Vol 12, No 3-4 (2021)
Review paper
Published online: 2021-10-18

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Acute promyelocytic leukemia: from genetic lesions identification to molecularly targeted therapy

Marcelina Majka1, Paweł R. Bednarek1, Matylda Nowicki1, Jagoda Chełmikowska1, Krystian Kaczmarek1, Eliza Kędzierska1, Krzysztof Lewandowski1
Hematology in Clinical Practice 2021;12(3-4):105-120.


Acute promyelocytic leukemia (APL) differs from other types of acute myeloid leukemia both in terms of the spectrum of clinical symptoms, as well as cytogenetic and molecular background. Fast diagnosis of APL enables highly effective targeted therapy initiation and avoiding of serious organ/tissue damage (including fatal bleeding into the central nervous system). In the initial diagnostic process the most important is the rapid identification of the presence of specific cytogenetic and molecular changes involving the retinoic acid receptor alpha (RARA) gene located on the 17q21 chromosome. In patients with APL, alongside the most commonly observed translocation t(15;17)(q24;q21) leading to the formation of the PML-RARA fusion, several dozen variant cases have also been identified as a result of other translocations involving RARA gene with different clinical symptomatology and variable sensitivity to the targeted therapy with all-trans retinoic acid and arsenic trioxide. The paper presents the recent data concerning the epidemiology, symptomatology and accurate diagnostics methods useful for early identification of APL and immediate initiation of the molecularly targeted therapy

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  1. De Kouchkovsky I, Abdul-Hay M. Acute myeloid leukemia: a comprehensive review and 2016 update. Blood Cancer J. 2016; 6(7): e441.
  2. Arnone M, Konantz M, Hanns P, et al. Acute myeloid leukemia stem cells: the challenges of phenotypic heterogeneity. Cancers (Basel). 2020; 12(12).
  3. Noguera N, Catalano G, Banella C, et al. Acute promyelocytic leukemia: update on the mechanisms of leukemogenesis, resistance and on innovative treatment strategies. Cancers (Basel). 2019; 11(10): 1591.
  4. Brunner AM, Kim P, Sadrzadeh H, et al. Clustered incidence of adult acute promyelocytic leukemia. Leuk Res. 2018; 74: 47–50.
  5. Zhang L, Samad A, Pombo-de-Oliveira MS, et al. Global characteristics of childhood acute promyelocytic leukemia. Blood Rev. 2015; 29(2): 101–125.
  6. Seferyńska I. [Incidence of acute myeloid and lymphoblastic leukemias in adults in Poland between 2004–2010] [Article in Polish]. Hematologia. 2015; 6(Suppl B): 1–40.
  7. Podhorecka M, Macheta A. Ostra białaczka promielocytowa — nowe podejście do patogenezy choroby i terapii różnicuja̧cej. Postepy Hig Med Dosw. 2013; 67: 1083–1089.
  8. Paulson K, Serebrin A, Lambert P, et al. Acute promyelocytic leukaemia is characterized by stable incidence and improved survival that is restricted to patients managed in leukaemia referral centres: a pan-Canadian epidemiological study. Br J Haematol. 2014; 166(5): 660–666.
  9. Dinmohamed AG, Visser O. Incidence of acute promyelocytic leukemia across Europe: results of RARECAREnet — a population-based study. Stem Cell Investig. 2019; 6: 37.
  10. Yamamoto JF, Goodman MT. Patterns of leukemia incidence in the United States by subtype and demographic characteristics, 1997-2002. Cancer Causes Control. 2008; 19(4): 379–390.
  11. Otero JC, Santillana S, Fereyros G. High frequency of acute promyelocytic leukemia among Latinos with acute myeloid leukemia [letter; comment]. Blood. 1996; 88(1): 377–377.
  12. Matasar MJ, Ritchie EK, Consedine N, et al. Incidence rates of acute promyelocytic leukemia among Hispanics, blacks, Asians, and non-Hispanic whites in the United States. Eur J Cancer Prev. 2006; 15(4): 367–370.
  13. Chen Z, Mai W, Li Z, et al. The epidemiological trend of acute promyelocytic leukemia over past four decades: a population-based analysis. Leuk Lymphoma. 2019; 60(14): 3470–3481.
  14. 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(7): 1128–1134.
  15. Venkitachalam R, Szabo A, Guru Murthy GS. Population-level outcomes of pediatric acute promyelocytic leukemia in the United States. J Pediatr. 2020; 223: 114–119.e5.
  16. Duffield AS, Aoki J, Levis M, et al. Clinical and pathologic features of secondary acute promyelocytic leukemia. Am J Clin Pathol. 2012; 137(3): 395–402.
  17. Adams J, Nassiri M. Acute promyelocytic leukemia: a review and discussion of variant translocations. Arch Pathol Lab Med. 2015; 139(10): 1308–1313.
  18. Hillestad LK. Acute promyelocytic leukemia. Acta Med Scand. 1957; 159(3): 189–194.
  19. Abedin S, Altman JK. Acute promyelocytic leukemia: preventing early complications and late toxicities. Hematology Am Soc Hematol Educ Program. 2016; 2016(1): 10–15.
  20. Thomas X. Acute promyelocytic leukemia: a history over 60 years — from the most malignant to the most curable form of acute leukemia. Oncol Ther. 2019; 7(1): 33–65.
  21. Daver N, Kantarjian H, Marcucci G, et al. Clinical characteristics and outcomes in patients with acute promyelocytic leukaemia and hyperleucocytosis. Br J Haematol. 2015; 168(5): 646–653.
  22. Van der Horst C, Stuebinger H, Seif C, et al. Priapism — etiology, pathophysiology and management. Int Braz J Urol. 2003; 29(5): 391–400.
  23. Stahl M, Tallman MS. Acute promyelocytic leukemia (APL): remaining challenges towards a cure for all. Leuk Lymphoma. 2019; 60(13): 3107–3115.
  24. Kata D, Kyrcz-Krzemień S. [Acute myelogenous leukemia — recent views on the pathogenesis, diagnostic approach, classification, prognostic stratification and treatment] [Article in Polish]. Post Nauk Med. 2011(7): 601–609.
  25. Testa U, Lo-Coco F. Prognostic factors in acute romyelocytic leukemia: strategies to define high-risk atients [Internet]. Vol. 95, Annals of Hematology. Sringer Verlag; 2016 [cited 2021 Jun 2]. Ann Hematol. 2016; 95(5): 673–680.
  26. Walker DK, Held-Warmkessel J. Acute promyelocytic leukemia: an overview with implications for oncology nurses. Clin J Oncol Nurs. 2010; 14(6): 747–759.
  27. Sakata Y, Murakami T, Noro A, et al. The specific activity of plasminogen activator inhibitor-1 in disseminated intravascular coagulation with acute promyelocytic leukemia. Blood. 1991; 77(9): 1949–1957.
  28. Wang ZY, Chen Z. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood. 2008; 111(5): 2505–2515.
  29. Sanz MA, Fenaux P, Tallman MS, et al. Management of acute promyelocytic leukemia: updated recommendations from an expert panel of the European LeukemiaNet. Blood. 2019; 133(15): 1630–1643.
  30. Choudhry A, DeLoughery T. Bleeding and thrombosis in acute promyelocytic leukemia. Am J Hematol. 2012; 87(6): 596–603.
  31. Naymagon L, Mascarenhas J. Hemorrhage in acute promyelocytic leukemia: can it be predicted and prevented? Leuk Res. 2020; 94: 106356.
  32. Jillella AP, Kota VK. The global problem of early deaths in acute promyelocytic leukemia: a strategy to decrease induction mortality in the most curable leukemia. Blood Rev. 2018; 32(2): 89–95.
  33. Coombs CC, Tavakkoli M, Tallman MS. Acute promyelocytic leukemia: where did we start, where are we now, and the future. Blood Cancer J. 2015; 5: e304.
  34. Di Bona E, Avvisati G, Castaman G, et al. Early haemorrhagic morbidity and mortality during remission induction with or without all-trans retinoic acid in acute promyelocytic leukaemia. Br J Haematol. 2000; 108(4): 689–695.
  35. Falanga A, Russo L, Tartari CJ. Pathogenesis and treatment of thrombohemorrhagic diathesis in acute promyelocytic leukemia. Mediterr J Hematol Infect Dis. 2011; 3(1): e2011068.
  36. Sobas M, Czyż A, Montesinos P, et al. Outcome of a real-life population of patients with acute promyelocytic leukemia treated according to the PETHEMA guidelines: the Polish Adult Leukemia Group (PALG) experience. Clin Lymphoma Myeloma Leuk. 2020; 20(2): 105–113.
  37. Sanz MA, Montesinos P. Open issues on bleeding and thrombosis in acute promyelocytic leukemia. Thromb Res. 2010; 125: S51–S54.
  38. Jimenez JJ, Chale RS, Abad AC, et al. Acute promyelocytic leukemia (APL): a review of the literature. Oncotarget. 2020; 11(11): 992–1003.
  39. Collins C, Knoderer H. Central nervous system involvement at the time of presentation in acute promyelocytic leukemia. Pediatr Blood Cancer. 2010; 54(4): 603–605.
  40. Sahin DG, Gunduz E, Akay OM, et al. Central nervous system relapse in a patient with acute promyelocytic leukaemia: does the risk stratification matter? BMJ Case Rep. 2013; 2013.
  41. Sultan S, Irfan SM, Ashar S. Acute promyelocytic leukemia: a single center study from Southern Pakistan. Asian Pac J Cancer Prev. 2015; 16(17): 7893–7895.
  42. Shameli A, Jamani K. Acute promyelocytic leukemia presenting with atypical basophils. Clin Case Rep. 2020; 8(3): 584–585.
  43. Das Gupta A, Sapre RS, Shah AS, et al. Cytochemical and immunophenotypic heterogeneity in acute promyelocytic leukemia. Acta Haematol. 1989; 81(1): 5–9.
  44. Mantha S, Tallman MS, Devlin SM, et al. Predictive factors of fatal bleeding in acute promyelocytic leukemia. Thromb Res. 2018; 164 Suppl 1: S98–S9S102.
  45. Lee HJ, Park HJ, Kim HW, et al. Comparison of laboratory characteristics between acute promyelocytic leukemia and other subtypes of acute myeloid leukemia with disseminated intravascular coagulation. Blood Res. 2013; 48(4): 250–253.
  46. Xu F, Yin CX, Wang CL, et al. Immunophenotypes and immune markers associated with acute promyelocytic leukemia prognosis. Dis Markers. 2014; 2014: 421906.
  47. Ren F, Zhang Na, Xu Z, et al. The CD9 CD11b HLA-DR immunophenotype can be used to diagnose acute promyelocytic leukemia. Int J Lab Hematol. 2019; 41(2): 168–175.
  48. Tran VT, Phan TT, Mac HP, et al. The diagnostic power of CD117, CD13, CD56, CD64, and MPO in rapid screening acute promyelocytic leukemia. BMC Res Notes. 2020; 13(1): 394.
  49. Alcalay M, Zangrilli D, Pandolfi PP, et al. Translocation breakpoint of acute promyelocytic leukemia lies within the retinoic acid receptor alpha locus. Proc Natl Acad Sci U S A. 1991; 88(5): 1977–1981.
  50. Jensen K, Shiels C, Freemont P. PML protein isoforms and the RBCC/TRIM motif. Oncogene. 2001; 20(49): 7223–7233.
  51. Hjalt TA, Murray JC. Genomic structure of the human retinoic acid receptor-alpha1 gene. Mamm Genome. 1999; 10(5): 528–529.
  52. Mannan A, Muhsen IN, Barragán E, et al. Role of hematopoietic stem cell transplantation in acute promyelocytic leukemia. Hematol Oncol Stem Cell Ther. 2020; 13(4): 189–201.
  53. Zelent A, Guidez F, Melnick A, et al. Translocations of the RARalpha gene in acute promyelocytic leukemia. Oncogene. 2001; 20(49): 7186–7203.
  54. Madan V, Shyamsunder P, Han L, et al. Comprehensive mutational analysis of primary and relapse acute promyelocytic leukemia. Leukemia. 2016; 30(8): 1672–1681.
  55. Lin X, Qiao N, Shen Y, et al. Integration of genomic and transcriptomic markers improves the prognosis prediction of acute promyelocytic leukemia. Clin Cancer Res. 2021; 27(13): 3683–3694.
  56. Zhu HH, Yang MC, Wang F, et al. Identification of a novel NUP98-RARA fusion transcript as the 14th variant of acute promyelocytic leukemia. Am J Hematol. 2020; 95(7): E184–E186.
  57. Nakanishi T, Nakaya A, Nishio Y, et al. A variant of acute promyelocytic leukemia with t(4;17)(q12;q21) showed two different clinical symptoms. Hematol Rep. 2019; 11(3): 7971.
  58. Sanz MA, Grimwade D, Tallman MS, et al. Management of acute romyelocytic leukemia: recommendations from an exert anel on behalf of the Euroean LeukemiaNet. Blood. 2009; 113(9): 1875–1891.
  59. Sanz MA, Lo-Coco F. Modern approaches to treating acute promyelocytic leukemia. J Clin Oncol. 2011; 29(5): 495–503.
  60. Lo-Coco F, Avvisati G, Vignetti M, et al. Gruppo Italiano Malattie Ematologiche dell'Adulto, German-Austrian Acute Myeloid Leukemia Study Group, Study Alliance Leukemia. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013; 369(2): 111–121.
  61. Tallman MS, Andersen JW, Schiffer CA, et al. All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol. Blood. 2002; 100(13): 4298–4302.
  62. 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. Blood. 1999; 94(4): 1192–1200.
  63. Borlenghi E, Cattaneo C, Schieppati F, et al. Acute promyelocytic leukemia in patients aged >70 years is not rare and highly curable: a single center series of 21 unselected patients. Leuk Lymphoma. 2019; 60(2): 531–534.
  64. Sanz MA, Montesinos P, Vellenga E, et al. Risk-adapted treatment of acute promyelocytic leukemia with all-trans retinoic acid and anthracycline monochemotherapy: long-term outcome of the LPA 99 multicenter study by the PETHEMA Group. Blood. 2008; 112(8): 3130–3134.
  65. Lo-Coco F, Avvisati G, Vignetti M, et al. Italian GIMEMA Cooperative Group. 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(17): 3171–3179.
  66. Burnett AK, Russell NH, Hills RK, et al. UK National Cancer Research Institute Acute Myeloid Leukaemia Working Group. 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(13): 1295–1305.
  67. Fouzia NA, Sharma V, Ganesan S, et al. Management of relapse in acute promyelocytic leukaemia treated with up-front arsenic trioxide-based regimens. Br J Haematol. 2021; 192(2): 292–299.
  68. Abaza Y, Kantarjian H, Garcia-Manero G, et al. Long-term outcome of acute promyelocytic leukemia treated with all — retinoic acid, arsenic trioxide, and gemtuzumab. Blood. 2017; 129(10): 1275–1283.
  69. Li X, Wang C, Chen G, et al. Combined chemotherapy for acute promyelocytic leukemia: a meta-analysis. Hematology. 2017; 22(8): 450–459.
  70. Sasijareonrat N, Jahn N, Ungprasert P, et al. Efficacy and the adverse effects of oral versus intravenous arsenic for acute promyelocytic leukemia: a meta-analysis of randomized-controlled studies. Technol Cancer Res Treat. 2020; 19: 1533033820937008.
  71. Wu F, Wu Di, Ren Y, et al. Bayesian network meta-analysis comparing five contemporary treatment strategies for newly diagnosed acute promyelocytic leukaemia. Oncotarget. 2016; 7(30): 47319–47331.
  72. Sanz J, Labopin M, Sanz MA, et al. Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT). Hematopoietic stem cell transplantation for adults with relapsed acute promyelocytic leukemia in second complete remission. Bone Marrow Transplant. 2021; 56(6): 1272–1280.
  73. Liu Y, Xu J, Chu L, et al. A rare case of acute promyelocytic leukemia with ider(17)(q10)t(15;17)(q22;q21) and favorable outcome. Mol Cytogenet. 2020; 13: 13.
  74. Schuurhuis GJ, Heuser M, Freeman S, et al. Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party. Blood. 2018; 131(12): 1275–1291.
  75. Campana D, Coustan-Smith E. Detection of minimal residual disease in acute leukemia by flow cytometry. Cytometry. 1999; 38(4): 139–152, doi: 10.1002/(sici)1097-0320(19990815)38:4<139::aid-cyto1>3.0.co;2-h.
  76. Kopeć-Szlęzak J, Woźniak J. Standardowe oznaczanie immunofenotypu komórek białaczkowych w rozpoznawaniu i monitorowaniu ostrej białaczki szpikowej (OBS). Now Lek. 2008; 77(4): 273–279.
  77. Al-Mawali A, Gillis D, Lewis I. The role of multiparameter flow cytometry for detection of minimal residual disease in acute myeloid leukemia. Am J Clin Pathol. 2009; 131(1): 16–26.
  78. Lukes J, Winkowska L, Zwyrtkova M, et al. Identification of fusion gene breakpoints is feasible and facilitates accurate sensitive minimal residual disease monitoring on genomic level in patients with PML-RARA, CBFB-MYH11, and RUNX1-RUNX1T1. Hemasphere. 2020; 4(6): e489.
  79. Lo-Coco F, Diverio D, Falini B. Genetic diagnosis and molecular monitoring in the management of acute promyelocytic leukemia. Blood. 1999; 94(1): 12–22.
  80. Gabert J, Beillard E, van der Velden VHJ, et al. Standardization and quality control studies of 'real-time' quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia - a Europe Against Cancer program. Leukemia. 2003; 17(12): 2318–2357.
  81. Zhang Li, Cao Z, Zou Y, et al. Quantification of PML/RARa transcript after induction predicts outcome in children with acute promyelocytic leukemia. Int J Hematol. 2012; 95(5): 500–508.
  82. Grimwade D, Jovanovic JV, Hills RK, 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(22): 3650–3658.
  83. Brunetti C, Anelli L, Zagaria A, et al. Droplet digital PCR is a reliable tool for monitoring minimal residual disease in acute promyelocytic leukemia. J Mol Diagn. 2017; 19(3): 437–444.
  84. Reiter A, Lengfelder E, Grimwade D. Pathogenesis, diagnosis and monitoring of residual disease in acute promyelocytic leukaemia. Acta Haematol. 2004; 112(1-2): 55–67.
  85. Santolaria A, Perales A, Montesinos P, et al. Acute promyelocytic leukemia during pregnancy: a systematic review of the literature. Cancers (Basel). 2020; 12(4).
  86. Mokany E, Todd AV, Fuery CJ, et al. Diagnosis and monitoring of PML-RARalpha-positive acute promyelocytic leukemia by quantitative RT-PCR. Methods Mol Med. 2006; 125: 127–147.
  87. National Comprehensive Cancer Network — Home . https://www.nccn.org/ (June 3, 2021).
  88. Yohe S, Thyagarajan B. Review of clinical next-generation sequencing. Arch Pathol Lab Med. 2017; 141(11): 1544–1557.

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