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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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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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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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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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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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Central nervous system involvement at first relapse in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline monochemotherapy without intrathecal prophylaxis.
Montesinos, P, Díaz-Mediavilla, J, Debén, G, Prates, V, Tormo, M, Rubio, V, Pérez, I, Fernández, I, Viguria, M, Rayón, C, et al
Haematologica. 2009;(9):1242-9
Abstract
BACKGROUND The prevalence of and risk factors for central nervous system recurrence in patients with acute promyelocytic leukemia are not well established and remain a controversial matter. DESIGN AND METHODS Between 1996 and 2005, 739 patients with newly diagnosed acute promyelocytic leukemia enrolled in two consecutive trials (PETHEMA LPA96 and LPA99) received induction therapy with all-trans retinoic acid and idarubicin. Consolidation therapy comprised three courses of anthracycline monochemotherapy (LPA96), with all-trans retinoic acid and reinforced doses of idarubicin in patients with an intermediate or high risk of relapse (LPA99). Central nervous system prophylaxis was not given. RESULTS Central nervous system relapse was documented in 11 patients. The 5-year cumulative incidence of central nervous system relapse was 1.7% (LPA96 3.2% and LPA99 1.2%; p=0.09). The cumulative incidence was 0%, 0.8%, and 5.5% in low-, intermediate-, and high-risk patients, respectively. Relapse risk score (p=0.0001) and the occurrence of central nervous system hemorrhage during induction (5-year cumulative incidence 18.7%, p=0.006) were independent risk factors for central nervous system relapse. CONCLUSIONS This study shows a low incidence of central nervous system relapse in patients with acute promyelocytic leukemia following therapy with all-trans retinoic acid and anthracycline without specific central nervous system prophylaxis. Central nervous system relapse was significantly associated with high white blood cell counts and prior central nervous system hemorrhage, which emerged as independent prognostic factors.
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Potential curability of newly diagnosed acute promyelocytic leukemia without use of chemotherapy: the example of liposomal all-trans retinoic acid.
Estey, E, Koller, C, Tsimberidou, AM, O'Brien, S, Beran, M, Cortes, J, Tirado-Gomez, M, Lopez-Berestein, G, Kantarjian, H
Blood. 2005;(3):1366-7
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Use of arsenic trioxide (As2O3) in the treatment of patients with acute promyelocytic leukemia: the M. D. Anderson experience.
Lazo, G, Kantarjian, H, Estey, E, Thomas, D, O'Brien, S, Cortes, J
Cancer. 2003;(9):2218-24
Abstract
BACKGROUND Approximately 20-30% of patients with acute promyelocytic leukemia (APL) who are treated with all-trans retinoic acid (ATRA) and an anthracycline develop recurrent disease. It has been reported that arsenic trioxide (As(2)O(3)) is effective in this setting. The authors report the experience of The M. D. Anderson Cancer Center with As(2)O(3) in the treatment of patients with recurrent APL. METHODS Twelve patients who developed recurrent APL after treatment with ATRA were included. Patients received intravenous As(2)O(3) 0.15 mg/kg per day until they achieved a complete remission (CR) or up to a maximum of 60 days. Their median age was 44 years (range, 26-72 years), and the median duration of first remission was 52 weeks (range, 23-292 weeks). RESULTS All 12 patients achieved a CR. The median time to achieve CR was 52 days (range, 27-75 days). Seven of 10 evaluable patients achieved a molecular remission (i.e., polymerase chain reaction [PCR] analysis was negative for the gene encoding fusion of the nuclear receptor for retinoic acid to the PML gene at the time of CR; 70% of patients; 95% confidence interval, 0.35-0.93), and all other patients had negative PCR results after they received post-remission therapy. All patients received subsequent therapy: Four patients received As(2)O(3) alone, six patients received As(2)O(3) with other chemotherapeutic agents, and two patients received idarubicin plus ATRA without As(2)O(3). Eight patients continued in CR after a median follow-up of 24 months (range, 9-45 months). Side effects were mild, except for two patients who developed Grade 2 and 3 peripheral neuropathy, respectively; one of those patients required discontinuation of therapy. CONCLUSIONS As(2)O(3) is effective and well tolerated therapy for patients with recurrent APL. Molecular remission may be achieved at the time of CR in the majority of patients, and remissions are durable.
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Experience with gemtuzumab ozogamycin ("mylotarg") and all-trans retinoic acid in untreated acute promyelocytic leukemia.
Estey, EH, Giles, FJ, Beran, M, O'Brien, S, Pierce, SA, Faderl, SH, Cortes, JE, Kantarjian, HM
Blood. 2002;(11):4222-4
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We administered gemtuzumab ozogamycin ("mylotarg"; 9 mg/m(2) day 1 or 5) and all-trans retinoic acid (ATRA) to 19 patients with untreated acute promyelocytic leukemia (APL). There were 3 patients who also received idarubicin because of a white blood cell (WBC) count of more than 30 000/microL. In complete remission (CR), patients were to receive 8 courses of mylotarg (9 mg/m(2) every 4 to 5 weeks) and ATRA; idarubicin was added only for persistent or recurrent polymerase chain reaction (PCR) positivity. The CR rate was 16/19 (84%). All 12 patients tested to date were PCR-negative 2 to 4 months from CR date; none of the 7 patients evaluated subsequently have reverted to PCR positivity (median follow-up in CR was 5 months, up to 14 months). Mylotarg was well tolerated. A median of 5 post-CR courses have been given to date with 3 patients having currently received 8 post-CR courses, and 4 patients receiving 7 post-CR courses. Mylotarg appears active in APL, and repeated administration is feasible.
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Tetra-arsenic tetra-sulfide for the treatment of acute promyelocytic leukemia: a pilot report.
Lu, DP, Qiu, JY, Jiang, B, Wang, Q, Liu, KY, Liu, YR, Chen, SS
Blood. 2002;(9):3136-43
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In the past 6 years, we treated 129 patients who had acute promyelocytic leukemia (APL) with a new arsenic agent, oral tetra-arsenic tetra-sulfide (As(4)S(4)). Nineteen of the patients had newly diagnosed APL, 7 had first relapse, and 103 had hematologic complete remission (HCR). HCR was achieved in all patients with newly diagnosed APL and in all those with hematologic relapse. Of 16 patients with newly diagnosed disease and available cytogenetic and molecular analyses, 14 had cytogenetic and molecular complete remission (CR). Cytogenetic and molecular CR was also obtained in 5 of the 7 patients with hematologic relapse. In the HCR group, 35 of 44 patients positive for PML-RARalpha at baseline became negative. In the newly diagnosed group, estimated disease-free survival (DFS) rates for 1 and 3 years were 86.1% and 76.6%, respectively, with a median follow-up time of 13.5 months (range, 2-40 months). In the HCR group, DFS rates for 1 and 6 years were 96.7% and 87.4%, respectively, with a median follow-up of 23 months (range, 2-71 months). Treatment with As(4)S(4) was well tolerated, with only moderate side effects, including asymptomatic prolongation of corrected QT interval, transient elevation in liver enzyme levels, rash, and mild gastrointestinal discomfort; neither myelosuppression nor appreciable long-term side effects occurred. Degeneration or apoptosis of APL promyelocytes was observed during As(4)S(4) therapy. Pharmacokinetic studies showed that the agent was absorbed rapidly. Most urinary arsenic excretion occurred within the first 24 hours. Both blood and urinary arsenic levels declined after discontinuation of As(4)S(4). Our results show, for the first time, that As(4)S(4) treatment alone is highly effective and safe in both remission induction and maintenance therapy in patients with APL, regardless of disease stage.
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Sudden death among patients with acute promyelocytic leukemia treated with arsenic trioxide.
Westervelt, P, Brown, RA, Adkins, DR, Khoury, H, Curtin, P, Hurd, D, Luger, SM, Ma, MK, Ley, TJ, DiPersio, JF
Blood. 2001;(2):266-71
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Arsenic trioxide has been shown to be effective in treating acute promyelocytic leukemia (APL), with minimal overall toxicity reported to date. A phase I/II study was initiated in June 1998 using arsenic trioxide for relapsed APL to determine the maximum tolerated or minimal effective dose and to determine the efficacy of treatment at that dose. Ten patients received 1 to 4 monthly cycles of treatment with 0.1 mg/kg per day intravenous arsenic trioxide. Six of 7 patients evaluable for response achieved cytogenetic or molecular complete remission. However, 3 patients died suddenly during the first cycle of treatment. Autopsies obtained on 2 of these failed to identify a cause of sudden death, despite evidence of pulmonary hemorrhage in one. A third patient, for whom an autopsy was not performed, became asystolic and died while on continuous cardiac telemetry. These observations suggest that arsenic trioxide may be significantly or even fatally toxic at doses currently used and that caution is warranted in its use.