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Treatment of Refractory and Relapsed APL

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Abstract

The prognosis of acute promyelocytic leukemia (APL) has improved significantly during the last few decades. Relapses have become quite rare, and although cure may still be possible after relapse, the optimal management of the individual patient is a major challenge. Arsenic trioxide (ATO)-based salvage therapy is the treatment of choice after frontline therapy with all-trans-retinoic acid (ATRA) and chemotherapy. Current data suggest autologous or allogeneic stem cell transplantation after re-induction of remission depending on the individual risk profile. Patients not qualifying for transplantation probably benefit from prolonged application of ATO. Even after frontline therapy with ATO, salvage therapy with ATO may still be effective. This chapter gives an overview on the currently available treatment options for relapsed APL, as well as on prognostic factors, which may influence the relapse management in the individual patient.

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Abbreviations

AML:

Acute myeloid leukemia

APL:

Acute promyelocytic leukemia

Ara-C:

Cytosine arabinoside

ATO:

Arsenic trioxide

ATRA:

All-trans retinoic acid

CIR:

Cumulative incidence of relapse

CNS:

Central nervous system

CR:

Complete remission

EBMT:

European Society for Blood and Marrow Transplantation

GVHD:

Graft versus host disease

HSCT:

Hematopoietic stem cell transplantation

NCCN:

National Comprehensive Cancer Network

OS:

Overall survival

PML:

Promyelocytic leukemia

RARA:

Retinoic acid receptor alpha

RT-PCR:

Reverse transcriptase polymerase chain reaction

TRM:

Transplant related mortality

WBC:

White blood cell

References

  1. Bernard J, Weil M, Boiron M, Jacquillat C, Flandrin G, Gemon MF. Acute promyelocytic leukemia: results of treatment by daunorubicin. Blood. 1973;41:489–96.

    CAS  PubMed  Google Scholar 

  2. Wang ZY, Chen Z. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood. 2008;111:2505–15. https://doi.org/10.1182/blood-2007-07-102798.

    Article  CAS  PubMed  Google Scholar 

  3. Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013;369:111–21. https://doi.org/10.1056/NEJMoa1300874.

    Article  CAS  PubMed  Google Scholar 

  4. Burnett AK, Russell NH, Hills RK, Bowen D, Kell J, Knapper S, et al. Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2015;16:1295–305. https://doi.org/10.1016/S1470-2045(15)00193-X.

    Article  CAS  PubMed  Google Scholar 

  5. Diverio D, Rossi V, Avvisati G, De Santis S, Pistilli A, Pane F, et al. Early detection of relapse by prospective reverse transcriptase-polymerase chain reaction analysis of the PML/RARalpha fusion gene in patients with acute promyelocytic leukemia enrolled in the GIMEMA-AIEOP multicenter “AIDA” trial. GIMEMA-AIEOP Multicenter “AIDA” Trial. Blood. 1998;92:784–9.

    CAS  PubMed  Google Scholar 

  6. 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;94:2225–9.

    CAS  PubMed  Google Scholar 

  7. Esteve J, Escoda L, Martín G, Rubio V, Díaz-Mediavilla J, González M, et al. Outcome of patients with acute promyelocytic leukemia failing to front-line treatment with all-trans retinoic acid and anthracycline-based chemotherapy (PETHEMA protocols LPA96 and LPA99): benefit of an early intervention. Leukemia. 2007;21:446–52.

    Article  CAS  PubMed  Google Scholar 

  8. Grimwade D, Jovanovic JV, Hills RK, Nugent EA, Patel Y, 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;27:3650–8. https://doi.org/10.1200/JCO.2008.20.1533.

    Article  CAS  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;83:714–7.

    CAS  PubMed  Google Scholar 

  10. Fenaux P, Chevret S, Guerci A, Fegueux N, Dombret H, Thomas X, et al. Long-term follow-up confirms the benefit of all-trans retinoic acid in acute promyelocytic leukemia. European APL group. Leukemia. 2000;14:1371–7.

    Article  CAS  PubMed  Google Scholar 

  11. 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;14:1006–13.

    Article  CAS  PubMed  Google Scholar 

  12. Degos L, Dombret H, Chomienne C, Daniel MT, Micléa JM, Chastang C, et al. All-trans-retinoic acid as a differentiating agent in the treatment of acute promyelocytic leukemia. Blood. 1995;85:2643–53.

    CAS  PubMed  Google Scholar 

  13. 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;94:3315–24.

    CAS  PubMed  Google Scholar 

  14. Lengfelder E, Hofmann WK, Nowak D. Impact of arsenic trioxide in the treatment of acute promyelocytic leukemia. Leukemia. 2012;26:433–42. https://doi.org/10.1038/leu.2011.245.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  16. 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 U S A. 2004;101:5328–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wang H, Chen XY, Wang BS, Rong ZX, Qi H, Chen HZ. The efficacy and safety of arsenic trioxide with or without all-trans retinoic acid for the treatment of acute promyelocytic leukemia: a meta-analysis. Leuk Res. 2011;35:1170–7. https://doi.org/10.1016/j.leukres.2011.06.002.

    Article  CAS  PubMed  Google Scholar 

  18. Lengfelder E, Lo-Coco F, Ades L, Montesinos P, Grimwade D, Kishore B, et al. Arsenic trioxide-based therapy of relapsed acute promyelocytic leukemia: registry results from the European LeukemiaNet. Leukemia. 2015;29:1084–91. https://doi.org/10.1038/leu.2015.12.

    Article  CAS  PubMed  Google Scholar 

  19. Sanz MA, Grimwade D, Tallman MS, Lowenberg B, Fenaux P, Estey EH, et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2009;113:1875–91. https://doi.org/10.1182/blood-2008-04-150250.

    Article  CAS  PubMed  Google Scholar 

  20. Seftel MD, Barnett MJ, Couban S, Leber B, Storring J, Assaily W, et al. A Canadian consensus on the management of newly diagnosed and relapsed acute promyelocytic leukemia in adults. Curr Oncol. 2014;21:234–50. https://doi.org/10.3747/co.21.2183.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. NCCN. NCCN guidelines: acute myeloid leukemia, version 2.2016. Fort Washington: National Comprehensive Cancer Network; 2016. https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed 4 Aug 2016.

    Google Scholar 

  22. de Botton S, Fawaz A, Chevret S, Dombret H, Thomas X, Sanz M, 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 

  23. Sanz MA, Labopin M, Gorin NC, de la Rubia J, Arcese W, Meloni G, et al. Hematopoietic 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;39:461–9.

    Article  CAS  PubMed  Google Scholar 

  24. Yanada M, Tsuzuki M, Fujita H, Fujimaki K, Fujisawa S, Sunami K, et al. Phase 2 study of arsenic trioxide followed by autologous hematopoietic cell transplantation for relapsed acute promyelocytic leukemia. Blood. 2013;121:3095–102. https://doi.org/10.1182/blood-2012-11-466862.

    Article  CAS  PubMed  Google Scholar 

  25. Ramadan SM, Di Veroli A, Camboni A, Breccia M, Iori AP, Aversa F, et al. Allogeneic stem cell transplantation for advanced acute promyelocytic leukemia in the ATRA and ATO era. Haematologica. 2012;97:1731–5.

    Article  PubMed  PubMed Central  Google Scholar 

  26. 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;15:1479–84. https://doi.org/10.1016/j.bbmt.2009.07.010.

    Article  CAS  PubMed  Google Scholar 

  27. Ganzel C, Mathews V, Alimoghaddam K, Ghavamzadeh A, Kuk D, Devlin S, et al. Autologous transplant remains the preferred therapy for relapsed APL in CR2. Bone Marrow Transplant. 2016;51:1180–3. https://doi.org/10.1038/bmt.2016.96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Milone G, Inghilterra G, Li Gioi F, Peluso D, Giustolisi R. Testicular and cutaneous relapse after hematopoietic transplantation in a patient affected with APL. Bone Marrow Transplant. 1999;23:751.

    Article  CAS  PubMed  Google Scholar 

  29. Pacilli L, Lo Coco F, Ramadan SM, Giannì L, Pingi A, Remotti D, et al. Promyelocytic sarcoma of the spine: a case report and review of the literature. Adv Hematol. 2010;2010:137608. https://doi.org/10.1155/2010/137608.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Ochs RC, Gormley RH, Luger S, Bagg A. Isolated bowel relapse in acute promyelocytic leukemia: an unusual site of extramedullary recurrence. J Clin Oncol. 2010;28:e550–3. https://doi.org/10.1200/JCO.2010.29.7424.

    Article  PubMed  Google Scholar 

  31. Tirado CA, Chen W, Valdez F, Karandikar N, Arbini A, Acevedo I, et al. Unusual presentation of myeloid sarcoma in a case of acute promyelocytic leukemia with a cryptic PML-RARA rearrangement involving multiple sites including the atrium. Cancer Genet Cytogenet. 2010;200:47–53. https://doi.org/10.1016/j.cancergencyto.2010.03.016.

    Article  CAS  PubMed  Google Scholar 

  32. Montesinos P, Díaz-Mediavilla J, Debén G, Prates V, Tormo M, Rubio V, et al. 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. Haematologica. 2009;94:1242–9. https://doi.org/10.3324/haematol.2009.007872.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 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.

    Article  PubMed  Google Scholar 

  34. 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;107:3012–3.

    Article  CAS  PubMed  Google Scholar 

  35. Wang H, Cao F, Li J, Li L, Li Y, Shi C, et al. Arsenic trioxide and mannitol for the treatment of acute promyelocytic leukemia relapse in central nervous system. Blood. 2014;124:1998–2000. https://doi.org/10.1182/blood-2014-04-568121.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zhu HH, Qin YZ, Huang XJ. Resistance to arsenic therapy in acute promyelocytic leukemia. N Engl J Med. 2014;370:1864–6. https://doi.org/10.1056/NEJMc1316382.

    Article  CAS  PubMed  Google Scholar 

  37. Lo-Coco F, Cimino G, Breccia M, Noguera NI, Diverio D, Finolezzi E, 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 

  38. Breccia M, Cimino G, Diverio D, Gentilini F, Mandelli F, Lo Coco F. 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 

  39. Tobita T, Takeshita A, Kitamura K, Ohnishi K, Yanagi M, Hiraoka A, 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 

  40. Sanford D, Lo-Coco F, Sanz MA, Di Bona E, Coutre S, Altman JK, et al. Tamibarotene in patients with acute promyelocytic leukaemia relapsing after treatment with all-trans retinoic acid and arsenic trioxide. Br J Haematol. 2015;171:471–7. https://doi.org/10.1111/bjh.13607.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Hematology and Oncology, University Hospital Mannheim, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany

    Eva Lengfelder M.D.

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  1. Eva Lengfelder M.D.
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Correspondence to Eva Lengfelder M.D. .

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Editors and Affiliations

  1. Division of Hematology/Oncology, The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada

    Oussama Abla

  2. Department of Hematology, University of Tor Vergata, Rome, Italy

    Francesco Lo Coco

  3. Department of Medicine, Hospital Universitari i Politecnic La Fe, University of Valencia, Valencia, Spain

    Miguel A. Sanz

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Lengfelder, E. (2018). Treatment of Refractory and Relapsed APL. In: Abla, O., Lo Coco, F., Sanz, M. (eds) Acute Promyelocytic Leukemia . Springer, Cham. https://doi.org/10.1007/978-3-319-64257-4_12

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  • DOI: https://doi.org/10.1007/978-3-319-64257-4_12

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