journal Submit your manuscript here: http://www.dovepress.com/oncotargets-and-therapy-journal OncoTargets and Therapy is an international, peer-reviewed, open access journal focusing on the pathological basis of all cancers, potential targets for therapy and treatment protocols employed to improve the management of cancer patients. The journal also focuses on the impact of management programs and new therapeutic agents and protocols on patient perspectives such as quality of life, adherence and satisfaction. The manuscript management system is completely online and includes a very quick and fair peer-review system, which is all easy to use. Visit http://www.dovepress.com/testimonials.php to read real quotes from published authors.