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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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Abstract
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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Arsenic Trioxide Consolidation Allows Anthracycline Dose Reduction for Pediatric Patients With Acute Promyelocytic Leukemia: Report From the Children's Oncology Group Phase III Historically Controlled Trial AAML0631.
Kutny, MA, Alonzo, TA, Gerbing, RB, Wang, YC, Raimondi, SC, Hirsch, BA, Fu, CH, Meshinchi, S, Gamis, AS, Feusner, JH, et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2017;(26):3021-3029
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Abstract
Purpose The Children's Oncology Group AAML0631 trial for newly diagnosed pediatric acute promyelocytic leukemia (APL) was a phase III historically controlled trial to determine the survival of patients receiving arsenic trioxide (ATO) consolidation and reduced doses of anthracyclines. Patients and Methods Patients age 2 to 21 years with de novo APL confirmed by PML-RARα polymerase chain reaction were stratified as standard risk (SR) or high risk (HR) on the basis of diagnostic WBC count. All patients received all-trans retinoic acid (ATRA) during induction, each consolidation course, and maintenance. All patients received two cycles of ATO therapy during consolidation 1, an additional two (SR) or three (HR) consolidation courses that included high-dose cytarabine and anthracycline, and maintenance therapy comprising ATRA, oral methotrexate, and mercaptopurine. Results One hundred one patients (66 SR and 35 HR) were evaluable for outcome. The 3-year overall survival was 94%, and event-free survival (EFS) was 91%. For SR and HR patients with APL, the overall survival was 98% versus 86% ( P = .003), and EFS was 95% versus 83% ( P = .03), respectively. The EFS for SR patients in AAML0631 was noninferior to that of patients in the AIDA 0493 historical control, which used a significantly higher anthracycline dose and did not include ATO consolidation. Relapse risk for patients in AAML0631 from end consolidation 1 (after ATO treatment) was only 4% at 3 years and did not differ significantly between SR and HR patients. Conclusion ATO consolidation cycles were well tolerated in pediatric patients with APL and allowed significant reduction in cumulative anthracycline doses while maintaining excellent survival and a low relapse risk for both SR and HR patients with APL.
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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.
Iland, HJ, Collins, M, Bradstock, K, Supple, SG, Catalano, A, Hertzberg, M, Browett, P, Grigg, A, Firkin, F, Campbell, LJ, et al
The Lancet. Haematology. 2015;(9):e357-66
Abstract
BACKGROUND Initial treatment of acute promyelocytic leukaemia traditionally involves tretinoin (all-trans retinoic acid) combined with anthracycline-based risk-adapted chemotherapy, with arsenic trioxide being the treatment of choice at relapse. To try to reduce the relapse rate, we combined arsenic trioxide with tretinoin and idarubicin in induction therapy, and used arsenic trioxide with tretinoin as consolidation therapy. METHODS Patients with previously untreated genetically confirmed acute promyelocytic leukaemia were eligible for this study. Eligibilty also required Eastern Cooperative Oncology Group performance status 0-3, age older than 1 year, normal left ventricular ejection fraction, Q-Tc interval less than 500 ms, absence of serious comorbidity, and written informed consent. Patients with genetic variants of acute promyelocytic leukaemia (fusion of genes other than PML with RARA) were ineligible. Induction comprised 45 mg/m(2) oral tretinoin in four divided doses daily on days 1-36, 6-12 mg/m(2) intravenous idarubicin on days 2, 4, 6, and 8, adjusted for age, and 0·15 mg/kg intravenous arsenic trioxide once daily on days 9-36. Supportive therapy included blood products for protocol-specified haemostatic targets, and 1 mg/kg prednisone daily as prophylaxis against differentiation syndrome. Two consolidation cycles with tretinoin and arsenic trioxide were followed by maintenance therapy with oral tretinoin, 6-mercaptopurine, and methotrexate for 2 years. The primary endpoints of the study were freedom from relapse and early death (within 36 days of treatment start) and we assessed improvement compared with the 2 year interim results. To assess durability of remission we compared the primary endpoints and disease-free and overall survival at 5 years in APML4 with the 2 year interim APML4 data and the APML3 treatment protocol that excluded arsenic trioxide. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12605000070639. FINDINGS 124 patients were enrolled between Nov 10, 2004, and Sept 23, 2009, with data cutoff of March 15, 2012. Four (3%) patients died early. After a median follow-up of 4·2 years (IQR, 3·2-5·2), the 5 year freedom from relapse was 95% (95% CI 89-98), disease-free survival was 95% (89-98), event-free survival was 90% (83-94), and overall survival was 94% (89-97). The comparison with APML3 data showed that hazard ratios were 0·23 (95% CI 0·08-0·64, p=0·002) for freedom from relapse, 0·21 (0·07-0·59, p=0·001) for disease-free survival, 0·34 (0·16-0·69, p=0·002) for event-free survival, and 0·35 (0·14-0·91, p=0·02) for overall survival. INTERPRETATION Incorporation of arsenic trioxide in initial therapy induction and consolidation for acute promyelocytic leukaemia reduced the risk of relapse when compared with historical controls. This improvement, together with a non-significant reduction in early deaths and absence of deaths in remission, translated into better event-free and overall survival. FUNDING Phebra.
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[Efficacy Analysis of Arsenic Trioxide Combined with All Trans Retinoic Acid for Acute Promyelocytic Leukemia].
Wang, LL, Ren, YQ
Zhongguo shi yan xue ye xue za zhi. 2015;(5):1292-5
Abstract
OBJECTIVE To investigate the efficacy of arsenic trioxide combined with all trans retinoic acid (ATRA) for patients with acute promyelocytic leukemia (APL). METHODS A total of 159 cases of APL were selected from January 2011 to December 2014 in our hospital, among them 75 cases were treated by As₂O₃combined with ATRA, 43 cases were treated with As₂O₃alone, 41 cases were treated with ATRA alone. The cardiac enzymes level, lever function index change, death rate, complate remission (CR) rate, time of reaching CR and complicatiens were compared in 3 groups. RESULTS After treatment of 8 courses, ALT and AST levels in As₂O₃+ ATRA group were significantly higher than those in As₂O₃and ATRA alone groups; the CK-MB and TnI-UI index increased in As₂O₃group (P < 0.05); as compared with As₂O₃group, the mortality and CR rate in As₂O₃+ ATRA group were no significant different, but the time of reaching CR was significantly shortened. For relapsed patients, the CR rate in As₂O₃+ ATRA group was no significantly different from that in As₂O₃group, while was significantly higher than that in ATRA group. The ratio of liver function damage in As₂O₃+ ATRA group was increased, moreover the incidence of leukocytosis and headache in ATRA group was significantly higher than that in As₂O₃+ ATRA and As₂O₃group (P < 0.05). CONCLUSIONS The efficacy of As₂O₃conbined with ATRA for inducing remission is better than that of single drug treatment, moreover the adverse reactions occur less.
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Oral arsenic and retinoic acid for non-high-risk acute promyelocytic leukemia.
Zhu, HH, Huang, XJ
The New England journal of medicine. 2014;(23):2239-41
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All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4).
Iland, HJ, Bradstock, K, Supple, SG, Catalano, A, Collins, M, Hertzberg, M, Browett, P, Grigg, A, Firkin, F, Hugman, A, et al
Blood. 2012;(8):1570-80; quiz 1752
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Abstract
The treatment of acute promyelocytic leukemia has improved considerably after recognition of the effectiveness of all-trans-retinoic acid (ATRA), anthracycline-based chemotherapy, and arsenic trioxide (ATO). Here we report the use of all 3 agents in combination in an APML4 phase 2 protocol. For induction, ATO was superimposed on an ATRA and idarubicin backbone, with scheduling designed to exploit antileukemic synergy while minimizing cardiotoxicity and the severity of differentiation syndrome. Consolidation comprised 2 cycles of ATRA and ATO without chemotherapy, followed by 2 years of maintenance with ATRA, oral methotrexate, and 6-mercaptopurine. Of 124 evaluable patients, there were 4 (3.2%) early deaths, 118 (95%) hematologic complete remissions, and all 112 patients who commenced consolidation attained molecular complete remission. The 2-year rate for freedom from relapse is 97.5%, failure-free survival 88.1%, and overall survival 93.2%. These outcomes were not influenced by FLT3 mutation status, whereas failure-free survival was correlated with Sanz risk stratification (P[trend] = .03). Compared with our previously reported ATRA/idarubicin-based protocol (APML3), APML4 patients had statistically significantly improved freedom from relapse (P = .006) and failure-free survival (P = .01). In conclusion, the use of ATO in both induction and consolidation achieved excellent outcomes despite a substantial reduction in anthracycline exposure. This trial was registered at the Australian New Zealand Clinical Trials Registry (www.anzctr.org.au) as ACTRN12605000070639.
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Phase II study of single-agent arsenic trioxide for the front-line therapy of acute promyelocytic leukemia.
Ghavamzadeh, A, Alimoghaddam, K, Rostami, S, Ghaffari, SH, Jahani, M, Iravani, M, Mousavi, SA, Bahar, B, Jalili, M
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;(20):2753-7
Abstract
PURPOSE The long-term follow-up results of patients with acute promyelocytic leukemia (APL) treated with all-trans retinoic acid and chemotherapy show high cure rates. Several studies have shown high efficacy of single-agent arsenic trioxide in newly diagnosed APL. However, long-term follow-up results are needed. PATIENTS AND METHODS One hundred ninety-seven patients with newly diagnosed APL were treated with arsenic trioxide 0.15 mg/kg daily intravenous infusion until complete remission (CR). After achieving CR, the patients received one to four more courses of therapy with arsenic trioxide as consolidation and were observed with reverse-transcriptase polymerase chain reaction studies from peripheral blood (to detect of minimal residual disease) every 3 months or until relapse or death. RESULTS The morphologic CR rate was 85.8%. The most common cause of remission failure was early death owing to APL differentiation syndrome (13.2%). The most important prognostic factor for early mortality was a high WBC count at presentation. The 5-year disease-free survival (DFS) rate was 66.7% ± 4% (SE). Relapse after 5 years in CR was rare. The 5-year overall survival (OS) rate by intention-to-treat analysis was 64.4% ± 4%. In patients who achieved CR, OS and DFS were identical. CONCLUSION The long-term follow-up of newly diagnosed patients with APL treated with single-agent arsenic trioxide shows high rates of DFS and OS.
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High efficacy and low toxicity of APL induction with concurrent idarubicin/ATRA followed by a novel and simplified outpatient post-remission therapy using single doses of idarubicin and intermittent ATRA.
Aljurf, M, Al Qurashi, F, Al Mohareb, F, Sahovic, E, Al Sharif, F, Al Zahrani, H, Al Shanqeeti, A, Owaidah, T, Iqbal, A, Zaidi, SZ, et al
Medical oncology (Northwood, London, England). 2010;(3):702-7
Abstract
Acute promyelocytic leukemia (APL) is one of the most curable myeloid malignancies because of its great sensitivity to all-trans retinoic acid (ATRA) and response to anthracycline therapy. In an attempt to simplify post-remission therapy, deliver adequate dose of anthracycline and reduce treatment related toxicity, we entered 26 consecutively newly diagnosed, previously untreated APL patients in a pilot treatment program consisting of concurrent induction using idarubicin/ATRA followed by an exclusive outpatient post-remission therapy using single dose of idarubicin and intermittent ATRA, every 4 weeks. Of 25 evaluable patients, two (8%) died early during induction due to hemorrhagic complications, and 23 (92%) achieved complete remission. Overall survival at 4.2 years was 90% (CI 76.4-100), and 3.6 years disease-free survival was 78% (CI 60.6-95.4). The treatment outcome of this program is encouraging; however, the result of this study needs to be validated in larger cohort of patients and optimally in a randomized comparison with other current post-remission approaches.
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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.