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Characteristics of fibrinolytic disorders in acute promyelocytic leukemia.
Wang, P, Zhang, Y, Yang, H, Hou, W, Jin, B, Hou, J, Li, H, Zhao, H, Zhou, J
Hematology (Amsterdam, Netherlands). 2018;(10):756-764
Abstract
OBJECTIVES Catastrophic hemorrhage remains the main cause of acute promyelocytic leukemia (APL) treatment failure. This study was aimed to study the pathogenesis of coagulopathy in patients with APL. METHODS Multiple procoagulant and profibrinolytic parameters in plasma and peripheral leukocytes from 24 patients with newly diagnosed APL accompanied by coagulopathy before and after arsenic trioxide (ATO) treatment were evaluated. RESULTS Prior to the treatment, the patients had elevated D-dimer and decreased fibrinogen levels. Plasma urokinase-type plasminogen activator receptor (uPAR) and plasmin-ɑ2 antiplasmin complexes (PAP) levels, plasmin (Pn) activity, and cell surface levels of urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) were significantly higher; plasma plasminogen activator inhibitor-1 (PAI-1) levels and plasminogen (Pg) activity were significantly decreased; plasma plasminogen activator (PA) activity, uPA and tPA levels; and cell surface levels of uPAR and annexin II were not significantly different from levels in the control group. During ATO treatment, both patients' plasma PA activity and uPAR on leukocytes gradually increased, annexin II on leukocytes increased initially and decreased afterwards, and tPA and uPA on leukocytes remained consistently higher in the patients than in the controls. Other parameters gradually tended toward normal values. CONCLUSIONS In APL, activated coagulation system activated fibrinolytic system, and increased uPAR levels could contribute to the hyperfibrinolysis. Annexin II might not be involved in the coagulopathy.
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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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Arsenic trioxide suppressed mantle cell lymphoma by downregulation of cyclin D1.
Lo, RK, Kwong, YL
Annals of hematology. 2014;(2):255-65
Abstract
Mantle cell lymphoma (MCL) is aggressive with poor prognosis. Due to t(11;14)(q13;q32), cyclin D1 is overexpressed. The in vitro activities of arsenic trioxide (As2O3) in MCL were investigated. In MCL lines Jeko-1 and Granta-519, As2O3 induced dose-dependent and time-dependent increases in apoptosis accompanied by cyclin D1 suppression. Downregulation of cyclin D1 resulted in decreased retinoblastoma protein phosphorylation, which led to repressed G1 progression to S/G2 phases. As2O3 did not affect cyclin D1 gene transcription. Instead, As2O3 activated glycogen synthase kinase-3beta (by tyrosine-216 phosphorylation) and IkappaB kinase alpha/beta (by serine-176/180 phosphorylation), both of which phosphorylated cyclin D1 at threonine-286, leading to its poly-ubiquitination and degradation in the proteasome. These observations were recapitulated partly in primary MCL samples obtained from patients refractory to conventional treatment. Our findings suggested that As2O3 might be clinically useful in MCL.
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Adding ascorbic acid to arsenic trioxide produces limited benefit in patients with acute myeloid leukemia excluding acute promyelocytic leukemia.
Aldoss, I, Mark, L, Vrona, J, Ramezani, L, Weitz, I, Mohrbacher, AM, Douer, D
Annals of hematology. 2014;(11):1839-43
Abstract
Arsenic trioxide (ATO) is highly effective in acute promyelocytic leukemia (APL), but despite its multiple mechanism of action, it has no activity in acute myeloid leukemia (AML) that excludes APL (non-APL AML). Ascorbic acid (AA) and ATO induces apoptosis in AML cell lines by depleting intracellular glutathione and generation of reactive oxygen species. In this study, we evaluated the effect of ATO plus AA in patients with non-APL AML. The study enrolled patient aged 18 or older with relapsed or refractory AML (non-APL) after conventional chemotherapy or previously untreated patients 55 years or older who were unfit for standard induction chemotherapy for AML. Intravenous ATO (0.25 mg/kg/day over 1-4 h) was given with intravenous AA (1 g/day over 30 min after ATO) for 5 days a week for 5 weeks (25 doses). Eleven AML patients were enrolled, including six previously untreated elderly patients aged 66-84 years in whom five had antecedent hematological disorder (ADH). Among 10 evaluable patients, one achieved a CR one a CRi and 4 patients had disappearance of blasts from peripheral blood and bone marrow. Five of the six responders were seen in previously untreated elderly patients. ATO related toxicity was mild. The combination of ATO and AA has limited clinical meaningful antileukemia activity in patients with non-APL AML.
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Arsenic trioxide in front-line therapy of acute promyelocytic leukemia (C9710): prognostic significance of FLT3 mutations and complex karyotype.
Poiré, X, Moser, BK, Gallagher, RE, Laumann, K, Bloomfield, CD, Powell, BL, Koval, G, Gulati, K, Holowka, N, Larson, RA, et al
Leukemia & lymphoma. 2014;(7):1523-32
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The addition of arsenic trioxide (ATO) to frontline therapy of acute promyelocytic leukemia (APL) has been shown to result in significant improvements in disease-free survival (DFS). FLT3 mutations are frequently observed in APL, but its prognostic significance remains unclear. We analyzed 245 newly diagnosed adult patients with APL treated on intergroup trial C9710 and evaluated previously defined biological and prognostic factors and their relationship to FLT3 mutations and to additional karyotypic abnormalities. FLT3 mutations were found in 48% of patients, including 31% with an internal tandem duplication (FLT3-ITD), 14% with a point mutation (FLT3-D835) and 2% with both mutations. The FLT3-ITD mutant level was uniformly low, < 0.5. Neither FLT3 mutation had an impact on remission rate, induction death rate, DFS or overall survival (OS). The addition of ATO consolidation improved outcomes regardless of FLT3 mutation type or level, initial white blood cell count, PML-RARA isoform type or transcript level. The presence of a complex karyotype was strongly associated with an inferior OS independently of post-remission treatment. In conclusion, the addition of ATO to frontline therapy overcomes the impact of previously described adverse prognostic factors including FLT3 mutations. However, complex karyotype is strongly associated with an inferior OS despite ATO therapy.
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Randomized phase III trial of retinoic acid and arsenic trioxide versus retinoic acid and chemotherapy in patients with acute promyelocytic leukemia: health-related quality-of-life outcomes.
Efficace, F, Mandelli, F, Avvisati, G, Cottone, F, Ferrara, F, Di Bona, E, Specchia, G, Breccia, M, Levis, A, Sica, S, et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2014;(30):3406-12
Abstract
PURPOSE A randomized clinical trial compared efficacy and toxicity of standard all-trans-retinoic acid (ATRA) plus chemotherapy versus ATRA plus arsenic trioxide in patients with newly diagnosed, low- or intermediate-risk acute promyelocytic leukemia (APL). Here, we report health-related quality-of-life (HRQOL) results. PATIENTS AND METHODS HRQOL was a secondary end point of this trial. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 was used to assess HRQOL at end of induction and after consolidation therapy. All analyses were based on 156 patients who received at least one dose of treatment, with groups defined according to randomly assigned treatment. Primary analysis was performed, estimating mean HRQOL score over time and differences between treatment arms using a linear mixed model. RESULTS Overall, 162 patients age 18 to 70 years were enrolled. Of these, 150 and 142 patients were evaluable for HRQOL after induction therapy and third consolidation course, respectively. Overall compliance with HRQOL forms was 80.1%. The largest difference, favoring patients treated with ATRA plus arsenic trioxide, was found for fatigue severity (mean score difference, -9.3; 95% CI, -17.8 to -0.7; P = .034) at end of induction therapy. This difference was also clinically relevant. HRQOL differences between treatment arms at end of consolidation showed that for several scales, differences between treatment arms were marginal. CONCLUSION Overall, current HRQOL findings further support the use of ATRA plus arsenic trioxide as preferred first-line treatment in patients with low- or intermediate-risk APL.
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Phase 2 study of arsenic trioxide followed by autologous hematopoietic cell transplantation for relapsed acute promyelocytic leukemia.
Yanada, M, Tsuzuki, M, Fujita, H, Fujimaki, K, Fujisawa, S, Sunami, K, Taniwaki, M, Ohwada, A, Tsuboi, K, Maeda, A, et al
Blood. 2013;(16):3095-102
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The optimal treatments for relapsed acute promyelocytic leukemia (APL) remain equivocal. We conducted a phase 2 study to evaluate the efficacy and feasibility of a sequential treatment consisting of induction and consolidation with arsenic trioxide (ATO), peripheral blood stem cell (PBSC) harvest after high-dose cytarabine chemotherapy, and autologous hematopoietic cell transplantation (HCT). Between 2005 and 2009, 35 patients (26 with hematologic and 9 with molecular relapse) were enrolled. Induction therapy resulted in complete remission in 81% of those with hematologic relapse, and most patients became negative for PML-RARα after the first ATO consolidation course, but 4 remained positive. Administration of the second ATO consolidation course further decreased the transcript levels in 3 patients. In total, 25 patients proceeded to PBSC harvest, all of whom successfully achieved the target CD34+ cell doses, and 23 underwent autologous HCT with PML-RARα-negative PBSC graft. Posttransplant relapse occurred in 3 patients, and there was no transplant-related mortality. With a median follow-up of 4.9 years, the 5-year event-free and overall survival rates were 65% and 77%, respectively. These findings demonstrate the outstanding efficacy and feasibility of the sequential treatment featuring ATO and autologous HCT for relapsed APL. This study was registered at http://www.umin.ac.jp/ctr/ as #C000000302.
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Allogeneic stem cell transplantation for advanced acute promyelocytic leukemia in the ATRA and ATO era.
Ramadan, SM, Di Veroli, A, Camboni, A, Breccia, M, Iori, AP, Aversa, F, Cupelli, L, Papayannidis, C, Bacigalupo, A, Arcese, W, et al
Haematologica. 2012;(11):1731-5
Abstract
The role of allogeneic stem cell transplant in advanced acute promyelocytic leukemia patients who received standard first- and second-line therapy is still unknown. We report the outcome of 31 acute promyelocytic leukemia patients (median age 39 years) who underwent allogeneic transplant in second remission (n=15) or beyond (n=16). Sixteen patients were real-time polymerase chain reaction positive and 15 negative for PML/RARA pre-transplant. The 4-year overall survival was 62% and 31% for patients transplanted in second remission and beyond, respectively (P=0.05), and 64% and 27% for patients with pre-transplant negative and positive real-time polymerase chain reaction, respectively (P=0.03). The 4-year cumulative incidence of relapse was 32% and 44% for patients transplanted in second remission and beyond, respectively (P=0.37), and 30% and 47% for patients transplanted with negative and positive real-time polymerase chain reaction, respectively (P=0.30). Transplant-related mortality was 19.6%. In conclusion, allogeneic transplant is effective in advanced acute promyelocytic leukemia in the all-trans-retinoic acid and arsenic trioxide era, and should be considered once relapse is diagnosed.