Chronic Myeloid Leukaemia


Chronic myeloid leukaemia (CML) is a clonal BCR–ABL1‐positive myeloproliferative disorder that results from an acquired genetic change in a single pluripotential haematopoietic stem cell. Although CML is rare, the lessons learned from unravelling its molecular biology over the past three decades have resulted in successful treatment for patients and also in a major paradigm shift in cancer medicine in general. Today many forms of cancer are being treated with drugs that target various molecular abnormalities known to play a role in the pathogenesis of the candidate disease. For CML patients, the introduction of the original tyrosine kinase inhibitor (TKI), imatinib mesylate, in 1998 was an important therapeutic milestone with most patients achieving a complete cytogenetic response and prolongation of survival compared with the previous therapies other than allogeneic stem cell transplantation (allo‐SCT). A small minority of patients were also able to achieve a complete molecular remission (CMR). With the more recent introduction of the second generation TKIs, dasatinib and nilotinib, the treatment results for the newly diagnosed patient in chronic phase (CP) seem even better, in particular the number of patients achieving CMR. Allo‐SCT is increasingly being offered when patients fail at least two lines of TKIs, except for children, where some specialists feel, it is appropriate to offer SCT as first or second line therapy. Efforts are also made to assess the potential for immunotherapy and other novel drugs, such as ponatinib, targeting specific subgroups of patients, for example, those with a mutant T315I clone have been developed.

Key Concepts:

  • Concept of targeted therapy in cancer medicine.

  • Molecular pathogenesis of CML in CP: a single pathogenetic abnormality.

  • Imatinib as a paradigm for successful molecularly targeted therapy.

  • Second and third generation tyrosine kinase inhibitors: successes and challenges.

  • Role of allogeneic stem transplantation in the era of the second generation TKI.

Keywords: chronic myeloid leukaemia; Philadelphia chromosome; BCR–ABL1 gene; tyrosine kinase inhibitors; imatinib; dasatinib; nilotinib; bosutinib; allogeneic stem cell transplant; kinase domain mutations; mutant T315 clone; ponatinib

Figure 1.

allo‐SCT for CML in CP in Europe (2009).

Figure 10.

DASISION 24 months results – Cumulative incidence of MMR. Adapted from Kantarjian et al. . © American Society of Hematology.

Figure 11.

Forest plot comparing differences in adverse events rates for dasatinib and imatinib in the DASISION trial. Adapted with permission from Mughal et al. .

Figure 12.

ENESTnd 36 months results – Cumulative incidence of MMR. Adapted from Van Etten et al. .

Figure 13.

Forest plot comparing differences in adverse event rates for nilotinib and imatinib in the ENESTnd trail. Adapted with permission from Mughal et al. .

Figure 14.

The risk for transplantation in accordance to the Gratwohl EBMT score. Adapted from Gratwohl et al. . © Elsevier.

Figure 15.

Survival rates by decade of transplantation. Probability of overall survival for patients with CML in first chronic (A) and advanced (B) phase after allogeneic transplantation at the Hammersmith Hospital, London, stratified by decade of transplantation. Reproduced with permission from Pavlů et al. . © American Society of Hematology.

Figure 2.

Peripheral blood appearances of a patient with CML in CP. Note increased numbers of leucocytes including immature granulocytes.

Figure 3.

The t(9;22) translocation and its products: the BCRABL1 oncogene on the Ph chromosome and the reciprocal ABL1–BCR on the derivative 9q chromosome.

Figure 4.

The structure of the normal BCR and ABL1 genes and the fusion transcripts found in CML and Ph+ ALL.

Figure 5.

The presumed mechanism of action of imatinib. The phosphorylation of a substrate is shown schematically (left panel). ATP occupies the pocket in the ABL component of the BCR–ABL oncoprotein, whereas it donates a phosphate (P) group to a tyrosine (Y) residue on an unspecified substrate. The substrate then detaches itself from the BCR–ABL oncoprotein and makes functional contact with a further downstream effector molecule. (Right panel) Shows imatinib occupies the ATP‐binding site and thereby prevents phosphorylation of the substrate. This molecule in turn fails to make contact with the effector protein and the signal transduction pathway that would otherwise transmit the ‘leukaemia signal’ is interrupted.

Figure 6.

Preliminary Kaplan–Meier estimates of sustained CMR after discontinuation of imatinib from the French STIM () study. Adapted from Mahon et al. . © Elsevier.

Figure 7.

Leukaemia‐free survival in patients with CML based on the IRIS trial (an intention to treat analysis) at 8 years. Courtesy of Professor Deininger M, presented at ASH 2009 Annual Meeting.

Figure 8.

Improvements in overall survival for patients with CML in CP receiving imatinib 400 mg/day (Based on the IRIS trial).

Figure 9.

A schematic depiction of some of the currently established ABL1 kinase domain mutations. Courtesy of Dr Simona Soverini.



Baccarani M, Cortes J, Pane F et al. (2009) Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. Journal of Clinical Oncology 27: 6041–6051.

Cortes J, Hochhaus A, Hughes T and Kantarjian H (2011) Front‐line and salvage therapies with tyrosine kinase inhibitors and other treatments in chronic myeloid leukemia. Journal of Clinical Oncology 29: 524–531.

Druker BJ, Guilhot F, O'Brien SG et al. (2006) Five year follow‐up of imatinib therapy for chronic‐phase chronic myeloid leukemia. New England Journal of Medicine 355: 2408–2417.

Druker BJ, Talpaz M, Resta DJ et al. (2001) Efficacy and safety of a specific inhibitor of the BCR–ABL tyrosine kinase in chronic myeloid leukemia. New England Journal of Medicine 344: 1031–1037.

Goldman JM (2007) How I treat chronic myeloid leukemia in the imatinib era. Blood 110: 2828–2935.

Gratwohl A, Hermans J, Goldman JM et al. (1998) Risk assessment for patients with chronic myeloid leukaemia before allogeneic blood or marrow transplantation. Chronic leukemia working party of the European Group for Blood and Marrow Transplantation. Lancet 352: 1087–1092.

Kantarjian H and Cortes J (2011) Considerations in the management of patients with Philadelphia chromosome‐positive chronic myeloid leukemia receiving tyrosine kinase inhibitor therapy. Journal of Clinical Oncology 12: 1512–1516.

Kantarjian H, O'Brien S, Jabbour E et al. (2012a) Improved survival in chronic myeloid leukemia since the introduction of imatinib therapy: a single institution historical experience. Blood 119: 1981–1987.

Kantarjian H, Shah NP, Cortes J et al. (2012b) Dasatinib or imatinib in newly diagnosed chronic‐phase chronic myeloid leukemia: 2‐year follow‐up from a randomized phase 3 trial (DASISION). Blood 119: 1123–1129.

Kantarjian H, Shah NP, Hochhaus A et al. (2010) Dasatinib versus imatinib in newly diagnosed chronic‐phase chronic myeloid leukemia. New England Journal of Medicine 362: 2260–2270.

Mahon FX, Réa D, Guilhot J et al. (2010) Intergroupe Français des Leucémies Myéloïdes Chroniques. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncology 11: 1029–1035.

Mughal TI, Radich JP, Van Etten RA et al. (2011) Successes, challenges, and strategies – proceedings of the 5th Annual BCR–ABL1 positive and BCR–ABL negative myeloproliferative neoplasms workshop. American Journal of Hematology 86(9): 811–816.

Mughal TI and Schreiber A (2010) Principal long‐term adverse effects of imatinib in patients with chronic myeloid leukemia in chronic phase. Biologicals 4: 315–323.

Oehler VG, Yeung KY, Choi YE et al. (2009) The derivation of diagnostic markers of chronic myeloid leukemia progression from microarray data. Blood 114: 3292–3298.

Okimoto RA and Van Etten RA (2011) Navigating the road toward optimal initial therapy for chronic myeloid leukemia. Current Opinion in Hematology 18: 89–97.

Pavlů J, Szydlo R, Goldman JM et al. (2011) Three decades of transplantation for chronic myeloid leukemia: what have we learned? Blood 117: 755–763.

Saglio G, Kim DW, Issaragrisil S et al. (2010) Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. New England Journal of Medicine 362: 2251–2259.

Van Etten RA, Mauro M, Radich J et al. (2012) Advances in the biology and therapy of chronic myeloid leukemia: proceedings from the sixth Post‐ASH International CML and MPN Workshop. Leukemia & Lymphoma. doi:10.3109/10428194.2012.745524.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Mughal, Tariq I, and Goldman, John M(Feb 2013) Chronic Myeloid Leukaemia. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0002181.pub2]