Blast phase of chronic myeloid leukaemia

Czech version

Authors: N. Čuřík ^1,2; A. Láznička ^1,3
Authors‘ workplace: Ústav hematologie a krevní transfuze, Oddělení molekulární genetiky, Praha ¹; Ústav patologické fyziologie, 1. LF UK, Praha ²; 2. LF UK, Praha ³
Published in: Transfuze Hematol. dnes,29, 2023, No. 1, p. 16-26.
Category: Review/Educational Papers
doi: https://doi.org/10.48095/cctahd202316

Overview

Chronic myeloid leukaemia represents a model disease where the identification of driving molecular mechanisms and their targeted therapy has led to dramatic improvement in treatment outcomes. Nevertheless, a small proportion of patients still experience therapy failure followed by disease progression into a blast phase with poor outcomes even on intensive therapy. This review focuses on the current state of knowledge regarding the pathobiology of the blast phase and its fundamental characteristics, including blockade of cell differentiation, genetic instability, the occurrence of chromosomal aberrations and somatic mutations, and their impact on disease prognosis. The article also provides a brief overview of the current treatment options for the blast phase, its challenges, and possible perspectives.

Keywords:

chronic myeloid leukaemia – Chromosomal aberrations – somatic mutations – blast phase – blasts – blockade of differentiation

Sources

1. Hoffmann VS, Baccarani M, Hasford J, et al. Treatment and outcome of 2904 CML patients from the EUTOS population-based registry. Leukemia. 2017; 31: 593–601.

2. Faber E, Mužík J, Koza V, et al. Treatment of consecutive patients with chronic myeloid leukaemia in the cooperating centres from the Czech Republic and the whole of Slovakia after 2000 – a report from the population-based CAMELIA Registry. Eur J Haematol. 2011; 87: 157–168.

3. Bonifacio M, Stagno F, Scaffidi L, Krampera M, Di Raimondo F. Management of chronic myeloid leukemia in advanced phase. Front Oncol. 2019; 9: 1132.

4. Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization classification of haematolymphoid tumours: myeloid and histiocytic/dendritic neoplasms. Leukemia. 2022; 36: 1703–1719.

5. DeFilipp Z, Khoury HJ. Management of advanced-phase chronic myeloid leukemia. Curr Hematol Malig Rep. 2015; 10: 173–181.

6. Saußele S, Silver RT. Management of chronic myeloid leukemia in blast crisis. Ann Hematol. 2015; 94 Suppl 2: S159–S165.

7. Hehlmann R, Lauseker M, Saußele S, et al. Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10-year survival results of the randomized CML study IV and impact of non-CML determinants. Leukemia. 2017; 31: 2398–2406.

8. Bavaro L, Martelli M, Cavo M, Soverini S. Mechanisms of disease progression and resistance to tyrosine kinase inhibitor therapy in chronic myeloid leukemia: an update. Int J Mol Sci. 2019; 20: 6141.

9. Radich JP. The biology of CML blast crisis. Hematology Am Soc Hematol Educ Program. 2007: 384–391.

10. Chereda B, Melo JV. Natural course and biology of CML. Ann Hematol. 2015; 94 (Suppl 2): S107–S121.

11. Neviani P, Harb JG, Oaks JJ, et al. PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells. J Clin Invest. 2013; 123: 4144–4157.

12. Giustacchini A, Thongjuea S, Barkas N, et al. Single-cell transcriptomics uncovers distinct molecular signatures of stem cells in chronic myeloid leukemia. Nat Med. 2017; 23: 692–702.

13. Zhang W, Yang B, Weng L, et al. Single cell sequencing reveals cell populations that predict primary resistance to imatinib in chronic myeloid leukemia. Aging (Albany NY). 2020; 12: 25337–25355.

14. Abraham SA, Hopcroft LE, Carrick E, et al. Dual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells. Nature. 2016; 534: 341–346.

15. Holyoake T, Jiang X, Eaves C, Eaves A. Isolation of a highly quiescent subpopulation of primitive leukemic cells in chronic myeloid leukemia. Blood 1999; 94: 2056–2064.

16. Holyoake TL, Vetrie D. The chronic myeloid leukemia stem cell: stemming the tide of persistence. Blood. 2017; 129: 1595–1606.

17. Jamieson CH, Ailles LE, Dylla SJ, et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med. 2004; 351: 657–667.

18. Kinstrie R, Karamitros D, Goardon N, et al. Heterogeneous leukemia stem cells in myeloid blast phase chronic myeloid leukemia. Blood Adv. 2016; 1: 160–169.

19. El Rassi F, Bergsagel JD, Arellano M, et al. Predicting early blast transformation in chronic-phase chronic myeloid leukemia: is immunophenotyping the missing link? Cancer. 2015; 121: 872–875.

20. Khalidi HS, Brynes RK, Medeiros LJ, et al. The immunophenotype of blast transformation of chronic myelogenous leukemia: a high frequency of mixed lineage phenotype in „lymphoid“ blasts and A comparison of morphologic, immunophenotypic, and molecular findings. Mod Pathol. 1998; 11: 1211–1221.

21. Reid AG, De Melo VA, Elderfield K, et al. Phenotype of blasts in chronic myeloid leukemia in blastic phase-Analysis of bone marrow trephine biopsies and correlation with cytogenetics. Leuk Res. 2009; 33: 418–425.

22. Sadovnik I, Herrmann H, Eisenwort G, et al. Expression of CD25 on leukemic stem cells in BCR-ABL1+ CML: Potential diagnostic value and functional implications. Exp Hematol. 2017; 51: 17–24.

23. Lee MY, Park CJ, Cho YU, et al. Differences in PD-1 expression on CD8+ T-cells in chronic myeloid leukemia patients according to disease phase and TKI medication. Cancer Immunol Immunother. 2020; 69: 2223–2232.

24. Barnes DJ, Palaiologou D, Panousopoulou E, et al. Bcr-Abl expression levels determine the rate of development of resistance to imatinib mesylate in chronic myeloid leukemia. Cancer Res. 2005; 65: 8912–8919.

25. Huntly BJ, Shigematsu H, Deguchi K, et al. MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors. Cancer Cell. 2004; 6: 587–596.

26. Radich JP, Dai H, Mao M, et al. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci U S A. 2006; 103: 2794–2799.

27. Walz C, Ahmed W, Lazarides K, et al. Essential role for Stat5a/b in myeloproliferative neoplasms induced by BCR-ABL1 and JAK2 (V617F) in mice. Blood. 2012; 119: 3550–3560.

28. Heidel FH, Bullinger L, Feng Z, et al. Genetic and pharmacologic inhibition of b-catenin targets imatinib-resistant leukemia stem cells in CML. Cell Stem Cell. 2012; 10: 412–424

29. Tomasello L, Vezzalini M, Boni C, et al. Regulative loop between b-catenin and protein tyrosine receptor type g in chronic myeloid leukemia. Int J Mol Sci. 2020; 21: 2298.

30. Manachai N, Saito Y, Nakahata S, Bahirvani AG, Osato M, Morishita K. Activation of EVI1 transcription by the LEF1/b-catenin complex with p53-alteration in myeloid blast crisis of chronic myeloid leukemia. Biochem Biophys Res Commun. 2017; 482: 994–1000.

31. Sato T, Goyama S, Kataoka K, Nasu R, et al. Evi1 defines leukemia-initiating capacity and tyrosine kinase inhibitor resistance in chronic myeloid leukemia. Oncogene. 2014; 33: 5028–5038.

32. Laricchia-Robbio L, Premanand K, Rinaldi CR, Nucifora G. EVI1 Impairs myelopoiesis by deregulation of PU.1 function. Cancer Res. 2009; 69: 1633–1642.

33. Yoshimi A, Goyama S, Watanabe-Okochi N, et al. Evi1 represses PTEN expression and activates PI3K/AKT/mTOR via interactions with polycomb proteins. Blood. 2011; 117: 3617–3628.

34. Desterke C, Hugues P, Hwang JW, Bennaceur-Griscelli A, Turhan AG. Embryonic program activated during blast crisis of chronic myelogenous leukemia (CML) implicates a TCF7L2 and MYC cooperative chromatin binding. Int J Mol Sci. 2020; 21: 4057.

35. Lauseker M, Bachl K, Turkina A, et al. Prognosis of patients with chronic myeloid leukemia presenting in advanced phase is defined mainly by blast count, but also by age, chromosomal aberrations and hemoglobin. Am J Hematol. 2019; 94: 1236–1243

36. Heller G, Topakian T, Altenberger C, et al. Next-generation sequencing identifies major DNA methylation changes during progression of Ph+ chronic myeloid leukemia. Leukemia. 2016; 30: 1861–1868.

37. Ko TK, Javed A, Lee KL, et al. An integrative model of pathway convergence in genetically heterogeneous blast crisis chronic myeloid leukemia. Blood. 2020; 135: 2337–2353.

38. Koptyra M, Cramer K, Slupianek A, Richardson C, Skorski T. BCR/ABL promotes accumulation of chromosomal aberrations induced by oxidative and genotoxic stress. Leukemia. 2008; 22: 1969–1972.

39. Warsch W, Grundschober E, Berger A, et al. STAT5 triggers BCR-ABL1 mutation by mediating ROS production in chronic myeloid leukaemia. Oncotarget. 2012; 3: 1669–1687.

40. Nieborowska-Skorska M, Flis S, Skorski T. AKT-induced reactive oxygen species generate imatinib-resistant clones emerging from chronic myeloid leukemia progenitor cells. Leukemia. 2014; 28: 2416–2418.

41. Yuan H, Wang Z, Gao C, et al. BCR-ABL gene expression is required for its mutations in a novel KCL-22 cell culture model for acquired resistance of chronic myelogenous leukemia. J Biol Chem. 2010; 285: 5085–5096.

42. Grant H, Jiang X, Stebbing J, et al. Analysis of BCR-ABL1 tyrosine kinase domain mutational spectra in primitive chronic myeloid leukemia cells suggests a unique mutator phenotype. Leukemia. 2010; 24: 1817–1821.

43. Stoklosa T, Poplawski T, Koptyra M, et al. BCR/ABL inhibits mismatch repair to protect from apoptosis and induce point mutations. Cancer Res. 2008; 68: 2576–2580.

44. Dkhissi F, Aggoune D, Pontis J, et al. The downregulation of BAP1 expression by BCR-ABL reduces the stability of BRCA1 in chronic myeloid leukemia. Exp Hematol. 2015; 43: 775–780.

45. Deutsch E, Dugray A, AbdulKarim B, et al. BCR-ABL down-regulates the DNA repair protein DNA-PKcs. Blood. 2001; 97: 2084–2090.

46. Wang Z, Yuan H, Roth M, et al. SIRT1 deacetylase promotes acquisition of genetic mutations for drug resistance in CML cells. Oncogene. 2013; 32: 589–598.

47. Muvarak N, Kelley S, Robert C, et al. c-MYC generates repair errors via increased transcription of alternative-NHEJ factors, LIG3 and PARP1, in tyrosine kinase-activated leukemias. Mol Cancer Res. 2015; 13: 699–712

48. Curik N, Polivkova V, Burda P, et al. Somatic mutations in oncogenes are in chronic myeloid leukemia acquired de novo via deregulated base-excision repair and alternative non-homologous end joining. Front Oncol. 2021; 11: 744373.

49. Chen Z, Shao C, Wang W, et al. Cytogenetic landscape and impact in blast phase of chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy. Leukemia. 2017; 31: 585–592.

50. Mitelman F, Levan G, Nilsson PG, Brandt L. Non-random karyotypic evolution in chronic myeloid leukemia. Int J Cancer. 1976; 18: 24–30.

51. Johansson B, Fioretos T, Mitelman F. Cytogenetic and molecular genetic evolution of chronic myeloid leukemia. Acta Haematol. 2002; 107: 76–94.

52. Čičátková P, Jarošová M, Mazalová M, et al. Přídatné cytogenetické abnormality prokázané při diagnóze chronické myeloidní leukemie a jejich vliv na prognózu – analýza z databáze INFINITY. Transfuze Hematol Dnes. 2022; 28 (Suppl 2): 2S48.

53. Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013; 122: 872–884.

54. Hehlmann R, Voskanyan A, Lauseker M, et al. High-risk additional chromosomal abnormalities at low blast counts herald death by CML. Leukemia. 2020; 34: 2074–2086.

55. Hochhaus A, Baccarani M, Silver RT, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020; 34: 966–984.

56. Issa GC, Kantarjian H, Nogueras Gonzalez G, et al. Clonal chromosomal abnormalities appearing in Philadelphia chromosome-negative metaphases during CML treatment. Blood. 2017; 130: 2084–2091.

57. Wang W, Cortes JE, Tang G, et al. Risk stratification of chromosomal abnormalities in chronic myelogenous leukemia in the era of tyrosine kinase inhibitor therapy. Blood. 2016; 127: 2742–2750.

58. Wang L, Li L, Chen R, Huang X, Ye X. Understanding and monitoring chronic myeloid leukemia blast crisis: how to better manage patients. Cancer Manag Res. 2021; 13: 4987–5000.

59. Branford S, Kim DDH, Apperley JF, et al. Laying the foundation for genomically-based risk assessment in chronic myeloid leukemia. Leukemia. 2019; 33: 1835–1850.

60. Nteliopoulos G, Bazeos A, Claudiani S, et al. Somatic variants in epigenetic modifiers can predict failure of response to imatinib but not to second-generation tyrosine kinase inhibitors. Haematologica. 2019; 104: 2400–2409.

61. Adnan-Awad S, Kankainen M, Mustjoki S. Mutational landscape of chronic myeloid leukemia: more than a single oncogene leukemia. Leuk Lymphoma. 2021; 62: 2064–2078.

62. Gelsi-Boyer V, Brecqueville M, Devillier R, Murati A, Mozziconacci MJ, Birnbaum D. Mutations in ASXL1 are associated with poor prognosis across the spectrum of malignant myeloid diseases. J Hematol Oncol. 2012; 5: 12.

63. Kim T, Tyndel MS, Kim HJ, et al. Spectrum of somatic mutation dynamics in chronic myeloid leukemia following tyrosine kinase inhibitor therapy. Blood. 2017; 129: 38–47.

64. Wu W, Xu N, Zhou X, et al. Integrative genomic analysis reveals cancer-associated gene mutations in chronic myeloid leukemia patients with resistance or intolerance to tyrosine kinase inhibitor. Onco Targets Ther. 2020; 13: 8581–8591.

65. Schmitt MW, Pritchard JR, Leighow SM, et al. Single-molecule sequencing reveals patterns of preexisting drug resistance that suggest treatment strategies in Philadelphia-positive leukemias. Clin Cancer Res. 2018; 24: 5321–5334.

66. Mologni L, Piazza R, Khandelwal P, Pirola A, Gambacorti-Passerini C. Somatic mutations identified at diagnosis by exome sequencing can predict response to imatinib in chronic phase chronic myeloid leukemia (CML) patients. Am J Hematol. 2017; 92: E623–E625.

67. Grossmann V, Kohlmann A, Zenger M, et al. A deep-sequencing study of chronic myeloid leukemia patients in blast crisis (BC-CML) detects mutations in 76.9% of cases. Leukemia. 2011; 25: 557–560.

68. Branford S, Wang P, Yeung DT, et al. Integrative genomic analysis reveals cancer-associated mutations at diagnosis of CML in patients with high-risk disease. Blood. 2018; 132: 948–961.

69. Ochi Y, Yoshida K, Huang YJ, et al. Clonal evolution and clinical implications of genetic abnormalities in blastic transformation of chronic myeloid leukaemia. Nat Commun. 2021; 12: 2833.

70. Abdel-Wahab O, Adli M, LaFave LM, et al. ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression. Cancer Cell. 2012; 22: 180–193.

71. Uni M, Masamoto Y, Sato T, et al. Modeling ASXL1 mutation revealed impaired hematopoiesis caused by derepression of p16Ink4a through aberrant PRC1-mediated histone modification. Leukemia. 2019; 33: 191–204.

72. Khan M, Cortes J, Kadia T, et al. Clinical outcomes and co-occurring mutations in patients with RUNX1-mutated acute myeloid leukemia. Int J Mol Sci. 2017; 18: 1618.

73. Adnan Awad S, Dufva O, Ianevski A, et al. RUNX1 mutations in blast-phase chronic myeloid leukemia associate with distinct phenotypes, transcriptional profiles, and drug responses. Leukemia. 2021; 35: 1087–1099.

74. Kelly MJ, So J, Rogers AJ, et al. Bcor loss perturbs myeloid differentiation and promotes leukaemogenesis. Nat Commun. 2019; 10: 1347.

75. Schaefer EJ, Wang HC, Karp HQ, et al. BCOR and BCORL1 mutations drive epigenetic reprogramming and oncogenic signaling by unlinking PRC1.1 from target genes. Blood Cancer Discov. 2022; 3: 116–135.

76. Zhang SJ, Ma LY, Huang QH, et al. Gain-of-function mutation of GATA-2 in acute myeloid transformation of chronic myeloid leukemia. Proc Natl Acad Sci U S A. 2008; 105: 2076–2081.

77. Magistroni V, Mauri M, D‘Aliberti D, et al. De novo UBE2A mutations are recurrently acquired during chronic myeloid leukemia progression and interfere with myeloid differentiation pathways. Haematologica. 2019; 104: 1789–1797.

78. Williams RT, Sherr CJ. BCR-ABL and CDKN2A: a dropped connection. Nat Rev Cancer. 2008; 8: 563.

79. Nakayama H, Ishimaru F, Avitahl N, et al. Decreases in Ikaros activity correlate with blast crisis in patients with chronic myelogenous leukemia. Cancer Res. 1999; 59: 3931–3934.

80. Thomson DW, Shahrin NH, Wang PPS, et al. Aberrant RAG-mediated recombination contributes to multiple structural rearrangements in lymphoid blast crisis of chronic myeloid leukemia. Leukemia. 2020; 34: 2051–2063.

81. Jain P, Kantarjian HM, Ghorab A, et al. Prognostic factors and survival outcomes in patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era: Cohort study of 477 patients. Cancer. 2017; 123: 4391–4402.

82. How J, Venkataraman V, Hobbs GS. Blast and accelerated phase CML: room for improvement. Hematology Am Soc Hematol Educ Program. 2021; 2021: 122–128.

83. Hehlmann R. How I treat CML blast crisis. Blood. 2012; 120: 737–747.

84. Strati P, Kantarjian H, Thomas D, et al. HCVAD plus imatinib or dasatinib in lymphoid blastic phase chronic myeloid leukemia. Cancer. 2014; 120: 373–380.

85. Copland M, Slade D, McIlroy G, et al. Ponatinib with fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor chemotherapy for patients with blast-phase chronic myeloid leukaemia (MATCHPOINT): a single-arm, multicentre, phase 1/2 trial. Lancet Haematol. 2022; 9: e121–e132.

86. Saxena K, Jabbour E, Issa G, et al. Impact of frontline treatment approach on outcomes of myeloid blast phase CML. J Hematol Oncol. 2021; 14: 94.

87. DeFilipp Z, Ancheta R, Liu Y, et al. Maintenance tyrosine kinase inhibitors following allogeneic hematopoietic stem cell transplantation for chronic myelogenous leukemia: A Center for International Blood and Marrow Transplant Research Study. Biol Blood Marrow Transplant. 2020; 26: 472–479.

88. Kishida Y, Najima Y, Otsuka Y, et al. Post-transplant maintenance treatment with ponatinib for Philadelphia chromosome positive leukemia. Blood 2019; 134 (Suppl 1): 5694.

89. Pietarinen PO, Pemovska T, Kontro M, et al. Novel drug candidates for blast phase chronic myeloid leukemia from high-throughput drug sensitivity and resistance testing. Blood Cancer J. 2015; 5: e309.

90. Maiti A, Franquiz MJ, Ravandi F, et al. Venetoclax and BCR-ABL tyrosine kinase inhibitor combinations: outcome in patients with Philadelphia chromosome-positive advanced myeloid leukemias. Acta Haematol. 2020; 143: 567–573.

Labels

Haematology Internal medicine Clinical oncology

Editorial

Leukemic stem cell surface markers in chronic myeloid leukaemia

Vascular adverse events in chronic myeloid leukaemia patients during tyrosine kinase inhibitor therapy in daily clinical practice – analysis from the INFINITY database

Rare and unfavorable course of chronic myeloid leukemia – a case report and review of the literature

Recommendations for thrombotic risk stratification and targeted thromboprophylaxis in women during assisted reproduction

Prevention, diagnosis and treatment of cancer-associated thromboembolism

Recommendations of the Czech Society of Haematology for the diagnosis and treatment of immune thrombocytopenia in adults

Symposium and workshop – actual challenges and implementation of new technologies in the treatment of chronic myeloid leukaemia

Fixní délka léčby CLL – realita, nebo fikce?

Jubileum primářky Lenky Walterové

Article was published in

Transfusion and Haematology Today

2023 Issue 1