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Contemporary Treatment of APL

  • Acute Leukemias (R Stone, Section Editor)
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Abstract

Acute promyelocytic leukemia (APL) is characterized by coagulopathy, leukopenic presentation and sensitivity to anthracyclines, all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). For the last 25 years, APL has been treated with a combination of ATRA and chemotherapy for induction followed by consolidation and maintenance therapy. This general treatment approach has resulted in cure rates of 80–90 %. ATO, originally approved in relapsed APL, has been incorporated into contemporary upfront treatment regimens with excellent response rates. Recent studies show that most patients with APL can be cured with ATRA and ATO alone, eliminating cytotoxic chemotherapy and resulting in superior outcomes compared to standard treatment. We will herein review historical treatment of APL, treatment considerations in specific patient populations, and therapeutic updates.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Douer D. The epidemiology of acute promyelocytic leukemia. Balliere’s Best Pract Clin Hematol. 2003;16:357–67.

    Article  Google Scholar 

  2. Estey E, Thall P, Kantarjian H, et al. Association between increased body mass index and a diagnosis of acute promyelocytic leukemia in patients with acute myeloid leukemia. Leukemia. 1997;11:1661–4.

    Article  CAS  PubMed  Google Scholar 

  3. Scaglioni PP, Pandolfi PP. The theory of APL revisited. Curr Top Microbiol Immunol. 2007;313:85–100.

    CAS  PubMed  Google Scholar 

  4. Huang ME, Ye YC, Chen SR, et al. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood. 1988;72:567–72.

    CAS  PubMed  Google Scholar 

  5. Castaigne S, Chomienne C, Daniel MT, et al. All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clinical results. Blood. 1990;76:1704–9.

    CAS  PubMed  Google Scholar 

  6. Warrell Jr RP, Frankel SR, Miller Jr WH, et al. Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid). N Engl J Med. 1991;324:1385–93.

    Article  PubMed  Google Scholar 

  7. Chen ZX, Xue YQ, Zhang R, et al. A clinical and experimental study on all-trans retinoic acid-treated acute promyelocytic leukemia patients. Blood. 1991;78:1413–9.

    CAS  PubMed  Google Scholar 

  8. Fenaux P, Castaigne S, Dombret H, et al. All-transretinoic acid followed by intensive chemotherapy gives a high complete remission rate and may prolong remissions in newly diagnosed acute promyelocytic leukemia: a pilot study on 26 cases. Blood. 1992;80:2176–81.

    CAS  PubMed  Google Scholar 

  9. Kanamaru A, Takemoto Y, Tanimoto M, et al. All-trans retinoic acid for the treatment of newly diagnosed acute promyelocytic leukemia. Japan Adult Leukemia Study Group. Blood. 1995;85:1202–6.

    CAS  PubMed  Google Scholar 

  10. Tallman MS, Andersen JW, Schiffer CA, et al. All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med. 1997;337:1021–8.

    Article  CAS  PubMed  Google Scholar 

  11. Tallman MS, Nabhan C, Feusner JH, Rowe JM. Acute promyelocytic leukemia: evolving therapeutic strategies. Blood. 2002;99:759–67.

    Article  CAS  PubMed  Google Scholar 

  12. Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013;369:111–21. Phase III trial that randomized standard risk patients with APL to treatment with ATRA/chemotherapy vs. ATRA/ATO. Results showed non-inferiority of ATRA/ATO regimen compared to ATRA/chemotherapy.

    Article  CAS  PubMed  Google Scholar 

  13. Fenaux P, Chastang C, Chevret S, et al. A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood. 1999;94:1192–200.

    CAS  PubMed  Google Scholar 

  14. Mandelli F, Diverio D, Avvisati G, et al. Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto and Associazione Italiana di Ematologia ed Oncologia Pediatrica Cooperative Groups. Blood. 1997;90:1014–21.

    CAS  PubMed  Google Scholar 

  15. Sanz MA, Martin G, Rayon C, et al. A modified AIDA protocol with anthracycline-based consolidation results in high antileukemic efficacy and reduced toxicity in newly diagnosed PML/RARalpha-positive acute promyelocytic leukemia. PETHEMA group. Blood. 1999;94:3015–21.

    CAS  PubMed  Google Scholar 

  16. Fenaux P, Le Deley MC, Castaigne S, et al. Effect of all transretinoic acid in newly diagnosed acute promyelocytic leukemia. Results of a multicenter randomized trial. European APL 91 Group. Blood. 1993;82:3241–9.

    CAS  PubMed  Google Scholar 

  17. Ades L, Sanz MA, Chevret S, et al. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008;111:1078–84.

    Article  CAS  PubMed  Google Scholar 

  18. Sanz MA, Lo Coco F, Martin G, et al. Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups. Blood. 2000;96:1247–53.

    CAS  PubMed  Google Scholar 

  19. Sanz MA, Martin G, Gonzalez M, et al. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood. 2004;103:1237–43.

    Article  CAS  PubMed  Google Scholar 

  20. Ades L, Chevret S, Raffoux E, et al. Is cytarabine useful in the treatment of acute promyelocytic leukemia? Results of a randomized trial from the European Acute Promyelocytic Leukemia Group. J Clin Oncol. 2006;24:5703–10.

    Article  CAS  PubMed  Google Scholar 

  21. Nasr R, Guillemin MC, Ferhi O, et al. Eradication of acute promyelocytic leukemia-initiating cells through PML-RARA degradation. Nat Med. 2008;14:1333–42.

    Article  CAS  PubMed  Google Scholar 

  22. Niu C, Yan H, Yu T, 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;94:3315–24.

    CAS  PubMed  Google Scholar 

  23. Soignet SL, Frankel SR, Douer D, et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol. 2001;19:3852–60.

    CAS  PubMed  Google Scholar 

  24. Estey E, Garcia-Manero G, Ferrajoli A, et al. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood. 2006;107:3469–73.

    Article  CAS  PubMed  Google Scholar 

  25. Iland HJ, Bradstock K, Supple SG, et al. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood. 2012;120:1570–80. They used a consolidation regimen of ATO/ATRA, eliminating chemotherapy from the consolidation phase and reported excellent response rates and OS.

    Article  CAS  PubMed  Google Scholar 

  26. Powell BL, Moser B, Stock W, et al. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010;116:3751–7. They added ATO to the consolidation phase and reported improved outcomes, particularly in high risk APL patients.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Ravandi F, Estey E, Jones D, et al. Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol. 2009;27:504–10.

    Article  CAS  PubMed  Google Scholar 

  28. Shen ZX, Shi ZZ, Fang J, 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 U S A. 2004;101:5328–35.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Iland HJ CM, Seymour J. The Australasian Leukaemia and lymphoma group APML4 trial - update on APL treatment down under [abstract]. In: 6th International Symposium on Acute Promyelocytic Leukemia Abstract Book 2013 Sept 29-Oct 2; Rome, Italy.

  30. National Comprehensive Cancer Network. Acute Myeloid Leukemia version 2.2013. http://www.nccn.org/professionals/physician_gls/pdf/aml.pdf.

  31. Sanz MA, Montesinos P, Rayon C, 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;115:5137–46.

    Article  CAS  PubMed  Google Scholar 

  32. Coutre S OM, Powell B, et al. A phase III randomized trial (S0521) of maintenance versus observation for patients with previously untreated low/intermediate risk acute promyelocytic leukemia. In: 6th International Symposium on Acute Promyelocytic Leukemia Abstract Book 2013 Sept 29-Oct 2. Phase III randomized trial that compared maintenance therapy to no maintenance therapy in standard risk patients and reported no differences in relapse rates or OS.

  33. de la Serna J, Montesinos P, Vellenga E, et al. Causes and prognostic factors of remission induction failure in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and idarubicin. Blood. 2008;111:3395–402.

    Article  PubMed  Google Scholar 

  34. Micol JB Raffoux E, Boissel N, 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. 2010;116:473. ASH Annual Meeting Abstracts.

    Google Scholar 

  35. Lehmann S, Ravn A, Carlsson 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;25:1128–34.

    Article  CAS  PubMed  Google Scholar 

  36. Altman JK, Rademaker A, Cull E, et al. Administration of ATRA to newly diagnosed patients with acute promyelocytic leukemia is delayed contributing to early hemorrhagic death. Leuk Res. 2013;37:1004–9.

    Article  CAS  PubMed  Google Scholar 

  37. Rahmé R, Thomas X, Recher C, et al. Early Deaths (ED) in Acute Promyelocytic Leukemia (APL) in France: a retrospective multicenter study in 355 patients (pts). Blood. 2012;120:890. ASH annual Meeting Abstracts.

    Google Scholar 

  38. Tallman MS, Altman JK. How I treat acute promyelocytic leukemia. Blood. 2009;114:5126–35.

    Article  CAS  PubMed  Google Scholar 

  39. Tallman MS, Brenner B, Serna Jde L, et al. Meeting report. Acute promyelocytic leukemia-associated coagulopathy, 21 January 2004, London, United Kingdom. Leuk Res. 2005;29:347–51.

    Article  PubMed  Google Scholar 

  40. Barbui T, Finazzi G, Falanga A. The impact of all-trans-retinoic acid on the coagulopathy of acute promyelocytic leukemia. Blood. 1998;91:3093–102.

    CAS  PubMed  Google Scholar 

  41. Kelaidi C, Ades L, Fenaux P. Treatment of acute promyelocytic leukemia with high white cell blood counts. Mediterr J Hematol Infect Dis. 2011;3:e2011038.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Frankel SR, Eardley A, Lauwers G, et al. The "retinoic acid syndrome" in acute promyelocytic leukemia. Ann Intern Med. 1992;117:292–6.

    Article  CAS  PubMed  Google Scholar 

  43. Kelaidi C, Chevret S, De Botton S, et al. Improved outcome of acute promyelocytic leukemia with high WBC counts over the last 15 years: the European APL Group experience. J Clin Oncol. 2009;27:2668–76.

    Article  PubMed  Google Scholar 

  44. Vahdat L, Maslak P, Miller Jr WH, et al. Early mortality and the retinoic acid syndrome in acute promyelocytic leukemia: impact of leukocytosis, low-dose chemotherapy, PMN/RAR-alpha isoform, and CD13 expression in patients treated with all-trans retinoic acid. Blood. 1994;84:3843–9.

    CAS  PubMed  Google Scholar 

  45. de Botton S, Sanz MA, Chevret S, et al. Extramedullary relapse in acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy. Leukemia. 2006;20:35–41.

    Article  PubMed  Google Scholar 

  46. Sanz MA, Grimwade D, Tallman MS, et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2009;113:1875–91.

    Article  CAS  PubMed  Google Scholar 

  47. Breccia M, Carmosino I, Diverio D, et al. Early detection of meningeal localization in acute promyelocytic leukaemia patients with high presenting leucocyte count. Br J Haematol. 2003;120:266–70.

    Article  PubMed  Google Scholar 

  48. Lengfelder E, Hofmann WK, Nolte F. Management of elderly patients with acute promyelocytic leukemia: progress and problems. Ann Hematol. 2013;92:1181–8.

    Article  PubMed Central  PubMed  Google Scholar 

  49. Park JH, Qiao B, Panageas KS, et al. Early death rate in acute promyelocytic leukemia remains high despite all-trans retinoic acid. Blood. 2011;118:1248–54.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Ades L, Chevret S, De Botton S, et al. Outcome of acute promyelocytic leukemia treated with all trans retinoic acid and chemotherapy in elderly patients: the European group experience. Leukemia. 2005;19:230–3.

    Article  CAS  PubMed  Google Scholar 

  51. Ono T, Takeshita A, Kishimoto Y, et al. Long-term outcome and prognostic factors of elderly patients with acute promyelocytic leukemia. Cancer Sci. 2012;103:1974–8.

    Article  CAS  PubMed  Google Scholar 

  52. Sanz MA, Vellenga E, Rayon C, et al. All-trans retinoic acid and anthracycline monochemotherapy for the treatment of elderly patients with acute promyelocytic leukemia. Blood. 2004;104:3490–3.

    Article  CAS  PubMed  Google Scholar 

  53. Latagliata R, Breccia M, Fazi P, et al. GIMEMA AIDA 0493 amended protocol for elderly patients with acute promyelocytic leukaemia. Long-term results and prognostic factors. Br J Haematol. 2011;154:564–8.

    Article  CAS  PubMed  Google Scholar 

  54. Zhang Y, Zhang Z, Li J, et al. Long-term efficacy and safety of arsenic trioxide for first-line treatment of elderly patients with newly diagnosed acute promyelocytic leukemia. Cancer. 2013;119:115–25.

    Article  CAS  PubMed  Google Scholar 

  55. Lo-Coco F, Cimino G, Breccia M, et al. Gemtuzumab ozogamicin (Mylotarg) as a single agent for molecularly relapsed acute promyelocytic leukemia. Blood. 2004;104:1995–9.

    Article  CAS  PubMed  Google Scholar 

  56. Breccia M, Cimino G, Diverio D, et al. Sustained molecular remission after low dose gemtuzumab-ozogamicin in elderly patients with advanced acute promyelocytic leukemia. Haematologica. 2007;92:1273–4.

    Article  CAS  PubMed  Google Scholar 

  57. Lo-Coco F, Orlando SM, Platzbecker U. Treatment of acute promyelocytic leukemia. N Engl J Med. 2013;369:1472.

    Article  CAS  PubMed  Google Scholar 

  58. Soignet SL, Maslak P, Wang ZG, et al. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med. 1998;339:1341–8.

    Article  CAS  PubMed  Google Scholar 

  59. Au WY, Lie AK, Chim CS, et al. Arsenic trioxide in comparison with chemotherapy and bone marrow transplantation for the treatment of relapsed acute promyelocytic leukaemia. Ann Oncol. 2003;14:752–7.

    Article  CAS  PubMed  Google Scholar 

  60. Raffoux E, Rousselot P, Poupon J, et al. Combined treatment with arsenic trioxide and all-trans-retinoic acid in patients with relapsed acute promyelocytic leukemia. J Clin Oncol. 2003;21:2326–34.

    Article  CAS  PubMed  Google Scholar 

  61. Shigeno K, Naito K, Sahara N, 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;82:224–9.

    Article  CAS  PubMed  Google Scholar 

  62. Aribi A, Kantarjian HM, Estey EH, et al. Combination therapy with arsenic trioxide, all-trans retinoic acid, and gemtuzumab ozogamicin in recurrent acute promyelocytic leukemia. Cancer. 2007;109:1355–9.

    Article  CAS  PubMed  Google Scholar 

  63. Lu J, Huang X, Bao L, et al. Treatment outcomes in relapsed acute promyelocytic leukemia patients initially treated with all- retinoic acid and arsenic compound-based combined therapies. Oncol Lett. 2014;7:177–82.

    CAS  PubMed Central  PubMed  Google Scholar 

  64. Thirugnanam R, George B, Chendamarai E, 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;15:1479–84.

    Article  CAS  PubMed  Google Scholar 

  65. de Botton S, Fawaz A, Chevret S, et al. Autologous and allogeneic stem-cell transplantation as salvage treatment of acute promyelocytic leukemia initially treated with all-trans-retinoic acid: a retrospective analysis of the European acute promyelocytic leukemia group. J Clin Oncol. 2005;23:120–6.

    Article  PubMed  Google Scholar 

  66. Pemmaraju N, Tanaka MF, Ravandi F, et al. Outcomes in patients with relapsed or refractory acute promyelocytic leukemia treated with or without autologous or allogeneic hematopoietic stem cell transplantation. Clin Lymphoma Myeloma Leuk. 2013;13:485–92.

    Article  PubMed  Google Scholar 

  67. Zhu HH, Wu DP, Jin J, et al. Oral tetra-arsenic tetra-sulfide formula versus intravenous arsenic trioxide as first-line treatment of acute promyelocytic leukemia: a multicenter randomized controlled trial. J Clin Oncol. 2013;31:4215–21. This is a randomized controlled trial comparing outcomes with IV arsenic vs. a novel form of oral arsenic. Demonstrated no difference in outcomes with the new formulation.

    Article  CAS  PubMed  Google Scholar 

  68. Ozpolat B, Lopez-Berestein G, Adamson P, et al. Pharmacokinetics of intravenously administered liposomal all-trans-retinoic acid (ATRA) and orally administered ATRA in healthy volunteers. J Pharm Pharm Sci. 2003;6:292–301.

    CAS  PubMed  Google Scholar 

  69. Tsimberidou AM, Tirado-Gomez M, Andreeff M, et al. Single-agent liposomal all-trans retinoic acid can cure some patients with untreated acute promyelocytic leukemia: an update of The University of Texas M. D. Anderson Cancer Center Series. Leuk Lymphoma. 2006;47:1062–8.

    Article  CAS  PubMed  Google Scholar 

  70. Jain P, Kantarjian H, Estey E et al. Single-Agent Liposomal All-Trans-Retinoic Acid as Initial Therapy for Acute Promyelocytic Leukemia: 13-Year Follow-Up Data. Clin Lymphoma Myeloma Leuk 2013.

  71. Warrell Jr RP. Retinoid resistance in acute promyelocytic leukemia: new mechanisms, strategies, and implications. Blood. 1993;82:1949–53.

    CAS  PubMed  Google Scholar 

  72. Shao W, Benedetti L, Lamph WW, et al. A retinoid-resistant acute promyelocytic leukemia subclone expresses a dominant negative PML-RAR alpha mutation. Blood. 1997;89:4282–9.

    CAS  PubMed  Google Scholar 

  73. Ohnishi K. PML-RARalpha inhibitors (ATRA, tamibaroten, arsenic troxide) for acute promyelocytic leukemia. Int J Clin Oncol. 2007;12:313–7.

    Article  CAS  PubMed  Google Scholar 

  74. Tobita T, Takeshita A, Kitamura K, et al. Treatment with a new synthetic retinoid, Am80, of acute promyelocytic leukemia relapsed from complete remission induced by all-trans retinoic acid. Blood. 1997;90:967–73.

    CAS  PubMed  Google Scholar 

  75. Naina HV, Levitt D, Vusirikala M, et al. Successful treatment of relapsed and refractory extramedullary acute promyelocytic leukemia with tamibarotene. J Clin Oncol. 2011;29:e534–6.

    Article  PubMed  Google Scholar 

  76. Di Veroli A, Ramadan SM, Divona M, et al. Molecular remission in advanced acute promyelocytic leukaemia after treatment with the oral synthetic retinoid Tamibarotene. Br J Haematol. 2010;151:99–101.

    Article  PubMed  Google Scholar 

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Acknowledgment

The project described was supported by Award Number P30 CA060553 from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.

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Conflict of Interest

Dr. Elizabeth H. Cull declares no potential conflicts of interest relevant to this article.

Dr. Jessica K. Altman is a consultant for Teva Pharmaceuticals, Astellas Pharmaceuticals, BMS, Novartis, and Ariad. Dr. Altman is supported, in part, by a Cancer Center supplement grant.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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  1. Division of Hematology and Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine and Northwestern Memorial Hospital, Chicago, IL, USA

    Elizabeth H. Cull & Jessica K. Altman

  2. Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center Northwestern University, Northwestern University Feinberg School of Medicine, 676 N. St. Clair, Suite 850, Chicago, IL, 60611, USA

    Elizabeth H. Cull

  3. Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center Northwestern University, Northwestern University Feinberg School of Medicine, Lurie 5-111, 303 E. Superior Street, Chicago, IL, 60611, USA

    Jessica K. Altman

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Cull, E.H., Altman, J.K. Contemporary Treatment of APL. Curr Hematol Malig Rep 9, 193–201 (2014). https://doi.org/10.1007/s11899-014-0205-6

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