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Treatment of non-high-risk acute promyelocytic leukemia with realgar-indigo naturalis formula (RIF) and all-trans retinoid acid (ATRA): study protocol for a randomized controlled trial.
Zhang, X, Liu, L, Yao, Y, Gong, S, Wang, M, Xi, J, Chen, L, Wei, S, Zhang, H, Zhao, C, et al
Trials. 2020;(1):7
Abstract
BACKGROUND Acute promyelocytic leukemia (APL) is a highly curable disease when treated with all-trans retinoid acid (ATRA) and arsenic trioxide (ATO). The combination of ATO and ATRA has become the standard therapeutic protocol for induction therapy in non-high-risk APL. An oral arsenic realgar-indigo naturalis formula (RIF) has also showed high efficacy and it has a more convenient route of administration than the standard intravenous regimen. Unlike in previous trials, the arsenical agent was used simultaneously with ATRA during post-remission therapy in this trial. METHODS This study was designed as a multicenter, randomized controlled trial. The trial has a non-inferiority design with superiority being explored if non-inferiority is identified. All patients receive ATRA-ATO during the induction therapy. After achieving hematologic complete remission (HCR), patients were randomly assigned (1:1) to receive treatment with ATRA-RIF (experimental group) or ATRA-ATO (control group) as the consolidation therapy. During the consolidation therapy, the two groups receive ATRA plus RIF or intravenous ATO 2 weeks on and 2 to ~ 4 weeks off until molecular complete remission (MCR), then ATRA and oral RIF 2 weeks on and 2 to ~ 4 weeks off giving a total of six courses. DISCUSSION This trial aims to compare the efficacy of ATRA-ATO versus ATRA-RIF in non-high-risk patients with APL, to demonstrate that oral RIF application reduces the total hospitalization days and medical costs. The simple schedule was studied in this trial. TRIAL REGISTRATION ClinicalTrials.gov, NCT02899169. Registered on 14 September 2016.
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Long-term results of all-trans retinoic acid and arsenic trioxide in non-high-risk acute promyelocytic leukemia: update of the APL0406 Italian-German randomized trial.
Cicconi, L, Platzbecker, U, Avvisati, G, Paoloni, F, Thiede, C, Vignetti, M, Fazi, P, Ferrara, F, Divona, M, Albano, F, et al
Leukemia. 2020;(3):914-918
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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.
Platzbecker, U, Avvisati, G, Cicconi, L, Thiede, C, Paoloni, F, Vignetti, M, Ferrara, F, Divona, M, Albano, F, Efficace, F, et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2017;(6):605-612
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Purpose The initial results of the APL0406 trial showed that the combination of all- trans-retinoic acid (ATRA) and arsenic trioxide (ATO) is at least not inferior to standard ATRA and chemotherapy (CHT) in first-line therapy of low- or intermediate-risk acute promyelocytic leukemia (APL). We herein report the final analysis on the complete series of patients enrolled onto this trial. Patients and Methods The APL0406 study was a prospective, randomized, multicenter, open-label, phase III noninferiority trial. Eligible patients were adults between 18 and 71 years of age with newly diagnosed, low- or intermediate-risk APL (WBC at diagnosis ≤ 10 × 109/L). Overall, 276 patients were randomly assigned to receive ATRA-ATO or ATRA-CHT between October 2007 and January 2013. Results Of 263 patients evaluable for response to induction, 127 (100%) of 127 patients and 132 (97%) of 136 patients achieved complete remission (CR) in the ATRA-ATO and ATRA-CHT arms, respectively ( P = .12). After a median follow-up of 40.6 months, the event-free survival, cumulative incidence of relapse, and overall survival at 50 months for patients in the ATRA-ATO versus ATRA-CHT arms were 97.3% v 80%, 1.9% v 13.9%, and 99.2% v 92.6%, respectively ( P < .001, P = .0013, and P = .0073, respectively). Postinduction events included two relapses and one death in CR in the ATRA-ATO arm and two instances of molecular resistance after third consolidation, 15 relapses, and five deaths in CR in the ATRA-CHT arm. Two patients in the ATRA-CHT arm developed a therapy-related myeloid neoplasm. Conclusion These results show that the advantages of ATRA-ATO over ATRA-CHT increase over time and that there is significantly greater and more sustained antileukemic efficacy of ATO-ATRA compared with ATRA-CHT in low- and intermediate-risk APL.
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[Homoharringtonine in newly diagnosed acute promyelocytic leukemia treatment: a prospective, randomized controlled trial].
Wang, Y, Liu, BC, Wei, H, Lin, D, Zhou, CL, Liu, KQ, Li, W, Wei, SN, Wang, JY, Gong, BF, et al
Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi. 2016;(3):183-8
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OBJECTIVE To compare the efficacy and toxicities of combining homoharringtonine (HHT)±daunorubicin (DNR) with all-trans-retinoic acid (ATRA) based therapy and DNR plus ATRA based therapy in newly diagnosed low/intermediate risk acute promyelocytic leukemia (APL). METHODS A total of 96 newly diagnosed patients with APL were randomized to HHT group, DNR group and HHT+ DNR group prospectively. The complete remission (CR) rate, the overall survival (OS) and event-free survival (EFS) of three groups were analyzed. RESULTS There were 31 patients in HHT group, 33 patients in DNR group and 32 patients in HHT+ DNR group. The baseline characteristics of three groups were similar. No patient died during induction therapy. The morphologic CR rate was 100.0%. The median time to peak WBC counts in HHT+DNR group (4 days, range: 1-23 days) was significantly shorter than that in HHT group (9 days, range: 1-27 days) (P=0.008) and DNR group (7 days, range: 1-27 days) (P=0.240). There was no difference among three groups about the incidence of differentiation syndrome, the median interval to achieve CR, peak WBC counts and transfusions (P >0.05). All patients achieved complete molecular remission (CMR) during consolidation therapy. The interval to achieve CMR was no significantly difference among three groups (P >0.05). The 3-year OS rates for HHT group, DNR group and HHT+DNR group were 95.0%, 100.0% and 91.0%, respectively (P=0.595). The 3-year EFS rates for three groups were 93.0%, 90.0% and 85.0% (P=0.382). No difference was found in the incidence of adverse events among three groups (P >0.05). CONCLUSIONS Similar to DNR plus ATRA based therapy, HHT plus ATRA based induction and consolidation therapy should be one of highly-efficient treatment options for newly diagnosed APL. Clinical trial registration Chinese Clinical Trial Registry, ChiCTR-TRC-12002628.
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Oral tetra-arsenic tetra-sulfide formula versus intravenous arsenic trioxide as first-line treatment of acute promyelocytic leukemia: a multicenter randomized controlled trial.
Zhu, HH, Wu, DP, Jin, J, Li, JY, Ma, J, Wang, JX, Jiang, H, Chen, SJ, Huang, XJ
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2013;(33):4215-21
Abstract
PURPOSE This randomized, multicenter, phase III noninferiority trial was designed to test the efficacy and safety of an oral tetra-arsenic tetra-sulfide (As4S4) -containing formula named the Realgar-Indigo naturalis formula (RIF) compared with intravenous arsenic trioxide (ATO) as both induction and maintenance therapies for newly diagnosed acute promyelocytic leukemia (APL). PATIENTS AND METHODS In all, 242 patients with APL were randomly assigned (1:1) to oral RIF (60 mg/kg) or ATO (0.16 mg/kg) combined with all-trans retinoic acid (ATRA; 25 mg/m(2)) during induction therapy. After achieving complete remission (CR), all patients received three courses of consolidation chemotherapy and maintenance treatment with sequential ATRA followed by either RIF or ATO for 2 years. The primary end point was the rate of disease-free survival (DFS) at 2 years, which was assessed for noninferiority with a 10% noninferiority margin. RESULTS The median follow-up time was 39 months. DFS at 2 years was 98.1% (106 of 108) in the RIF group and 95.5% (107 of 112) in the ATO group. The DFS difference was 2.6% (95% CI, -3.0% to 8.0%). The lower limit of the 95% CI of DFS difference was greater than the -10% noninferiority margin, confirming noninferiority (P < .001). No significant differences were noted between the RIF and ATO groups with regard to the CR rate (99.1% v 97.2%; P = .62) or the overall survival at 3 years (99.1% v 96.6%; P = .18). The rates of adverse events were similar in the two groups. CONCLUSION Oral RIF plus ATRA is not inferior to intravenous ATO plus ATRA as first-line treatment of APL and may be considered as a routine treatment option for appropriate patients.
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[Effects of all-trans retinoic acid and compound huangdai tablet sequential maintenance treatment on the long-term efficacy of acute promyelocytic leukemia patients].
Gong, JX, Meng, JB, Ma, Y
Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine. 2012;(11):1473-6
Abstract
OBJECTIVE To compare the difference in the long-term efficacy between all-trans retinoic acid (ATRA) combined Compound Huangdai Tablet and ATRA combined methotrexate (MTX) and 6-mercaptopurine (6MP) as the sequential maintenance treatment of acute promyelocytic leukemia (APL) patients. METHODS Totally 83 APL patients in the molecular remission (PML/RARalpha negative) were randomly assigned to two groups, the treatment group (45 cases) and the control group (38 cases) after they were induced to the complete remission (CR) by ATRA combined chemotherapy, and treated by sequential chemotherapy as the consolidated treatment for 3 therapeutic courses. Those in the treatment group were sequentially treated with ATRA and Compound Huangdai Tablet as maintenance therapy, while those in the control group were treated with ATRA and MTX + 6MP as maintenance therapy. After a long-term follow-up (2003 -2011), the long-term therapeutic efficacy and adverse reactions were compared between the two therapeutic regimens. RESULTS The 5-year relapse-free survival (RFS) rate was 84.4% +/- 5.4% in the treatment group and 63.2% +/- 7.8% in the control group, showing statistical difference between the two groups (P < 0.05). The 5-year overall survival rate (OSR) was 86.7% +/- 5. 1% in the treatment group and 78.7% +/- 6.7% in the control group, showing no statistical difference between the two groups (P > 0.05). There was no statistical difference in the adverse reaction between the two groups (P > 0.05). CONCLUSION The application of ATRA and Compound Huangdai Tablet as maintenance therapy could elevate the long-term RFS rate of APL patients.
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Favourable outcome of patients with childhood acute promyelocytic leukaemia after treatment with reduced cumulative anthracycline doses.
Creutzig, U, Zimmermann, M, Dworzak, M, Urban, C, Henze, G, Kremens, B, Lakomek, M, Bourquin, JP, Stary, J, Reinhardt, D
British journal of haematology. 2010;(3):399-409
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Acute promyelocytic leukaemia (APL) treatment often includes high cumulative doses of anthracyclines, which can cause long-term cardiotoxicity. Here, we report the favourable outcome in 81 paediatric APL patients treated according to the consecutive acute myeloid leukaemia-Berlin/Frankfurt/Muenster (AML-BFM) trials -93/-98/-2004 with an anthracycline-cytarabine regimen in combination with all-trans-retinoid acid (ATRA). Outcomes achieved by treatment with a reduced cumulative anthracycline dose (350 mg/m(2)) were comparable to those reported for studies with higher doses. Five-year overall survival of the total cohort was 89 +/- 4% and event-free survival (pEFS) was 73 +/- 6%. Overall survival was similar when comparing AML-BFM trial periods (trial 93: 88 +/- 8%, 98: 85 +/- 7% and 2004: 94 +/- 8%, P((logrank)) = 0.63). Seventy-five (93%) patients achieved complete remission. Most fatal events occurred during the first 6 weeks of treatment. Long-term cardiotoxicity was observed in one patient. Two patients suffered from secondary haematological malignancies. Salvage treatment was effective in 7/9 patients (78%) with relapsed APL, who now are long-term survivors after second line combination treatment with arsenic trioxide (4/7 patients) and stem cell transplantation (5/7 patients). Our results demonstrate that - combined with ATRA - a lower cumulative anthracycline dose can be used safely to maintain high cure rates and promote the reduction of long-term sequelae, such as cardiotoxicity in APL patients.
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Very long-term outcome of acute promyelocytic leukemia after treatment with all-trans retinoic acid and chemotherapy: the European APL Group experience.
Adès, L, Guerci, A, Raffoux, E, Sanz, M, Chevallier, P, Lapusan, S, Recher, C, Thomas, X, Rayon, C, Castaigne, S, et al
Blood. 2010;(9):1690-6
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Acute promyelocytic leukemia (APL) is highly curable with the combination of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy (CT), but very long-term results of this treatment, when CT should be added to ATRA and the role of maintenance treatment, remain uncertain. In our APL93 trial that included 576 newly diagnosed APL patients, with a median follow-up of 10 years, 10-year survival was 77%. Maintenance treatment significantly reduced 10-year cumulative incidence of relapses, from 43.2% to 33%, 23.4%, and 13.4% with no maintenance, maintenance using intermittent ATRA, continuous 6 mercaptopurine plus methotrexate, and both treatments, respectively (P < .001). Maintenance particularly benefited patients with white blood cell (WBC) count higher than 5 x 10(9)/L (5000/microL). Early addition of CT to ATRA significantly improved 10-year event-free survival (EFS), but without significant effect on overall survival (OS). The 10-year cumulative incidence of deaths in complete response (CR), resulting mainly from myelosuppression, was 5.7%, 15.4%, and 21.7% in patients younger than 55, 55 to 65, and older than 65 years, respectively, supporting the need for less myelosuppressive treatments, particularly for consolidation therapy. This study is registered at http://clinicaltrials.gov as NCT00599937.
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[Application of all-trans retinoic acid combining chemotherapy and As4S4 in the maintenance treatment of patients with acute promyelocytic leukemia].
Lin, QD, Wei, XD, Wang, P, Liu, YY, Zhang, LN, Li, YF, Gao, QL, Zhu, XH, Zhang, YL, Fang, BJ, et al
Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi. 2007;(1):19-21
Abstract
OBJECTIVE To compare the efficacy of all-trans retinoic acid (ATRA) combining chemotherapy and As4S4 with ATRA combining chemotherapy for the maintenance treatment of patients with acute promyelocytic leukemia (APL). METHODS Sixty patients with APL induced to complete remission by ATRA and consolidated by chemotherapy were randomly divided into two groups. Thirty patients as As4S4 group received ATRA + As4S4 + chemotherapy, and another thirty patients as non-As4S4 group were treated only with ATRA + chemotherapy as maintenance therapy. The therapeutic effects, side effects and PML-RARalpha gene expression were analyzed. RESULTS The three-year continuous complete remission (CCR) rate was 90.0% for As4S4 group and 61.1% for non-As4S4 group, the difference being statistically significant. Significant difference was also found in the positive rate of PML-RARalpha fusion gene between the two groups. The side effects were mild. CONCLUSION APL patients in maintenance therapy with ATRA + 6-MP + MTX + As4S4 can obtain a higher CCR.
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Is cytarabine useful in the treatment of acute promyelocytic leukemia? Results of a randomized trial from the European Acute Promyelocytic Leukemia Group.
Adès, L, Chevret, S, Raffoux, E, de Botton, S, Guerci, A, Pigneux, A, Stoppa, AM, Lamy, T, Rigal-Huguet, F, Vekhoff, A, et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2006;(36):5703-10
Abstract
PURPOSE Several phase II studies have suggested that cytarabine (AraC) was not required in the treatment of newly diagnosed acute promyelocytic leukemia (APL) patients receiving all-trans-retinoic acid (ATRA), an anthracycline, and maintenance therapy, and we aimed at confirming this finding in a randomized trial. PATIENTS AND METHODS Newly diagnosed APL patients younger than age 60 years with a WBC count of less than 10,000/microL were randomly assigned to receive either ATRA combined with and followed by three daunorubicin (DNR) plus AraC courses and a 2-year maintenance regimen (AraC group) or the same treatment but without AraC (no AraC group). Patients older than age 60 years and patients with initial WBC count of more than 10,000/microL were not randomly assigned but received risk-adapted treatment, with higher dose of AraC and CNS prophylaxis in patients with WBC counts more than 10,000/microL. RESULTS Overall, 328 (96.5%) of 340 patients achieved complete remission (CR). In the AraC and the no AraC groups, the CR rates were 99% and 94% (P = .12), the 2-year cumulative incidence of relapse (CIR) rates were 4.7% and 15.9% (P = .011), the event-free survival (EFS) rates were 93.3% and 77.2% (P = .0021), and survival rates were 97.9% and 89.6% (P = .0066), respectively. In patients younger than age 60 years with WBC counts more than 10,000/microL, the CR, 2-year CIR, EFS, and survival rates were 97.3%, 2.9%, 89%, and 91.9%, respectively. CONCLUSION These results support a role for AraC in addition to ATRA and anthracyclines in the treatment of newly diagnosed APL, at least using DNR at the cumulative dose we used and with the consolidation and maintenance regimens we used.