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

OncoTargets and Therapy, Apr 2017

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 Bin Liang,1,* Zhouyi Zheng,1,2,* Yifen Shi,1 Jingjing Chen,1 Xudong Hu,1 Honglan Qian,1 Zhijian Shen,1 Songfu Jiang,1 Kang Yu,1 Jianhua Feng1,3 1Division of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 2Division of Hematology-Oncology, Traditional Chinese Medical Hospital of Zhuji, Shaoxing, 3Division of Pediatric Hematology-Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China *These authors contributed equally to this work 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. Keywords: acute promyelocytic leukemia, all-trans retinoic acid, arsenic trioxide, maintenance therapy, survival

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

https://www.dovepress.com/getfile.php?fileID=36194

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

OncoTargets and Therapy 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 Zhouyi Zheng 1 2 Kang Yu 2 Jianhua Feng 0 2 0 Division of Pediatric h ematology-Oncology, The First a ffiliated h ospital of Wenzhou Medical University , Wenzhou, People's republic of china 1 Division of h ematology-Oncology, Traditional chinese Medical hospital of Zhuji , shaoxing 2 Division of hematology, The First a ffiliated h ospital of Wenzhou Medical University , Wenzhou PowerdbyTCPDF(ww.tcpdf.org) Yifen shi 1 Jingjing chen 1 Xudong hu 1 honglan Qian 1 Zhijian shen 1 songfu Jiang 1 *These authors contributed equally to this work 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 intermediaterisk 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 intermediaterisk APL patients who were effectively treated to achieve CR. Further clinical trials with reliable designs are needed to confirm these observations. acute promyelocytic leukemia; all-trans retinoic acid; arsenic trioxide; maintenance - open access to scientific and medical research O r i g i n a l r e s e a r c h Bin liang 1,* 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 8 1 0 2 l u J 2 1 n o 7 1 1 . 2 2 . 8 3 . 4 5 y b / m o c . s s re . (ATRA) has significantly improved the prognosis of APL. The combination of ATRA and anthracycline-based chemotherapy that is currently considered the standard of care for newly diagnosed APL2 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 (As2O3) has been shown to induce sustained molecular remission in APL patients who relapse after treatment with ATRA-containing regimens.5–7 Of greater relevance, several studies have shown that the early addition of As2O3 to induction and/or consolidation regimens might provide another approach to improve the outcome of APL.8–12 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 cat.vdoepw lsyeonu ecgheomryo.tMhearianptyen,aanncdeAws2itOh3dhiaffsebreenetncuosmedbionvaetriodnisffoerfeAntTtRimAe, /ww lan periods. Two previous randomized studies reported the ben/: o tsp rse efit of maintenance therapy with ATRA and/or low-dose th rp rom oF chemotherapy (6-mercaptopurine [6-MP] and methotrexate fd [MTX]),13,14 and this was later confirmed by the analysis of dea long-term outcomes.15,16 However, the Italian GIMEMA lonw group demonstrated no significant benefits in 12-year DFS ydo in patients administered maintenance therapy with any of raep those three options (6-MP plus MTX, ATRA, and both), hT compared with observation in APL patients achieving dan molecular CR by the AIDA 0493 protocol (ATRA plus trseg idarubicin [IDA]).17 Thus, for patients achieving molecular oaT CR after intensive induction and consolidation therapy, the cnO 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 As2O3 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 As2O3-based maintenance therapy in newly diagnosed APL patients.19,20 Furthermore, to our knowledge, the comparative efficacy of the ATRA plus As2O3 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 As2O3 and classic ATRA plus chemotherapy 2306 in low- to intermediate-risk APL patients reaching the first CR (CR1) after induction and consolidation therapy. Patients and methods Population and study design APL was initially diagnosed based on morphology and immunophenotyping, and confirmed genetically by the presence of the PML–RARA fusion gene and/or the t(15;17) chromosomal translocation. Eligible patients included adults ($15 years) with newly diagnosed APL, classified as low- to intermediate-risk category (white blood cell [WBC] count at diagnosis #10×109/L). The treatment strategies employed are shown in Figure 1. Remission induction therapy consisted of oral ATRA (25 mg/m2/day [day 1 until CR]) plus IDA (10–12 mg/m2/day [days 2, 4, and 6]) with or without intravenous As2O3 (0.16 mg/kg/day [days 1–28]). This was followed by four cycles of consolidation. Each cycle included the ATRA plus IDA or mitoxantrone (Mitox) regimen (ATRA: 25 mg/m2/day [days 1–14] and IDA: 10–12 mg/m2/day [days 1–3], or Mitox: 6 mg/m2/day [days 1–3]). During induction and consolidation therapy, IDA dosage was decided based upon the patient’s age: 12 mg/m2/day for patients aged 15–60 years; 10 mg/m2/day for those aged 61–70 years. To avoid central nervous system (CNS) relapse, all patients received at least three intrathecal injections of three drugs containing MTX (10 mg), dexamethasone (5 mg), and cytarabine (50 mg) during consolidation therapy. From February 2008 to November 2014, all adult patients with newly diagnosed APL reaching CR1 after induction and consolidation received 2 years of maintenance therapy with either the ATRA plus As2O3 regimen (ATRA [25 mg/m2/day] for 14 days, As2O3 [0.16 mg/kg/day] for 14 days, and sequential use of the two agents with an interval of 14 days), or eight 3-monthly cycles of the ATRA plus chemotherapy regimen (ATRA [25 mg/m2/day] for 14 days of each cycle, alternating with 6-MP [50 mg/m2/day] and MTX [10–15 mg/m2/week] for the remainder of each cycle). This retrospective study was reviewed and approved by the Institutional Review Board (IRB) at the First Affiliated Hospital of Wenzhou Medical University. The requirement for informed consent was waived by the IRB due to the retrospective nature of this study, but patient confidentiality was protected. 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, 8 1 0 2 l u J 2 1 n o 7 1 1 . 2 2 . 8 3 . 4 5 y b / m o c . s s re . .vdoep lsyeon w u /ww lan /: o tsp rse th rp rom oF f d e d a o l n w o d y p a r e h T d n a s t e g r a T o c n O 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). Results Patient characteristics In total, 58 eligible patients reaching CR1 after induction and consolidation therapy received maintenance therapy with either ATRA plus As2O3 (ATRA+As2O3 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+As2O3 group (40.0%) (P=0.034), while the percentage of patients with a WBC count at diagnosis ,5×109/L was significantly lower in the ATRA+chemotherapy group (71.4%) than in the ATRA+As2O3 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+As2O3 group vs 17 in the ATRA+chemotherapy group) were reported in Characteristic age (years), median (range) 15–39, n (%) 40–60, n (%) .60, n (%) sex 23 patients (seven in the ATRA+As2O3 group vs 16 in the ATRA+chemotherapy group) (Table 2). hematologic toxicity 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). Grade 3–4 thrombocytopenia was not observed in either group during maintenance. nonhematologic toxicity Three out of 30 patients (10.0%) in the ATRA+As2O3 group and four out of 28 patients (14.3%) in the ATRA+chemotherapy 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+As2O3 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+As2O3 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+As2O3 group). All clinical signs improved after symptomatic treatment only or observation, with the exception of hemolysis that was resolved with temporary discontinuation of As2O3 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+As2O3 group, whereas seven relapses were observed in the ATRA+chemotherapy group. Of the seven relapsed patients, five presented with ATRA+chemotherapy maintenance (N=28) 9 4 0 3 1 0 P-value 0.001 0.701 0.492 0.344 0.483 1.000 8 1 0 2 l u J 2 1 n o 7 1 1 . 2 2 . 8 3 . 4 5 y b / m o c . s s re . .vdoep lsyeon w u /ww lan /: o tsp rse th rp rom oF f d e d a o l n w o d y p a r e h T d n a s t e g r a T o c n O 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 As2O3, 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 (#5×109/L vs .5×109/L), platelet count at diagnosis (#40×109/L vs .40×109/L), hemoglobin level at diagnosis (,100 g/L vs $100 g/L), and types of induction regimen (ATRA+As2O3+IDA vs ATRA+IDA) and maintenance regimen (ATRA+As2O3 vs ATRA+chemotherapy) on relapse were all analyzed. The risk of relapse in patients administered ATRA+As2O3 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 As2O3 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+As2O3 group, hampering the multivariate analysis to test whether maintenance with ATRA and As2O3 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 8 1 0 2 l u J 2 1 n o 7 1 1 . 2 2 . 8 3 . 4 5 y b / m o c . s s re . .vdoep lsyeon w u /ww lan /: o tsp rse th rp rom oF f d e d a o l n w o d y p a r e h T d n a s t e g r a T o c n O Male 20 5 Female 20 2 age (years) 0.727 #40 20 3 .40 20 4 WBc count ( ×109/l) 0.492 #5 33 5 .5 7 2 Platelet count (×109/l) 0.331 #40 27 6 .40 13 1 hemoglobin (g/l) 0.086 ,100 30 3 $100 10 4 Maintenance regimens 0.007 aTra +as 2O3 22 0 aTra +chemotherapy 18 7 Abbreviations: aPl, acute promyelocytic leukemia; as 2O3, arsenic trioxide; aTra, all-trans retinoic acid; iDa, idarubicin; WBc, white blood cell. ATRA+As2O3 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 As2O3 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 As2O3 was an independent factor for RFS was hampered by the absence of relapse in the ATRA+As2O3 group. Futhermore, there were too few APL patients (N=11) receiving ATRA+As2O3+IDA as the induction regimen to make a similar analysis. Discussion In the present study, we retrospectively compared the efficacy and toxicity of ATRA plus As2O3 and classic ATRA plus chemotherapy as maintenance therapy in low- to intermediate-risk APL patients who achieved CR following consolidation therapy. The number of APL patients who received standard induction and consolidation with ATRA and anthracycline-based chemotherapy was 47 (81.0%) and 58 (100%), respectively. The 3-year RFS for patients receiving maintenance therapy with ATRA plus As2O3 and ATRA plus chemotherapy was 100% and 81.82%, respectively, with a statistically significant difference (P=0.0159). These clinical data suggest that maintenance with ATRA and As2O3 confers a survival benefit in low- to intermediate-risk APL patients 2310 submit your manuscript | www.dovepress.com Dovepress achieving CR after effective induction and consolidation with ATRA and anthracycline-based chemotherapy. Our results are consistent with observations from previous studies that report favorable survival attributed to the use of As2O3 during maintenance.19,20,23 Altogether, these findings show that As2O3-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, As2O3 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.24–27 The synergistic effects between ATRA and As2O3 have been demonstrated at both the biological28,29 and clinical levels. For example, recent studies report that the combination of ATRA with As2O3 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 As2O3, the best timing for the use of As2O3 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 As2O3 with conventional 8 1 0 2 l u J 2 1 n o 7 1 1 . 2 2 . 8 3 . 4 5 y b / m o c . s s re . .vdoep lsyeon w u /ww lan /: o tsp rse th rp rom oF f d e d a o l n w o d y p a r e h T d n a s t e g r a T o c n O chemotherapy. Myelosuppression was observed significantly less frequently in patients administered maintenance therapy with ATRA and As2O3 than in those administered chemotherapy. The commonly observed adverse effects during maintenance with ATRA and As2O3 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 As2O3, 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 As2O3 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 As2O3-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 As2O3 in newly diagnosed APL.35,36 Subsequently, several recent reports provide evidence of the efficacy and safety of ATRA plus As2O3, with or without a chemotherapy protocol, for firstline therapy in patients with newly diagnosed APL.37–39 Furthermore, a recent meta-analysis by Ma et al showed significant benefits of the ATRA plus As2O3 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 As2O3 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 As2O3 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 As2O3.40 The question of whether maintenance with ATRA and As2O3 benefits low- to intermediate-risk APL patients in whom As2O3 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 As2O3 was beneficial for low- to intermediate-risk APL patients who were effectively treated to achieve CR. In addition, the use of As2O3 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. Acknowledgments The authors thank Mrs Liyuan Tang, Mr Chongyun Xing, and Mr Qiang Zhuang for their assistance in data collection and analysis in this study. They also thank Mrs Sumayyah Hosany for her editing of the manuscript. This work was supported by the National Natural Science Foundation of China (number 81502793), the Natural Science Foundation of Zhejiang Province (numbers LQ14H080002, LY12H08002, and LY16H080006), and the Public Welfare Science and Technology Project of Wenzhou (numbers Y20160099 and Y20150034) . Disclosure The authors report no conflicts of interest in this work. submit your manuscript | www.dovepress.com Dovepress 2311 8 1 0 2 l u J 2 1 n o 7 1 1 . 2 2 . 8 3 . 4 5 y b / m o c . s s re . .vdoep lsyeon submit your manuscript | www.dovepress.com Dovepress om oF fr d e d a o l n w o d y p a r e h T d n a s t e g r a T o c n O Publish your work in this 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 1. Wang ZY , Chen Z. Acute promyelocytic leukemia: from highly fatal to highly curable . Blood . 2008 ; 111 ( 5 ): 2505 - 2515 . 2. Sanz MA , Grimwade D , Tallman MS , et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet . Blood . 2009 ; 113 ( 9 ): 1875 - 1891 . 3. Sanz MA , Montesinos P , Rayón C , et al. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome . Blood . 2010 ; 115 ( 25 ): 5137 - 5146 . 4. Lo-Coco F , Avvisati G , Vignetti M , et al; Italian GIMEMA Cooperative Group. Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group . Blood. 2010 ; 116 ( 17 ): 3171 - 3179 . 5. Shen ZX , Chen GQ , Ni JH , et al. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients . Blood . 1997 ; 89 ( 9 ): 3354 - 3360 . 6. Soignet SL , Frankel SR , Douer D , et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia . J Clin Oncol . 2001 ; 19 ( 18 ): 3852 - 3860 . 7. Breccia M , Lo-Coco F . Arsenic trioxide for management of acute promyelocytic leukemia: current evidence on its role in front-line therapy and recurrent disease . Expert Opin Pharmacother . 2012 ; 13 ( 7 ): 1031 - 1043 . 8. Iland HJ , Bradstock K , Supple SG , et al; Australasian Leukaemia and Lymphoma Group. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4) . Blood . 2012 ; 120 ( 8 ): 1570 - 1580 ; quiz 1752. 9. Powell BL , Moser B , Stock W , 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 - 3757 . 10. Ravandi F , Estey E , Jones D , et al. Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin . J Clin Oncol . 2009 ; 27 ( 4 ): 504 - 510 . 11. 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 . Proc Natl Acad Sci U S A . 2004 ; 101 ( 15 ): 5328 - 5335 . 12. Gore SD , Gojo I , Sekeres MA , et al. Single cycle of arsenic trioxidebased consolidation chemotherapy spares anthracycline exposure in the primary management of acute promyelocytic leukemia . J Clin Oncol . 2010 ; 28 ( 6 ): 1047 - 1053 . 13. Tallman MS , Andersen JW , Schiffer CA , et al. All-trans-retinoic acid in acute promyelocytic leukemia . N Engl J Med . 1997 ; 337 ( 15 ): 1021 - 1028 . 14. Fenaux P , Chastang C , Chevret S , et al. A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia . The European APL Group. Blood . 1999 ; 94 ( 4 ): 1192 - 1200 . 15. Tallman MS , Andersen JW , Schiffer CA , 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 - 4302 . 16. Adès L , Guerci A , Raffoux E , et al; European APL Group. Very longterm outcome of acute promyelocytic leukemia after treatment with all-trans retinoic acid and chemotherapy: the European APL Group experience . Blood . 2010 ; 115 ( 9 ): 1690 - 1696 . 17. Avvisati G , Lo-Coco F , Paoloni FP , 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 - 4725 . 18. 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 Syst Rev . 2013 ; (3): CD009594. 19. Lou Y , Qian W , Meng H , et al. High efficacy of arsenic trioxide plus all-trans retinoic acid based induction and maintenance therapy in newly diagnosed acute promyelocytic leukemia . Leuk Res . 2013 ; 37 ( 1 ): 37 - 42 . 20. Chiang YH , Chang YF , Hsieh RK , et al. Upfront maintenance therapy with arsenic trioxide in acute promyelocytic leukemia provides no benefit for non-t(15;17) subtype . Asia Pac J Clin Oncol . 2012 ; 8 ( 4 ): 330 - 336 . 21. US Department of Health and Human Services; National Institutes of Health; National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE), Version 4 .0. Published May 28, 2009 ( v4 .03: June 14, 2010 . Available from: http://evs.nci.nih.gov/ftp1/CTCAE/ CTCAE_4.03_ 2010 -06-14_QuickReference_ 8 .5x11.pdf). Accessed April 13 , 2017 . 22. Sagie A , Larson MG , Goldberg RJ , Bengtson JR , Levy D. An improved method for adjusting the QT interval for heart rate (the Framingham Heart Study) . Am J Cardiol . 1992 ; 70 ( 7 ): 797 - 801 . 23. Au WY , Kumana CR , Lee HK , et al. Oral arsenic trioxide-based maintenance regimens for first complete remission of acute promyelocytic leukemia: a 10-year follow-up study . Blood . 2011 ; 118 ( 25 ): 6535 - 6543 . 24. Zhu J , Koken MH , Quignon F , et al. Arsenic-induced PML targeting onto nuclear bodies: implications for the treatment of acute promyelocytic leukemia . Proc Natl Acad Sci U S A . 1997 ; 94 ( 8 ): 3978 - 3983 . 25. Shao W , Fanelli M , Ferrara FF , et al. Arsenic trioxide as an inducer of apoptosis and loss of PML/RAR alpha protein in acute promyelocytic leukemia cells . J Natl Cancer Inst . 1998 ; 90 ( 2 ): 124 - 133 . 26. Roboz GJ , Dias S , Lam G , et al. Arsenic trioxide induces dose- and time-dependent apoptosis of endothelium and may exert an antileukemic effect via inhibition of angiogenesis . Blood . 2000 ; 96 ( 4 ): 1525 - 1530 . 27. Chen SJ , Zhou GB , Zhang XW , Mao JH , de Thé H , Chen Z. From an old remedy to a magic bullet: molecular mechanisms underlying the therapeutic effects of arsenic in fighting leukemia . Blood . 2011 ; 117 ( 24 ): 6425 - 6437 . 28. Lallemand-Breitenbach V , Guillemin MC , Janin A , et al. Retinoic acid and arsenic synergize to eradicate leukemic cells in a mouse model of acute promyelocytic leukemia . J Exp Med . 1999 ; 189 ( 7 ): 1043 - 1052 . 29. de Thé H , Chen Z. Acute promyelocytic leukaemia: novel insights into the mechanisms of cure . Nat Rev Cancer . 2010 ; 10 ( 11 ): 775 - 783 . 30. Ma Y , Liu L , Jin J , Lou Y . All-trans retinoic acid plus arsenic trioxide versus all-trans retinoic acid plus chemotherapy for newly diagnosed acute promyelocytic leukemia: a meta-analysis . PLoS One . 2016 ; 11 ( 7 ): e0158760 . 31. Platzbecker U , Avvisati G , Cicconi L , et al. Improved outcomes with retinoic acid and arsenic trioxide compared with retinoic acid and chemotherapy in non-high-risk acute promyelocytic leukemia: final results of the randomized Italian-German APL0406 trial . J Clin Oncol . 2017 ; 35 ( 6 ): 605 - 612 . 32. Firkin F. Carcinogenic risk of retained arsenic after successful treatment of acute promyelocytic leukemia with arsenic trioxide: a cause for concern? Leuk Lymphoma . 2014 ; 55 ( 5 ): 977 - 978 . 33. Rezuke WN , Anderson C , Pastuszak WT , Conway SR , Firshein SI . Arsenic intoxication presenting as a myelodysplastic syndrome: a case report . Am J Hematol . 1991 ; 36 ( 4 ): 291 - 293 . 34. Hu J , Liu YF , Wu CF , et al. Long-term efficacy and safety of alltrans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia . Proc Natl Acad Sci U S A . 2009 ; 106 ( 9 ): 3342 - 3347 . 35. Ghavamzadeh A , Alimoghaddam K , Rostami S , et al. Phase II study of single-agent arsenic trioxide for the front-line therapy of acute promyelocytic leukemia . J Clin Oncol . 2011 ; 29 ( 20 ): 2753 - 2757 . 36. Mathews V , George B , Lakshmi KM , et al. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: durable remissions with minimal toxicity . Blood . 2006 ; 107 ( 7 ): 2627 - 2632 . 37. Lo-Coco F , Avvisati G , Vignetti M , et al; for Gruppo Italiano Malattie Ematologiche dell'Adulto, the German-Austrian Acute Myeloid Leukemia Study Group, and Study Alliance Leukemia . Retinoic acid and arsenic trioxide for acute promyelocytic leukemia . N Engl J Med . 2013 ; 369 ( 2 ): 111 - 121 . 38. Burnett AK , Russell NH , Hills RK , et al; UK National Cancer Research Institute Acute Myeloid Leukaemia Working Group. Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial . Lancet Oncol . 2015 ; 16 ( 13 ): 1295 - 1305 . 39. Iland HJ , Collins M , Bradstock K , et al; Australasian Leukaemia and Lymphoma Group. Use of arsenic trioxide in remission induction and consolidation therapy for acute promyelocytic leukaemia in the Australasian Leukaemia and Lymphoma Group (ALLG) APML4 study: a non-randomised phase 2 trial . Lancet Haematol . 2015 ; 2 ( 9 ): e357 - e366 . 40. Coutre SE , Othus M , Powell B , et al. Arsenic trioxide during consolidation for patients with previously untreated low/intermediate risk acute promyelocytic leukaemia may eliminate the need for maintenance therapy . Br J Haematol . 2014 ; 165 ( 4 ): 497 - 503 .


This is a preview of a remote PDF: https://www.dovepress.com/getfile.php?fileID=36194

Bin Liang, Zhouyi Zheng, Yifen Shi, Jingjing Chen, Xudong Hu, Honglan Qian, Zhijian Shen, Songfu Jiang, Kang Yu, Jianhua Feng. 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, OncoTargets and Therapy, 2017, 2305-2313, DOI: 10.2147/OTT.S135013