Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

CHRONIC MYELOGENOUS LEUKEMIA

Why chronic myeloid leukaemia cannot be cured by tyrosine kinase-inhibitors

Leukemia volume 35, pages 2199–2204 (2021)Cite this article

Subjects

There is remarkable success treating chronic myeloid leukaemia (CML) with tyrosine kinase inhibitors (TKIs) to the extent some physicians believe CML is cured [1, 2], but what exactly does this mean? As we discuss below, biologists, physicians and patients have different definitions of cure. Understanding these differences is fundamental to how we approach curing CML.

Some data indicate persons with CML, especially in countries with universal health care access, have a sex- and age-adjusted survival like normals which physicians and patients may consider a cure [1,2,3]. This is not so for most people worldwide with CML [4,5,6]. Also, many if not most of these cured persons must continue to receive TKI therapy, perhaps for their remaining lifetimes [1, 2]. This may be acceptable to a 75 years old with co-morbidities more likely to kill him/her than CML but perhaps not for an otherwise healthy 40 years old. Also, TKI-related adverse effects are not trivial over a lifetime, especially newer TKIs [7].

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

References

  1. Baccarani M, Abruzzese E, Accurso V, Albano F, Annunziata M, Barulli S, et al. Managing chronic myeloid leukemia for treatment-free remission: a proposal from the GIMEMA CML WP. Blood Adv. 2019;3:4280–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Hochhaus A, Baccarani M, Silver RT, Schiffer C, Apperley JF, Cervantes F, et al. European LeukemiaNet recommendations for treating chronic myeloid leukemia. Leukemia. 2020;34:966–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Boweer H, Bjorkholm M, Dickman PW, Hoglund M, Lambert PC, Andresson TM. Life expectancy of patients with chronic myeloid leukemia approaches the life expectancy of the general population. J Clin Oncol. 2016;34:2851–7.

    Article  CAS  Google Scholar 

  4. Lauseker M, Hasford J, Pfirrmann M, Hehlmann R, fort he German CML Study Group. The impact of health care settings on survival time of patients with chronic myeloid leukemia. Blood. 2014;123:2494–6.

    Article  CAS  PubMed  Google Scholar 

  5. Hehlmann R, Lauseker M, Saussele S, Pfirrmann M, Krause S, Kolb HJ, 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;31:2398–406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Malhotra H, Radich J, Garcia-Gonzalez P. Meeting the needs of CML patients in resource-poor countries. 61° Congress of the American Society of Hematology, 2019. Educ Program. 2019;1:433–42.

    Google Scholar 

  7. Steegmann JL, Baccarani M, Breccia M, Casado LF, Garcia-Gutierrez V, Hochhaus A, et al. European LeukemiaNet recommendations for the management and avoidance of adverse events of treatment in chronic myeloid leukaemia. Leukemia. 2016;30:1648–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Saussele S, Richter J, Hochhaus A, Mahon F-X. The concept of treatment-free remission in chronic myeloid leukemia. Leukemia. 2016;30:1638–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Etienne G, Guilhot J, Rea D, Rigal H, Huguet F, Nicolini F, et al. Long-term follow-up of the French Stop Imatinib (STIMI) Study in patients with chronic myeloid leukemia. J Clin Oncol. 2017;35:298–305.

    Article  PubMed  Google Scholar 

  10. Campiotti L, Suter MB, Guasti L, Piazza R, Gambacorti Passerini C, Grandi AM, et al. Imatinib discontinuation in chronic myeloid leukaemia patients with undetectable BCR-ABL transcript level: a systematic review and a meta-analysis. Eur J Cancer. 2017;77:48–56.

    Article  CAS  PubMed  Google Scholar 

  11. Saussele S, Richter J, Guilhot J, Gruber FX, Hjorth Hansen H, Almeida A, et al. Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicenter, non-randomized trial. Lancet Oncol. 2018;19:747–57.

    Article  CAS  PubMed  Google Scholar 

  12. Dulucq S, Astrugue C, Etienne G, Mahon FX, Bernard A. Risk of molecular recurrence after tyrosine kinase inhibitor discontinuation in chronic myeloid leukaemia patients: a systematic review of literature with a meta-analysis of studies over the last ten years. Br J Haematol. 2020;189:452–68.

    Article  PubMed  Google Scholar 

  13. Radivoyevitch T, Weaver D, Hobbs B, Maciejewski JP, Hehlmann R, Jiang Q, et al. Do persons with chronic myeloid leukaemia have normal or near normal survival? Leukemia. 2020;34:333–5.

    Article  PubMed  Google Scholar 

  14. Branford S. Why is it critical to achieve a deep molecular response in chronic myeloid leukemia? Haematologica. 2020;105:2730–273.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ross DM, Branford S, Seymour JF, Schwarer AP, Arthur C, Bartley PA, et al. Patients with chronic myeloid leukemia who maintain a complete molecular response after stopping imatinib treatment have evidence of persistent leukemia by DNA PCR. Leukemia. 2010;24:1719–24.

    Article  CAS  PubMed  Google Scholar 

  16. Jabbour E. Chronic myeloid leukemia: front-line drug of choice. Am J Hematol. 2016;91:59–66.

    Article  PubMed  Google Scholar 

  17. Hochhaus A, Rosti G, Cross NCP, Steegmann JL, le Coutre P, Osssenkoppele G, et al. Front-line nilotinib in patients with chronic myeloid leukemia in chronic phase:results from the European ENEST1st study. Leukemia. 2016;30:57–64.

    Article  CAS  PubMed  Google Scholar 

  18. Cortes JE, Saglio G, Kantarjian HM, Baccarani M, Mayer J, Boqué C, et al. Final 5-year study results of DASISION: the dasatinib versus imatinib study of treatment-naive chronic myeloid leukemia trial. J Clin Oncol. 2016;34:2333–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Pane F, Luciano L, Pugliese N. International prospective study comparing nilotinib versus imatinib with early switch to nilotinib to obtain sustained treatment-free remission in patients with chronic myeloid leukemia. A GIMEMA and HOVON study. Blood. 2018;132:1750.

    Article  Google Scholar 

  20. Kantarjian HM, Hughes TP, Larson RA, Kim D-W, Issaragrisil S, le Coutre P, et al. Long term outcomes with frontline nilotinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase: ENESTnd 10-year analysis. Leukemia. 2021;35:440–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Braun TP, Eide CA, Druker BJ. Response and resistance to BCR-ABL1-targeted therapies. Cancer Cell. 2020;37:530–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Masarova L, Cortes JE, Keyur PP, O’Brien S, Nogueras-Gonzalez GM, Konopleva M, et al. Long-term results of a phase 2 trial of Nilotinib 400 mg twice daily in newly diagnosed patients with chronic-phase chronic myeloid leukemia. Cancer. 2020. https://doi.org/10.1002/cncr.32623.

  23. Hehlmann R, Hochhaus A, Baccarani M, on behalf of the European LeukemiaNet. Chronic myeloid leukaemia. Lancet. 2007;370:342–50.

    Article  CAS  PubMed  Google Scholar 

  24. Killmann S-AA. Chronic myelogenous leukemia: preleukemia or leukemia? In: Tura S, Baccarani M, editors. Chronic myeloid leukemia, proceeding of an international Symposium, Bologna, 15–16 April 1972, Pavia: Haematologica publishing; 1972. p. 45–53.

  25. Jaisval S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl J Med. 2014;371:2488–98.

    Article  CAS  Google Scholar 

  26. Xie M, Lu C, Wang J, McLellan MD, Johnson KJ, Wendl MC, et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med. 2014;20:1472–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zoi K, Cross NCP. Genomics of myeloproliferative disorders. J Clin Oncol. 2017;35:947–54.

    Article  CAS  PubMed  Google Scholar 

  28. Williams R, Lee J, Moore L, Baxter JE, Hewinson J, Dawson KJ, et al. Driver mutation acquisition in utero and childhood followed by lifelong clonal evolution underlies myeloproliferative neoplasms. Blood. 2020;136:LBA1.

    Article  Google Scholar 

  29. Biernaux C, Loos M, Sels A, Huez G, Stryckmans P. Detection of major bcr-abl gene expression at a very low level in blood cells of some healthy individuals. Blood. 1995;86:3118–22.

    Article  CAS  PubMed  Google Scholar 

  30. Bose S, Deininger M, Gora-Tybor J, Goldman JM, Melo JV. The presence of typical and atypical BCR-ABL fusion genes in leukocytes of normal individuals: biologic significance and implication for the assessment of minimal residual disease. Blood. 1998;92:3362–7.

    Article  CAS  PubMed  Google Scholar 

  31. Boquett JA, Alves JRP, de Oliveira CEC. Analysis of BCR/ABL transcripts in healthy individuals. Genet Mol Res. 2013;12:4967–71.

    Article  CAS  PubMed  Google Scholar 

  32. Ismail SI, Naffa RG, Yousef Al-MF, Ghanim MT. Incidence of bcr-abl fusion transcripts in healthy individuals. Mol Med Rep. 2014;9:1271–6.

    Article  CAS  PubMed  Google Scholar 

  33. Score J, Chase A, Forsberg LA, Feng L, Waghorn K, Jones AV. Detection of leukemia- associated mutations in peripheral blood DNA of hematologically normal elderly individuals. Leukemia. 2015;29:1600–18.

    Article  CAS  PubMed  Google Scholar 

  34. Kuan JW, Su AT, Leong CF, Osato M, Sahida G. Systematic review of normal subjects harboring BCR-ABL1 fusion gene. Acta Haematol. 2020;143:96–111.

    Article  CAS  PubMed  Google Scholar 

  35. Gale RP, Apperley JF. Transmission of CML or of t(9;22) and BCR/ABL? They are not the same. Bone Marrow Transplant. 2015;50:1582–4.

    Article  CAS  PubMed  Google Scholar 

  36. Abecasis M, Cross NCP, Brito M, Ferreira I, Sakamoto KM, Hijiya N, et al. Is cancer latency an outdated concept? Lessons from chronic myeloid leukemia. Leukemia. 2020;34:2279–84.

    Article  PubMed  Google Scholar 

  37. Heyssel R, Brill AB, Woodbury LA, Nishimura ET, Ghose T, Hoshino T, et al. Leukemia in Hiroshima atomic bomb survivors. Blood. 1960;15:313–31.

    Article  CAS  PubMed  Google Scholar 

  38. Hsu WL, Preston DL, Soda M, Sogiyama H, Funamoto S, Kodama K, et al. The incidence of leukemia, lymphoma and multiple myeloma among atomic bomb survivors 1950–2001. Radiat Res. 2013;179:361–82.

    Article  CAS  PubMed  Google Scholar 

  39. Meral Gunes A, Millot F, Kalwak K, Lausen B, Sedlacek A, Versluys AB, et al. Features and outcome of chronic myeloid leukemia at very young age: data from the International Pediatric Chronic Myelogenous Leukemia Registry. Pediatr Blood Cancer. 2020. https://doi.org/10.1002/pbc.28706.

  40. Ross DM, Hughes TP. Counterpoint: there is a best duration of deep molecular response for treatment-free remission, but it is patient-specific, and that is the challenge. Br J Haematol. 2021;192:24–7.

    Article  PubMed  Google Scholar 

  41. Melo JV. The diversity of BCR-ABL fusion proteins and their relationship to leukemia phenotype. Blood. 1996;88:2375–84.

    Article  CAS  PubMed  Google Scholar 

  42. Baccarani M, Castagnetti F, Gugliotta G, Rosti G, Soverini S, Albeer A. The International BCR-ABL Study Group et al. The proportion of different BCR-ABL1 transcript types in chronic myeloid leukemia. An international overview. Leukemia. 2019;33:1173–83.

    Article  CAS  PubMed  Google Scholar 

  43. Baccarani M, Rosti G, Soverini S. Chronic myeloid leukemia: the concepts of resistance and persistence and the relationship with the BCR-ABL1 transcript type. Leukemia. 2019;33:2358–64.

    Article  CAS  PubMed  Google Scholar 

  44. Claudiani S, Apperley JF, Gale RP, Clark R, Szydlo R, Deplan S, et al. e14a2 BCR-ABL1 transcript is associated with a higher rate of treatment-free remission in individuals with chronic myeloid leukemia after stopping tyrosine kinase therapy. Haematologica. 2017;102:e297–e299.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ley TJ, Ding L, Walter MJ, McLellan MD, Lamprecht T, Larson DE, et al. DNMT3 mutations in acute myeloid leukemia. N. Engl J Med. 2010;363:2424–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Soverini S, Score J, Iacobucci I, Poerio A, Lonetti A, Gnani A, et al. IDH2 somatic mutations in chronic myeloid leukemia patients in blastic crisis. Leukemia. 2011;25:178–81.

    Article  CAS  PubMed  Google Scholar 

  47. Housmand M, Simonetti G, Circosta P, Gaidano V, Cignetti A, Martinelli G, et al. Chronic myeloid leukemia stem cells. Leukemia. 2019;33:1543–56.

    Article  CAS  Google Scholar 

  48. Vetrie D, Helgason GV, Copland Mhairi. The leukaemia stem cells: similarities, differences and clinical prospects in CML and AML. Nat Rev Cancer. 2020;28:158–73.

    Article  CAS  Google Scholar 

  49. Nteniopoulos G, Bazeos A, Claudiani S, Curry GG, Szydlo R, Alikian M, et al. Somatic variants in epigenetic modifiers can predict failure of response to imatinib but not to second generation tyrosine kinase inhibitors. Haematologica. 2019;104:2400–9.

    Article  CAS  Google Scholar 

  50. Morotti A, Carrà G, Panuzzo C, Crivellaro S, Taulli R, Guerrasio A, et al. Protein Kinase C2: a targetable BCR-ABL partner on Philadelphia-positive leukemias. Adv Hematol. 2015. https://doi.org/10.1155/2015/612567.

  51. Packer ML, Rana S, Hayward R, O’Hare T, Eide CA, Rebocho A, et al. Nilotinib and MEK inhibitors induce synthetic lethality through paradoxical activation of RAF in drug-resistant chronic myeloid leukemia. Cancer Cell. 2011;20:715–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Mahon F-X, Deininger MW, Schultheis B, Chabrol J, Reiffers J, Goldman JM, et al. Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance. Blood. 2000;96:1070–9.

    Article  CAS  PubMed  Google Scholar 

  53. Jordanides NE, Jorgensen HG, Holyoake TL, Mounford JC. Functional ABCG2 is overexpressed on primary CML CD34+cells and is inhibited by imatinib mesylate. Blood. 2006;108:1370–3.

    Article  CAS  PubMed  Google Scholar 

  54. White DL, Saunders VA, Dang P, Engler J, Zannettino ACW, Cambareri AC, et al. Most CML patients who have a suboptimal response to imatinib have low OCT-1 activity: higher doses of imatinib may overcome the negative impact of low OCT-1 activity. Blood. 2007;108:4064–72.

    Article  CAS  Google Scholar 

  55. Angelini S, Soverini S, Ravegnini G, Barnett M, Turrini E, Thornquist M, et al. Association between imatinib transporters and metabolyzing enzymes genotype and response in newly diagnosed chronic myeloid leukemia patients receiving imatinib therapy. Haematologica. 2013;98:193–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Giannoudis A, Davies A, Harris RJ, Lucas CM, Pirmohamed M, Clark RE. The clinical significance of ABCC3 as an imatinib transporter in chronic myeloid leukaemia. Leukemia. 2014;28:1360–3.

    Article  CAS  PubMed  Google Scholar 

  57. Eadle LN, Dang P, Saunders VA, Yeung DT, Osborn MP, Grigg AP, et al. The clinical significance of ABCB1 overexpression in predicting outcome of CML patients undergoing first-line imatinib treatment. Leukemia. 2017;31:75–82.

    Article  CAS  Google Scholar 

  58. Eadle LN, Hughes TP, White DL. Patients with low OCT-1 activity and high ABCB1 fold rise have poor long-term outcomes in response to tyrosine kinase inhibitors therapy. Leukemia. 2018;32:2288–91.

    Article  CAS  Google Scholar 

  59. Pagani MS, Dang P, Kommers IO, Goyne JM, Nicola M, Saunders VA. BCR-ABL1 genomic DNA PCR response kinetics during first-line imatinib treatment of chronic myeloid leukemia. Haematologica. 2018;103:2026–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Holyoake T, Jiang X, Eaves C, Eaves A. Isolation of a highly quiescent subpopulation of primitive leukemic cells in chronic myeloid leukemia. Blood. 1998;94:2056–66.

    Article  Google Scholar 

  61. Kinstrie R, Home GA, Morrison H, Irvine D, Munje C, Castaneda EG, et al. CD93 is expressed on chronic myeloid leukemia stem cells and identifies a quiescent population which persists after tyrosine kinase inhibitor therapy. Leukemia. 2020;34:1613–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Pagani IS, Dang P, Saunders VA, Grose R, Shanmuganathan N, Kok CH, et al. Lineage of measurable residual disease in patients with chronic myeloid leukemia in treatment-free remission. Leukemia. 2020;34:1052–61.

    Article  PubMed  Google Scholar 

  63. Bocchia M, Gentili S, Abruzzese E, Fanelli A, Iuliano F, Tabilio A, et al. Effect of a p210 multipeptide vaccine associated with imatinib or interferon in patients with chronic myeloid leukaemia and persistent residual disease: a multicentre observational study. Lancet. 2005;365:657–62.

    Article  CAS  PubMed  Google Scholar 

  64. Butt NM, Rojas JM, Wang L, Christmas SE, Abu-Eisha H, Clark RE. Circulating bcr-abl-specific CD8+ T cells in chronic myeloid leukemia patients and healthy subjects. Haematologica. 2005;90:1315–23.

    CAS  PubMed  Google Scholar 

  65. Kreutzman A, Juvonen V, Kairisto V, Ekblom M, Stenke L, Seggewiss R, et al. Mono/oligoclonal T and NK cells are common in chronic myeloid leukemia patients at diagnosis and expand during dasatinib therapy. Blood. 2010;116:772–82.

    Article  CAS  PubMed  Google Scholar 

  66. Giustacchini A, Thongjuea S, Narkas N, Woll PS, Povinelli BJ, Booth CAG, et al. Single cell transcriptomics uncovers distinct molecular signatures of stem cells in chronic myeloid leukemia. Nat Med. 2017;23:692–70.

    Article  CAS  PubMed  Google Scholar 

  67. Bilich T, Neelde A, Bichmann L, Roerden M, Salih HR, Kowalewski DJ, et al. The HLA ligandome landscape of chronic myeloid leukemia delineates novel T-cell epitopes for immunotherapy. Blood. 2019;133:550–65.

    Article  CAS  PubMed  Google Scholar 

  68. Gale RP, Opelz G. Is there immunosurveillance against chronic myeloid leukemia? Possibly, but not much. Leuk Res. 2017;57:111.

    Article  Google Scholar 

  69. Branford S, Wang P, Yeung DT, Thomson D, Purins A, Wadham C, et al. Integrative genomic analysis reveals cancer-associated mutations at diagnosis of CML in patients with high risk disease. Blood. 2018;132:948–61.

    Article  CAS  PubMed  Google Scholar 

  70. Sokal JE, Cox EB, Baccarani M, Tura S, Gomez GA, Robertson JE, et al. Prognostic discrimination in “good-risk” chronic granulocytic leukemia. Blood. 1984;63:789–99.

    Article  CAS  PubMed  Google Scholar 

  71. Pfirrmann M, Baccarani M, Saussele S, Guilhot J, Cervantes F, Ossenkoppele G, et al. Prognosis of long-term survival considering disease-specific death in patients with chronic myeloid leukemia. Leukemia. 2016;30:48–56.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

MB acknowledges support from the European LeukemiaNet Foundation. RPG acknowledges support from the National Institute of Health Research (NIHR) Biomedical Research Centre funding scheme.

Author information

Authors and Affiliations

  1. Department of Hematology, “L. and A Seràgnoli” University of Bologna and St.Orsola-Malpighi University Hospital, Bologna, Italy

    Michele Baccarani

  2. Haematology Research Centre, Department of Immunology and Inflammation, Imperial College London, London, UK

    Robert Peter Gale

Authors
  1. Michele Baccarani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert Peter Gale
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michele Baccarani.

Ethics declarations

Conflict of interest

MB is a consultant to Novartis, Incyte and Fusion Pharma. RPG is a consultant to BeiGene Ltd., Fusion Pharma LLC, LaJolla NanoMedical Inc., Mingsight Parmaceuticals Inc. and CStone Pharmaceuticals; advisor to Antegene Biotech LLC, Medical Director, FFF Enterprises Inc.; partner, AZAC Inc.; Board of Directors, Russian Foundation for Cancer Research Support; and Scientific Advisory Board: StemRad Ltd.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Baccarani, M., Gale, R.P. Why chronic myeloid leukaemia cannot be cured by tyrosine kinase-inhibitors. Leukemia 35, 2199–2204 (2021). https://doi.org/10.1038/s41375-021-01272-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-021-01272-8

This article is cited by

Search

Advanced search

Quick links