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Impact of arsenic trioxide in the treatment of acute promyelocytic leukemia

Abstract

Arsenic trioxide (ATO) is presently the most active single agent in the treatment of acute promyelocytic leukemia (APL). This review provides insights into the mode of action and the pharmacological properties of ATO, and summarizes the most relevant results of more than 20 treatment studies in relapsed or newly diagnosed APL published between 1997 and 2011. ATO acts by targeting multiple pathways in APL leading to apoptosis and myeloid differentiation. It induces complete remission without myelosuppression and causes only few adverse effects. In relapsed APL, ATO-based salvage therapy has been able to induce long-lasting remissions and possible cure in 50–81% of patients. In newly diagnosed APL, two main strategies are currently pursued. ATO is either included into induction therapy with the aim to minimize or eliminate chemotherapy, or it is incorporated as an additive into established first-line concepts with all-trans-retinoic acid and chemotherapy to reinforce their anti-leukemic efficacy. Recent results suggest a high efficacy of ATO in both concepts. In conclusion, experimental research and clinical studies have made contributions toward a better understanding of the molecular mechanisms induced by ATO in APL cells and have established this historic substance as an important candidate for the further improvement of APL therapy.

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References

  1. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnick HR et al. Proposals for the classification of acute leukaemias. Br J Haematol 1976; 33: 451–458.

    Article  CAS  PubMed  Google Scholar 

  2. Kakizuka A, Miller WH, Umesono K, Warrell RP, Frankel SR, Murty V et al. Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RARa with a novel putative transcription factor, PML. Cell 1991; 66: 663–674.

    CAS  PubMed  Google Scholar 

  3. Chen SJ, Zelent A, Tong JH, Yu HQ, Derré J, Berger R et al. Rearrangements of the retinoic acid receptor alpha and promyelocytic leukemia zinc finger genes resulting from t(11;17)(q23;q21) in a patient with acute promyelocytic leukemia. J Clin Invest 1993; 91: 2260–2267.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Tallman MS, Kwaan HC . Reassessing the hemostatic disorder associated with acute promyelocytic leukemia. Blood 1992; 79: 543–553.

    CAS  PubMed  Google Scholar 

  5. Huang M, Ye Y, Chen S, Chai S, Lu JX, Lin Z et al. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 1988; 72: 567–572.

    CAS  PubMed  Google Scholar 

  6. Grigniani F, Ferrucci PF, Testa U, Talamo G, Fagioli M, Alcalay M et al. The acute promyelocytic leukemia-specific PML-RARA fusion protein inhibits differentiation and promotes survival of myeloid precursor cells. Cell 1993; 74: 423–431.

    Google Scholar 

  7. Sanz M, Grimwade D, Tallman M, Lowenberg B, Fenaux P, Estey E et al. Guidelines on the management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2009; 113: 1875–1891.

    CAS  PubMed  Google Scholar 

  8. Lengfelder E, Saussele S, Weisser A, Büchner T, Hehlmann R . Treatment concepts of acute promyelocytic leukemia. Crit Rev Oncol Hematol 2005; 56: 261–274.

    PubMed  Google Scholar 

  9. Castagnola C, Lunghi M, Corso A, Tajana M, Zappasodi P, Dabusti M et al. Management of acute promyelocytic leukemia relapse in the ATRA era. Haematologica 1998; 83: 714–717.

    CAS  PubMed  Google Scholar 

  10. Thomas X, Dombret H, Cordonnier C, Pigneux A, Gardin C, Guerci A et al. Treatment of relapsing acute promyelocytic leukemia by all-trans retinoic acid therapy followed by timed sequential chemotherapy and stem cell transplantation. Leukemia 2000; 14: 1006–1013.

    CAS  PubMed  Google Scholar 

  11. Sanz MA, Labopin M, Gorin NC, de la Rubia J, Arcese W, Meloni G et al. Hemotopoietic stem cell transplantation for adults with acute promyelocytic leukemia in the ATRA era: a survey of the European Cooperative Group for Blood and Marrow Transplantation. Bone Marrow Transplant 2007; 39: 461–469.

    CAS  PubMed  Google Scholar 

  12. Doyle AC . Notes of a case of leukocythaemia. Lancet 1882; 119: 490.

    Google Scholar 

  13. Forkner CE, Scott TF . Arsenic as a therapeutic agent in chronic myelogenous leukemia. JAMA 1931; 97: 3–5.

    Google Scholar 

  14. Ghavamzadeh A, Alimoghaddam K, Ghaffari SH, Rostam S, Jahani M, Hosseini R et al. Treatment of acute promyelocytic leukemia with arsenic trioxide without ATRA and/or chemotherapy. Ann Oncol 2006; 17: 131–134.

    CAS  PubMed  Google Scholar 

  15. Mathews V, George B, Kavitha M, Lakshmi KM, Viswabandya A, Bajel A et al. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: durable remissions with minimal toxicity. Blood 2006; 107: 2627–2632.

    CAS  PubMed  Google Scholar 

  16. Miller Jr WH, Schipper HM, Lee JS, Singer J, Waxman S . Mechanisms of action of arsenic trioxide. Cancer Res 2002; 62: 3893–3903.

    CAS  PubMed  Google Scholar 

  17. Ablain J, de The H . Revisiting the differentiation paradigm in acute promyelocytic leukemia. Blood 2011; 117: 5795–5802.

    CAS  PubMed  Google Scholar 

  18. Chen GQ, Shi XG, Tang W, Xiong SM, Zhu J, Cai X et al. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): I. As2O3 exerts dose-dependent dual effects on APL cells. Blood 1997; 89: 3345–3353.

    CAS  PubMed  Google Scholar 

  19. Zhu J, Koken MH, Quignon F, Chelbi-Alix M, Degos L, Wang ZY et al. Arsenic-induced PML targeting onto nuclear bodies: implications for the treatment of acute promyelocytic leukemia. Proc Natl Acad Sci USA 1997; 94: 3978–3983.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Soignet SL, Maslak P, Wang ZG, Jhanwar S, Calleja E, Dardashti LJ et al. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med 1998; 339: 1341–1348.

    CAS  PubMed  Google Scholar 

  21. Chou WC, Hawkins AL, Barrett JF, Griffin CA, Dang CV . Arsenic inhibition of telomerase transcription leads to genetic instability. J Clin Invest 2001; 108: 1541–1547.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Roboz GJ, Dias S, Lam G, Lane WJ, Soignet SL, Warrell RP 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: 1525–1530.

    CAS  PubMed  Google Scholar 

  23. Goto E, Tomita A, Hayakawa F, Atsumi A, Kiyoi H, Naoe T . Missense mutations in PML-RARA critical for the lack of responsiveness to arsenic trioxide treatment. Blood 2011; 118: 1600–1609; e-pub ahead of print 25 May 2001; doi:10.1182/Blood-2011-01-329433.

    Article  CAS  PubMed  Google Scholar 

  24. Shen ZX, Chen GQ, Ni JH, Li XS, Xiong SM, Qiu QY 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: 3354–3360.

    CAS  PubMed  Google Scholar 

  25. Fujisawa S, Ohno R, Shigeno K, Sahara N, Nakamura S, Naito K et al. Pharmacokinetics of arsenic species in Japanese patients with relapsed or refractory acute promyelocytic leukemia treated with arsenic trioxide. Cancer Chemother Pharmacol 2007; 59: 485–493.

    CAS  PubMed  Google Scholar 

  26. Westervelt P, Brown A, Adkins DR, Khoury A, Curtin P, Hurd D et al. Sudden death among patients with acute promyelocytic leukemia treated with arsenic trioxide. Blood 2001; 98: 266–271.

    CAS  PubMed  Google Scholar 

  27. Wang Z, Zhou J, Lu X, Gong Z, Le XC . Arsenic speciation in urine from acute promyelocytic leukemia patients undergoing arsenic trioxide treatment. Chem Res Toxicol 2004; 17: 95–103.

    CAS  PubMed  Google Scholar 

  28. Sweeney J, Takimoto C, Wood L, Porter JM, Tracewell WG, Darwish M et al. A pharmacokinetic and safety study of intravenous arsenic trioxide in adult cancer patients with renal impairment. Cancer Chemother Pharmacol 2010; 66: 345–356.

    CAS  PubMed  Google Scholar 

  29. Au WY, Tam S, Fong BM, Kwong YL . Elemental arsenic entered the cerebrospinal fluid during oral arsenic trioxide treatment of meningeal relapse of acute promyelocytic leukemia. Blood 2006; 107: 3012–3013.

    CAS  PubMed  Google Scholar 

  30. Helwig A, Klemm M, Schüttig R, Röllig C, Wassilew N, Ehninger G et al. Arsenic-induced APL differentiation in cerebrospinal fluid. Leuk Res 2007; 31: 703–705.

    CAS  PubMed  Google Scholar 

  31. Knipp S, Gattermann N, Schapira M, Käferstein H, Germing U . Arsenic in the cerebrospinal fluid of a patient receiving arsenic trioxide for relapsed acute promyelocytic leukemia with CNS involvement. Leuk Res 2007; 31: 1585–1587.

    CAS  PubMed  Google Scholar 

  32. Au WY, Tam S, Fong BM, Kwong YL . Determinants of cerebrospinal fluid arsenic concentration in patients with acute promyelocytic leukemia on oral arsenic trioxide therapy. Blood 2008; 112: 3587–3590.

    CAS  PubMed  Google Scholar 

  33. Au WY, Chim CS, Lie AK, Liang R, Kwong YL . Combined arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia recurring from previous relapses successfully treated using arsenic trioxide. Br J Haematol 2002; 117: 130–132.

    CAS  PubMed  Google Scholar 

  34. Jing Y, Wang L, Xia L, Chen G, Chen Z, Miller WH et al. Combined effect of all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia cells in vitro and in vivo. Blood 2001; 97: 264–269.

    CAS  PubMed  Google Scholar 

  35. Shen ZX, Shi ZZ, Fang J, Gu BW, Li JM, Zhu YM 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 USA 2004; 101: 5328–5335.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Giannì M, Koken MH, Chelbi-Alix MK, Benoit G, Lanotte M, Chen Z et al. Combined arsenic and retinoic acid treatment enhances differentiation and apoptosis in arsenic-resistant NB4 cells. Blood 1998; 91: 4300–4310.

    PubMed  Google Scholar 

  37. Leung J, Pang A, Yuen WH, Kwong YL, Tse EW . Relationship of expression of aquaglyceroporin 9 with arsenic uptake and sensitivity in leukemic cells. Blood 2007; 109: 740–746.

    CAS  PubMed  Google Scholar 

  38. Zheng PZ, Wang KK, Zhang QY, Huang QH, Du YZ, Zhang QH et al. Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci USA 2005; 102: 7653–7658.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Jing Y, Dai J, Chalmers-Redman RM, Tatton WG, Waxman S . Arsenic trioxide selectively induces acute promyelocytic leukemia cell apoptosis via a hydrogen peroxide-dependent pathway. Blood 1999; 94: 2102–2111.

    CAS  PubMed  Google Scholar 

  40. Dai J, Weinberg RS, Waxman S, Jing Y . Malignant cells can be sensitized to undergo growth inhibition and apoptosis by arsenic trioxide through modulation of the glutathione redox system. Blood 1999; 93: 268–277.

    CAS  PubMed  Google Scholar 

  41. Bachleitner-Hofmann T, Gisslinger B, Grumbeck E, Gisslinger H . Arsenic trioxide and ascorbic acid: synergy with potential implications for the treatment of acute myeloid leukaemia? Br J Haematol 2001; 112: 783–786.

    CAS  PubMed  Google Scholar 

  42. Unnikrishnan D, Dutcher JP, Varshneya N, Lucariello R, Api M, Garl S et al. Torsades de pointes in 3 patients with leukemia treated with arsenic trioxide. Blood 2001; 97: 1514–1516.

    CAS  PubMed  Google Scholar 

  43. Zhang P, Wang S, Hu L, Qui F, yang H, Xiao Y et al. Seven years’ summary report on the treatment of acute promyelocytic leukemia with arsenic trioxide—an analysis of 242 cases. Zhonghua Xue Ye Xue Za Zhi 2000; 21: 67–70.

    PubMed  Google Scholar 

  44. Soignet SL, Frankel SR, Douer D, Tallman M, Kantarjian H, Calleja E et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol 2001; 19: 3852–3860.

    CAS  PubMed  Google Scholar 

  45. Niu C, Yan H, Yu T, Sun HP, Liu JX, Li XS et al. Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients. Blood 1999; 94: 3315–3324.

    CAS  PubMed  Google Scholar 

  46. Shen Y, Shen ZX, Yan H, Chen J, Zeng XY, Li JM et al. Studies on the clinical efficacy and pharmacokinetics of low-dose arsenic trioxide in the treatment of relapsed acute promyelocytic leukemia: a comparison with conventional dosage. Leukemia 2001; 15: 735–741.

    CAS  PubMed  Google Scholar 

  47. Kwong YL, Au WY, Chim CS, Pang A, Suen C, Liang R . Arsenic trioxide- and idarubicin-induced remissions in relapsed acute promyelocytic leukaemia: clinicopathological and molecular features of a pilot study. Am J Hematol 2001; 66: 274–279.

    CAS  PubMed  Google Scholar 

  48. Leoni F, Gianfaldoni G, Annunziata M, Fanci R, Ciolli S, Nozzoli C et al. Arsenic trioxide therapy for relapsed acute promyelocytic leukemia: a bridge to transplantation. Haematologica 2002; 87: 485–489.

    CAS  PubMed  Google Scholar 

  49. Ohnishi K, Yoshida H, Shigeno K, Nakamura S, Fujisawa S, Naito K et al. Arsenic trioxide therapy for relapsed or refractory Japanese patients with acute promyelocytic leukemia: need for careful electrocardiogram monitoring. Leukemia 2002; 16: 617–622.

    CAS  PubMed  Google Scholar 

  50. Lazo G, Kantarjian H, Estey E, Thomas D, O’Brien S, Cortes J . Use of arsenic trioxide (As2O3) in the treatment of patients with acute promyelocytic leukemia: the MD Anderson experience. Cancer 2003; 97: 2218–2224.

    CAS  PubMed  Google Scholar 

  51. Raffoux E, Rousselot P, Poupon J, Daniel MT, Cassinat B, Delarue R et al. Combined treatment with arsenic trioxide and all-trans-retinoic acid in patients with relapsed acute promyelocytic leukemia. J Clin Oncol 2003; 21: 2326–2334.

    CAS  PubMed  Google Scholar 

  52. Carmosino I, Latagliata R, Avvisati G, Breccia M, Finalezzi E, Lo-Coco F et al. Arsenic trioxide in the treatment of advanced acute promyelocytic leukemia. Haematologica 2004; 89: 615–617.

    CAS  PubMed  Google Scholar 

  53. Shigeno K, Naito K, Sahara N, Kobayashi M, Nakamura S, Fujisawa S et al. Arsenic trioxide therapy in relapsed or refractory Japanese patients with acute promyelocytic leukemia: updated outcomes of the phase II study and postremission therapies. Int J Hematol 2005; 82: 224–229.

    CAS  PubMed  Google Scholar 

  54. Thomas X, Pigneux A, Raffoux E, Huguet F, Caillot D, Fenaux P . Superiority of an arsenic trioxide-based regimen over a historic control combining all-trans retinoic acid plus intensive chemotherapy in the treatment of relapsed acute promyelocytic leukemia. Haematologica 2006; 91: 996–997.

    CAS  PubMed  Google Scholar 

  55. Aribi A, Kantarjian HM, Estey EH, Koller CA, Thomas DA, Kornblau SA et al. Combination therapy with arsenic trioxide, all-trans retinoic acid, and gemtuzumab ozogamicin in recurrent acute promyelocytic leukemia. Cancer 2007; 109: 1355–1359.

    CAS  PubMed  Google Scholar 

  56. Alimoghaddam K, Ghavamzadeh A, Jahani M, Mousavi A, Iravani M, Rostami S et al. Treatment of relapsed acute promyelocytic leukemia by arsenic trioxide in Iran. Arch Iran Med 2011; 14: 167–169.

    CAS  PubMed  Google Scholar 

  57. Douer D, Tallman MS . Arsenic trioxide: new clinical experience with an old medication in hematologic malignancies. J Clin Oncol 2005; 23: 2396–2410.

    CAS  PubMed  Google Scholar 

  58. Douer D, Hu W, Giralt S, Lill M, DiPersio J . Arsenic trioxide (trisenox) therapy for acute promyelocytic leukemia in the setting of hematopoietic stem cell transplantation. Oncologist 2003; 8: 132–140.

    CAS  PubMed  Google Scholar 

  59. Breccia M, Cicconi L, Minotti C, Latagliata R, Gianni L, Lo-Coco F . Efficacy of prolonged therapy with combined arsenic trioxide and ATRA for relapse of acute promyelocytic leukemia. Haematologica 2011; e-pub ahead of print 9 June 2011; doi:10.3324/haematol.2011.045500.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Thirugnanam R, George B, Chendamarai E, Lakshmi KM, Balasubramanian P, Viswabandya A et al. Comparison of clinical outcomes of patients with relapsed acute promyelocytic leukemia induced with arsenic trioxide and consolidated with either an autologous stem cell transplant or an arsenic trioxide-based regimen. Biol Blood Marrow Transplant 2009; 11: 1479–1484.

    Google Scholar 

  61. Au W, Lie A, Chim C, Liang R, Ma SK, Chan CH et al. Arsenic trioxide in comparison with chemotherapy and bone marrow transplantation for the treatment of relapsed acute promyelocytic leukaemia. Ann Oncol 2003; 14: 752–757.

    CAS  PubMed  Google Scholar 

  62. Grigg A, Kimber R, Szer J . Prolonged molecular remission after arsenic trioxide and all-trans retinoic acid for acute promyelocytic leukemia relapsed after allogeneic stem cell transplantation. Leukemia 2003; 17: 1916–1917.

    CAS  PubMed  Google Scholar 

  63. De Botton S, Sanz MA, Chevret S, Dombret H, Martin G, Thomas X et al. Extramedullary relapse in acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy. Leukemia 2006; 20: 35–41.

    CAS  PubMed  Google Scholar 

  64. Specchia G, Lo Coco F, Vignetti M, Avvisati G, Fazi P, Albano F et al. Extramedullary involvement at relapse in acute promyelocytic leukemia patients treated or not with all-trans retinoic acid: a report by the Gruppo Italiano Malattie Ematologiche dell’Adulto. J Clin Oncol 2001; 19: 4023–4028.

    CAS  PubMed  Google Scholar 

  65. Housman E, Chang P, Lane SW, Blinder R, Galinsky I, Kesari S et al. CNS relapse in acute promyeloctyic leukemia. J Clin Oncol 2010; 28: 409–411.

    Google Scholar 

  66. Tsimberidou AM, Estey E, Whitman GJ, Dryden M, Ratnam S, Pierce S et al. Extramedullary relapse in a patient with acute promyelocytic leukemia: successful treatment with arsenic trioxide, all-trans retinoic acid and gemtuzumab ozogamicin therapies. Leuk Res 2004; 28: 991–994.

    PubMed  Google Scholar 

  67. Kai T, Kimura H, Shiga Y, Ogawa K, Sato H, Maruyama Y . Recurrent extramedullary relapse of acute promyelocytic leukemia after allogeneic stem cell transplantation: successful treatment by arsenic trioxide in combination with local radiotherapy. Int J Hematol 2006; 83: 337–340.

    PubMed  Google Scholar 

  68. Estey E, Garcia-Manero G, Ferrajoli A, Faderl S, Verstovsek S, Jones D et al. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood 2006; 107: 3469–3473.

    CAS  PubMed  Google Scholar 

  69. Ravandi F, Estey E, Jones D, Faderl S, O’Brien S, Fiorentino J et al. Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol 2009; 27: 504–510.

    CAS  PubMed  Google Scholar 

  70. Ghavamzadeh A, Alimoghaddam K, Rostami S, Ghaffari SH, Jahani M, Iravani M et al. Phase II study of single-agent arsenic trioxide for the front-line therapy of acute promyelocytic leukemia. J Clin Oncol 2011; 29: 2753–2757.

    CAS  PubMed  Google Scholar 

  71. Mathews V, George B, Chendamarai E, Lakshmi KM, Desire S, Balasubramanian P et al. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: long-term follow-up data. J Clin Oncol 2010; 28: 3866–3871.

    CAS  PubMed  Google Scholar 

  72. Hu J, Liu YF, Wu CF, Xu F, Shen ZX, Zhu YM et al. Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci USA 2009; 106: 3342–3347.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM 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: 3751–3757.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Gore SD, Gojo I, Sekeres MA, Morris L, Devetten M, Jamieson K et al. Single cycle of arsenic trioxide-based consolidation chemotherapy spares anthracycline exposure in the primary management of acute promyelocytic leukemia. J Clin Oncol 2010; 28: 1047–1053.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Ades L, Raffoux E, Chevret S, Pigneux A, Thomas X, Bordessoule D et al. Arsenic trioxide (ATO) in the consolidation treatment of newly diagnosed APL—first interim analysis of a randomized trial (APL 2006) by the French Belgian Swiss APL group. Blood (ASH Annual Meeting Abstracts) 2010; 116: Abstract 505.

  76. Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E et al. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French–Belgian–Swiss and PETHEMA results. Blood 2008; 111: 1078–1084.

    PubMed  Google Scholar 

  77. Lengfelder E, Haferlach C, Saussele S, Haferlach T, Schultheis B, Schnittger S et al. High dose ara-C in the treatment of newly diagnosed acute promyelocytic leukemia: long-term results of the German AMLCG. Leukemia 2009; 23: 2248–2258.

    CAS  PubMed  Google Scholar 

  78. Sanz MA, Montesinos P, Rayón C, Holowieckia A, de la Serna J, Milone G 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: 5137–5146.

    CAS  PubMed  Google Scholar 

  79. Lo-Coco F, Avvisati G, Vignetti M, Breccia M, Gallo E, Rambaldi A et al. 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: 3171–3179.

    CAS  PubMed  Google Scholar 

  80. Frankel SR, Eardley A, Lauwers G, Weiss M, Warrell RP . The ‘retinoic acid syndrome’ in acute promyelocytic leukemia. Ann Intern Med 1992; 117: 292–296.

    CAS  PubMed  Google Scholar 

  81. Camacho LH, Soignet SL, Chanel S, Ho R, Heller G, Scheinberg DA et al. Leukocytosis and the retinoic acid syndrome in patients with acute promyelocytic leukemia treated with arsenic trioxide. J Clin Oncol 2000; 18: 2620–2625.

    CAS  PubMed  Google Scholar 

  82. Arnould C, Philippe C, Bourdon V, Grégoire MJ, Berger R, Jonveaux P . The signal transducer and activator of transcription STAT5b gene is a new partner of retinoic acid receptor alpha in acute promyelocytic-like leukaemia. Hum Mol Genet 1999; 8: 1741–1749.

    CAS  PubMed  Google Scholar 

  83. Wells RA, Catzavelos C, Kamel-Reid S . Fusion of retinoic acid receptor a to NuMA, the nuclear mitotic apparatus protein, by a variant translocation in acute promyelocytic leukemia. Nat Genet 1997; 17: 109–113.

    CAS  PubMed  Google Scholar 

  84. Redner RL, Rush EA, Faas S, Rudert WA, Corey SJ . The t(5;17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor fusion. Blood 1996; 87: 882–886.

    CAS  PubMed  Google Scholar 

  85. Kondo T, Mori A, Darmanin S, Hashino S, Tanaka J, Asaka M . The seventh pathogenic fusion gene FIP1L1-RARA was isolated from a t(4;17)-positive acute promyelocytic leukemia. Haematologica 2008; 93: 1414–1416.

    CAS  PubMed  Google Scholar 

  86. Chen Y, Gu L, Zhou C, Wu X, Gao J, Li Q et al. Relapsed APL patient with variant NPM-RARalpha fusion responded to arsenic trioxide-based therapy and achieved long-term survival. Int J Hematol 2010; 91: 708–710.

    PubMed  Google Scholar 

  87. Koken MH, Daniel MT, Gianni M, Zelent A, Licht J, Buzyn A et al. Retinoic acid, but not arsenic trioxide, degrades the PLZF/RARalpha fusion protein, without inducing terminal differentiation or apoptosis, in a RA-therapy resistant t(11;17)(q23;q21) APL patient. Oncogene 1999; 18: 1113–1118.

    CAS  PubMed  Google Scholar 

  88. Zhou J, Zhang Y, Li J, Li X, Hou J, Zhao Y et al. Single-agent arsenic trioxide in the treatment of children with newly diagnosed acute promyelocytic leukemia. Blood 2010; 115: 1697–1702.

    CAS  PubMed  Google Scholar 

  89. Sham RL, Tallman MS . Treatment of acute promyelocytic leukemia in the very elderly: case report and review of the literature. Leuk Res 2004; 28: 1347–1350.

    PubMed  Google Scholar 

  90. Lo-Coco F, Diverio D, Avvisati G, Petti MC, Meloni G, Pogliani EM et al. Therapy of molecular relapse in acute promyelocytic leukemia. Blood 1999; 94: 2225–2229.

    CAS  PubMed  Google Scholar 

  91. Lo-Coco F, Romano A, Mengarelli A . Allogeneic stem cell transplantation for advanced acute promyelocytic leukemia: results in patients treated in second molecular remission or with molecularly persistent disease. Leukemia 2003; 17: 1930–1933.

    CAS  PubMed  Google Scholar 

  92. Kohno A, Morishita Y, Iida H, Yanada M, Uchida T, Hamaguchi M et al. Hematopoietic stem cell transplantation for acute promyelocytic leukemia in second or third complete remission: a retrospective analysis in the Nagoya Blood and Marrow Transplantation Group. Int J Hematol 2008; 87: 210–216.

    PubMed  Google Scholar 

  93. Lengfelder E, Lo-Coco F, Montesinos P, Grimwade D, Ades L, Kishore B et al. Treatment of molecular and clinical relapse of acute promyelocytic leukemia (APL) with arsenic trioxide: results of the European Registry of Relapsed APL. Blood (ASH Annual Meeting Abstracts) 2010; 116: Abstract 15.

  94. Grimwade D, Jovanovic JV, Hills RK, Nugent EA, Patel J, Flora R et al. Prospective minimal residual disease monitoring to predict relapse of acute promyelocytic leukemia and to direct pre-emptive arsenic trioxide therapy. J Clin Oncol 2009; 27: 3650–3658.

    CAS  PubMed  Google Scholar 

  95. Lehmann S, Ravn A, Carlsson L, Antunovic P, Deneberg S, Möllgård L et al. Continuing high early death rate in acute promyelocytic leukemia: a population-based report from the Swedish Adult Acute Leukemia Registry. Leukemia 2011; 25: 1128–1134.

    CAS  PubMed  Google Scholar 

  96. Park JH, Panageas KS, Schymura MJ, Qiao B, Jurcic JG, Todd L et al. A population-based study in acute promyelocytic leukemia (APL) suggests a higher early death rate and lower overall survival than commonly reported in clinical trials: data from the surveillance, epidemiology, and end results (SEER) program and the New York state cancer registry in the United States between 1992–2007. Blood (ASH Annual Meeting Abstracts) 2010; 116: Abstract 872.

  97. Micol JB, Raffoux E, Boissel N, Lengliné E, Canet E, Leblanc T et al. Do early events excluding patients with acute promyelocytic leukemia (APL) from trial enrollment modify treatment result evaluation? Real-life management of 100 patients referred to the university hospital Saint-Louis between 2000 and 2010. Blood (ASH Annual Meeting Abstracts) 2010; 116: Abstract 1083.

  98. Sanz MA, Lo-Coco F, Martin G, Avvisati G, Rayón C, Barbui T et al. Definition of relapse risk and role of non-anthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups. Blood 2000; 96: 1247–1252.

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Correspondence to E Lengfelder.

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Eva Lengfelder has received research funding from CEPHALON. Wolf-Karsten Hofmann and Daniel Nowak have no conflict of interest to disclose.

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Lengfelder, E., Hofmann, WK. & Nowak, D. Impact of arsenic trioxide in the treatment of acute promyelocytic leukemia. Leukemia 26, 433–442 (2012). https://doi.org/10.1038/leu.2011.245

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