Review Article | Published:

Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukaemia

Nature Reviews Cancer volume 7, pages 345356 (2007) | Download Citation



Imatinib, a small-molecule ABL kinase inhibitor, is a highly effective therapy for early-phase chronic myeloid leukaemia (CML), which has constitutively active ABL kinase activity owing to the expression of the BCR-ABL fusion protein. However, there is a high relapse rate among advanced- and blast-crisis-phase patients owing to the development of mutations in the ABL kinase domain that cause drug resistance. Several second-generation ABL kinase inhibitors have been or are being developed for the treatment of imatinib-resistant CML. Here, we describe the mechanism of action of imatinib in CML, the structural basis of imatinib resistance, and the potential of second-generation BCR-ABL inhibitors to circumvent resistance.

Key points

  • The structural basis for imatinib resistance in chronic myeloid leukaemia (CML) involves the emergence of imatinib-resistant BCR-ABL point mutations; mutations are usually those that impair drug binding.

  • More than 50 different BCR-ABL mutations have been identified in patients with imatinib-resistant CML and through random mutagenesis assays.

  • Different imatinib-resistant BCR-ABL point mutants can have different transforming potentials in cells and different prognostic outcomes.

  • Methods to predict imatinib-resistant BCR-ABL mutants include PCR-based screening assays, such as the highly sensitive allele-specific oligonucleoside (ASO)-PCR method, and the denaturing high-performance liquid chromatography (D-HPLC)-based assay.

  • Imatinib-resistant BCR-ABL point mutations have been found to pre-exist in newly diagnosed patients with CML, as well as be acquired owing to selective pressure of imatinib. Furthermore, imatinib fails to deplete leukaemic stem cells.

  • New BCR-ABL inhibitors in clinical trials include ABL inhibitors (nilotinib), dual Src family and ABL kinase inhibitors (bosutinib, INNO-404 and AZD0530), non-ATP competitive inhibitors of BCR-ABL (ON012380) and Aurora kinase inhibitors (MK-0457 and PHA-739358). The dual Src and ABL inhibitor dasatinib has recently been approved by the US Food and Drug Administration for the treatment of patients with CML or Philadelphia chromosome positive acute lymphoblastic leukaemia resistant or intolerant to imatinib.

  • BCR-ABL point mutants resistant to the second generation inhibitors nilotinib and dasatinib have been identified through cell-based resistance screens.

  • Strategies to circumvent the emergence of resistance include combination therapy using inhibitors of BCR-ABL and other targets.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    et al. Translocation of c-abl oncogene correlates with the presence of a Philadelphia chromosome in chronic myelocytic leukaemia. Nature 306, 277–280 (1983).

  2. 2.

    et al. Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell 36, 93–99 (1984).

  3. 3.

    , , & Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science 247, 1079–1082 (1990).

  4. 4.

    et al. A novel abl protein expressed in Philadelphia chromosome positive acute lymphoblastic leukaemia. Nature 325, 635–637 (1987).

  5. 5.

    et al. Bcr-Abl kinase mutations and drug resistance to imatinib (STI571) in chronic myelogenous leukemia. Mini Rev. Med. Chem. 4, 285–299 (2004).

  6. 6.

    et al. Clinical resistance to the kinase inhibitor STI-571 in chronic myeloid leukemia by mutation of Tyr-253 in the ABL kinase domain P-loop. Proc. Natl Acad. Sci. USA 99, 10700–10705 (2002).

  7. 7.

    et al. Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukemia. Act. Cryst. D63, 80–93 (2007).

  8. 8.

    & Mechanism of resistance to the ABL tyrosine kinase inhibitor STI571 in BCR-ABL-transformed hematopoietic cell lines. Blood 95, 3498–3505 (2000).

  9. 9.

    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 96, 1070–1079 (2000).

  10. 10.

    et al. Induction of resistance to the Abelson inhibitor STI571 in human leukemic cells through gene amplification. Blood 95, 1758–1766 (2000).

  11. 11.

    et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293, 876–880 (2001). This paper describes the first discovery of a mechanism of imatinib resistance in patients with CML characterized by the existence of a point mutation in the BCR-ABL kinase domain. This finding led to the biorational development of second-generation ABL inhibitors, like nilotinib and dasatinib, which override this form of imatinib resistance.

  12. 12.

    et al. Structural mechanism for STI-571 inhibition of Abelson tyrosine kinase. Science 289, 1938–1942 (2000). This paper describes the binding of a precursor of imatinib to the inactive conformation of ABL, which is necessary for imatinib to bind to its target. This finding provides important insight into the mechanism of inhibition of BCR-ABL activity by imatinib.

  13. 13.

    , , & Analysis of the structural basis of specificity of inhibition of the ABL kinase by STI-571. J. Biol. Chem. 277, 32214–32219 (2002).

  14. 14.

    et al. Imatinib: a selective tyrosine kinase inhibitor. Eur. J. Cancer 38, S19–S27 (2002).

  15. 15.

    et al. Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571). Cancer Res. 62, 4236–4243 (2002).

  16. 16.

    , , & BCR-ABL gene mutations in relation to clinical resistance of Philadelphia-chromosome-positive leukaemia to STI571: a prospective study. Lancet 359, 487–491 (2002).

  17. 17.

    et al. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2, 117–125 (2002).

  18. 18.

    et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia 16, 2190–2196 (2002).

  19. 19.

    , & Mechanism of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL. Cell 112, 831–843 (2003). This paper describes the use of an in vitro screen of randomly mutagenized BCR-ABL to identify novel imatinib-resistant BCR-ABL point mutants, as well as mutants previously identified in patients with imatinib resistance.

  20. 20.

    , , Autoinhibition of c-ABL. Cell 108, 247–259 (2002).

  21. 21.

    et al. AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL. Br. J. Cancer 94, 1765–1769 (2006).

  22. 22.

    et al. Kinase domain mutants of Bcr-Abl exhibit altered transformation potency, kinase activity, and substrate utilization, irrespective of sensitivity to imatinib. Mol. Cell. Biol. 26, 6082–6093 (2006).

  23. 23.

    et al. Phosphorylation of the ATP-binding loop directs oncogenicity of drug-resistant BCR-ABL mutants. Proc. Natl Acad. Sci. USA 103, 19466–19471 (2006).

  24. 24.

    et al. The presence of a BCR-ABL mutant allele in CML does not always explain clinical resistance to imatinib. Leukemia 20, 658–663 (2006).

  25. 25.

    et al. ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working Party on Chronic Myeloid Leukemia. J. Clin. Oncol. 23, 4100–4109 (2005).

  26. 26.

    et al. High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance. Blood 99, 3472–3475 (2002).

  27. 27.

    et al. Mutation status and clinical outcome of 89 imatinib mesylate-resistant chronic myelogenous leukemia patients: a retrospective analysis from the French intergroup of CML (Fi (phi)-LMC GROUP). Leukemia 20, 1061–1066 (2006).

  28. 28.

    , & Two different point mutations in ABL gene ATP-binding domain conferring primary imatinib resistance in a chronic myeloid leukemia (CML) patient: a case report. Biol. Proced. Online 6, 144–148 (2004).

  29. 29.

    et al. Denaturing-HPLC-based assay for detection of ABL mutations in chronic myeloid leukemia patients resistant to imatinib. Clin. Chem. 50, 1205–1213 (2004).

  30. 30.

    et al. Selecting and deselecting imatinib-resistant clones: observations made by longitudinal, quantitative monitoring of mutated BCR-ABL. Leukemia 19, 2159–2165 (2005).

  31. 31.

    et al. Evolving concepts in the management of chronic myeloid leukemia. Recommendations from an expert panel on behalf of the European Leukemia Net. Blood 108, 1809–1820 (2006).

  32. 32.

    et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors – review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood 108, 28–37 (2006).

  33. 33.

    et al. Several types of mutations of the ABL gene can be found in chronic myeloid leukemia patients resistant to STI571, and they can pre-exist to the onset of treatment. Blood 100, 1014–1018 (2002).

  34. 34.

    et al. Presence of the BCR-ABL mutation Glu255Lys prior to STI571 (imatinib) treatment in patients with Ph+ acute lymphoblastic leukemia. Blood 102, 659–661 (2003).

  35. 35.

    et al. Ph(+) acute lymphoblastic leukemia resistant to the tyrosine kinase inhibitor STI571 has a unique BCR-ABL gene mutation. Blood 99, 1860–1862 (2002).

  36. 36.

    et al. Mutation in the ATP-binding site of BCR-ABL in a patient with chronic myeloid leukaemia with increasing resistance to STI571. Br. J. Haematol. 119, 109–111 (2002).

  37. 37.

    , & Resistance to tumor specific therapy with imatinib by clonal selection of mutated cells. Dtsch Med. Wochenschr. 127, 2205–2207 (2002).

  38. 38.

    et al. Dynamics of chronic myeloid leukemia. Nature 435, 1267–1270 (2005).

  39. 39.

    et al. Dynamic modeling of imatinib-treated chronic myeloid leukemia: functional insights and clinical implications. Nature Med. 12, 1181–1184 (2006).

  40. 40.

    et al. Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction. Blood 107, 4532–4539 (2006).

  41. 41.

    et al. Nilotinib exerts equipotent anti-proliferative effects to imatinib, functions as an ABCG2 inhibitor, but does not induce apoptosis in CD34+ CML cells. Blood 9 January 2007 [Epub ahead of print].

  42. 42.

    & Fusion tyrosine kinases: a result and cause of genomic instability. Oncogene 26, 11–20 (2007).

  43. 43.

    et al. The BCR/ABL tyrosine kinase induces production of reactive oxygen species in hematopoietic cells. J. Biol. Chem. 275, 24273–24278 (2000).

  44. 44.

    et al. BCR/ABL kinase induces self-mutagenesis via reactive oxygen species to encode imatinib resistance. Blood 108, 319–327 (2006).

  45. 45.

    , & Advances in the structural biology, design and clinical development of Bcr-Abl Kinase inhibitors for the treatment of chronic myeloid leukaemia. Biochim. Biophys. Acta 1754, 3–13 (2005).

  46. 46.

    et al. Effects of AMN107, a novel aminopyrimidine tyrosine kinase inhibitor, on human mast cells bearing wild-type or mutated codon 816 c-kit. Leukemia Res. 30, 1365–1370 (2006).

  47. 47.

    et al. Characterization of AMN107, a selective inhibitor of native and mutant BCR-ABL. Cancer Cell 7, 129–141 (2005). This paper describes the characterization of nilotinib, a second generation inhibitor of ABL that, in addition to being significantly more potent than imatinib against BCR-ABL-positive leukaemia, overrides many forms of imatinib resistance owing to point mutations in the kinase domain of BCR-ABL. This compound is in advanced-stage clinical trials.

  48. 48.

    et al. An efficient rapid system for profiling the cellular activities of molecular libraries. Proc. Natl Acad. Sci USA 103, 3153–3158 (2006).

  49. 49.

    et al. In vitro activity of BCR-ABL inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant ABL kinase domain mutants. Cancer Res. 65, 4500–4505 (2005).

  50. 50.

    et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N. Engl. J. Med. 354, 2542–2551 (2006). This paper describes results achieved in clinical trials testing the efficacy of nilotinib against imatinib-resistant leukaemia.

  51. 51.

    et al. A phase II study of nilotinib, a novel tyrosine kinase inhibitor administered to imatinib-resistant and-intolerant patients with chronic myelogenous leukemia (CML) in chronic phase (CP). Blood 108, 53a (2006).

  52. 52.

    et al. A phase II study of nilotinib, a novel tyrosine kinase inhibitor administered to imatinib resistant or intolerant patients with chronic myelogenous leukemia (CML) in blast crisis (BC) or relapsed/refractory Ph+ acute lymphoblastic leukemia (ALL). Blood 108, 528a (2006).

  53. 53.

    & SRC family tyrosine kinases and growth factor signaling. Exp. Cell Res. 254, 1–13 (2000).

  54. 54.

    et al. BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood 101, 690–698 (2003).

  55. 55.

    et al. 2-Aminothiazole as a novel kinase inhibitor template. Structure-activity relationship studies towards the discovery of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1, 3-thiazole-5-carboxamide (Dasatinib; BMS-354825) as a potent pan-Src kinase inhibitor. J. Med. Chem. 49, 6819–6832 (2006).

  56. 56.

    et al. The structure of dasatinib (BMS-354825) bound to activated ABL kinase domain elucidates its inhibitory activity against imatinib-resistant ABL mutants. Cancer Res. 66, 5790–5797 (2006).

  57. 57.

    et al. Combined ABL inhibitor therapy for minimizing drug resistance in chronic myeloid leukemia: SRC/ABL inhibitors are compatible with imatinib. Clin. Cancer Res. 11, 6987–6993 (2005).

  58. 58.

    et al. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 305, 399–401 (2004). This paper describes the characterization of dasatinib, a second generation dual inhibitor of Src and ABL that is significantly more potent than imatinib against BCR-ABL-positive leukaemia and overrides many forms of imatinib resistance owing to point mutations in the kinase domain of BCR-ABL.

  59. 59.

    , , , & Comparative analysis of two clinically active BCR-ABL kinase inhibitors reveals the role of conformation-specific binding in resistance. Proc. Natl Acad. Sci. USA 102, 3395–3400 (2005).

  60. 60.

    et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N. Eng. J. Med. 354, 2531–2541 (2006). This paper describes results achieved in clinical trials testing the efficacy of dasatinib against imatinib-resistant leukaemia.

  61. 61.

    et al. Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood 109, 3207–3213 (2007).

  62. 62.

    et al. Blockade of platelet-derived growth factor receptor-beta by CDP860, a humanized PEGylated di-Fab', leads to fluid accumulation and is associated with increased tumor vascularized volume. J. Clin. Oncol. 23, 973–981 (2005).

  63. 63.

    et al. In vitro and in vivo Activity of SKI-606, a novel Src-Abl inhibitor, against imatinib-resistant Bcr-Abl+ neoplastic cells. Cancer Res. 66, 11314–11322 (2006).

  64. 64.

    et al. SKI-606, a 4-anilino-3-quinolinecarbonitrile dual inhibitor of SRC and ABL kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice. Cancer Res. 63, 375–381 (2003).

  65. 65.

    et al. A phase 1/2 study of SKI-606, a dual inhibitor of Src and Abl kinases, in adult patients with Philadelphia Chromosome positive (Ph+) chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL) relapsed, refractory or intolerant of imatinib. Blood 108, 168a (2006).

  66. 66.

    et al. NS-187, a potent and selective dual BCR-ABL/LYN tyrosine kinase inhibitor, is a novel agent for imatinib-resistant leukemia. Blood 106, 3948–3954 (2005).

  67. 67.

    et al. Phase I ascending single and multiple dose studies to assess the safety, tolerability and pharmacokinetics of AZD0530, a highly selective, dual-specific SRC-ABL inhibitor. J. Clin. Oncol. ASCO Ann. Meet. Proc. 23, 3125a (2005).

  68. 68.

    et al. N-(5-Chloro-1, 3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5- (tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine, a novel, highly selective, orally available, dual-specific c-Src/Abl kinase inhibitor. J. Med. Chem. 49, 6465–6488 (2006).

  69. 69.

    et al. A non-ATP-competitive inhibitor of BCR-ABL overrides imatinib resistance. Proc. Natl Acad. Sci. USA 102, 1992–1997 (2005).

  70. 70.

    et al. Allosteric inhibitors of BCR-ABL-dependent cell proliferation. Nature Chem. Biol. 2, 95–102 (2006).

  71. 71.

    & Aurora-kinase inhibitors as anticancer agents. Nature Rev. Cancer 4, 927–936 (2004).

  72. 72.

    et al. VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo. Nature Med. 10, 262–267 (2004).

  73. 73.

    et al. MK-0457, a novel aurora kinase and BCR-ABL inhibitor, is active against BCR-ABL T315I mutant chronic myelogenous leukemia (CML). Blood 108, 163a (2006).

  74. 74.

    et al. Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases. Proc. Natl Acad. Sci. USA 102, 11011–11016 (2005).

  75. 75.

    et al. 1, 4, 5, 6-Tetrahydropyrrolo[3, 4-c]pyrazoles: identification of a potent aurora kinase inhibitor with a favorable antitumor kinase inhibition profile. J. Med. Chem. 49, 7247–7251 (2006).

  76. 76.

    et al. BCR-ABL resistance screening predicts a limited spectrum of point mutations to be associated with clinical resistance to the ABL kinase inhibitor nilotinib (AMN107). Blood 108, 1328–1333 (2006).

  77. 77.

    et al. Comparison of imatinib mesylate, dasatinib (BMS-354825), and nilotinib (AMN107) in an N-ethyl-N-nitrosourea (ENU)-based mutagenesis screen: high efficacy of drug combinations. Blood 108, 2332–2338 (2006).

  78. 78.

    , , , & Identification of BCR-ABL point mutations conferring resistance to the ABL kinase inhibitor AMN107 (nilotinib) by a random mutagenesis study. Blood 15 February 2007 [Epub ahead of print].

  79. 79.

    et al. A phase II study of nilotinib: a novel tyrosine kinase inhibitor administered to imatinib-resistant or intolerant patients with chronic myelogenous leukemia (CML) in accelerated phase (AP). Blood 108, 615a (2006).

  80. 80.

    et al. Response to dasatinib after imatinib failure according to type of preexisting BCR-ABL mutations. Blood 108, 225a (2006).

  81. 81.

    et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic phase chronic myeloid leukemia after failure of imatinib therapy. Blood 109, 2303–2309 (2007).

  82. 82.

    et al. A cell-based screen for resistance of BCR-ABL-positive leukemia identifies the mutation pattern for PD166326, an alternative ABL kinase inhibitor. Blood 105, 1652–1659 (2005).

  83. 83.

    et al. In vivo antiproliferative effect of NS-187, a dual Bcr-Abl/Lyn tyrosine kinase inhibitor, on leukemic cells harbouring ABL kinase domain mutations. Leuk. Res. 30, 1443–1446 (2006).

  84. 84.

    et al. Hematologic and cytogenetic response dynamics to nilotinib (AMN107) depend on the type of BCR-ABL mutations in patients with chronic myelogeneous leukemia (CML) after imatinib failure. Blood 108, 225a (2006).

  85. 85.

    et al. Dasatinib (SPRYCEL) in patients (pts) with chronic myelogenous leukemia in accelerated phase (AP-CML) that are imatinib-resistant (im-r) or -intolerant (im-i): updated results of the CA180–005 START-A phase II study. Blood 108, 613a (2006).

  86. 86.

    et al. Efficacy of dasatinib (SPRYCEL) in patients (pts) with chronic phase chronic myelogenous leukemia (CP-CML) resistant to or intolerant of imatinib: updated results of the CA180013 'START-C' phase II study. Blood 108, 53a (2006).

  87. 87.

    et al. Dasatinib (SPRYCEL) efficacy and safety in patients (pts) with chronic myelogenous leukemia in lymphoid (CML-LB) or myeloid blast (CML-MB) phase who are imatinib-resistant (im-r) or -intolerant (im-i). Blood 108, 224a (2006).

  88. 88.

    et al. Dasatinib (SPRYCEL) in patients (pts) with Philadelphia Chromosome-positive acute lymphoblastic leukemia who are imatinib-resistant (im-r) or-intolerant (im-i): updated results from the CA180–015 START-L study. Blood 108, 88a (2006).

Download references

Author information


  1. Dana Farber Cancer Institute, Mayer 540, 44 Binney St, Boston, Massachusetts 02115, USA.

    • Ellen Weisberg
  2. Novartis Institutes for BioMedical Research, WKL-136.4.86, Basel, CH-4002, Switzerland.

    • Paul W. Manley
  3. Novartis Institutes for BioMedical Research, WSJ-088.9.08A, Basel, CH-4056, Switzerland.

    • Sandra W. Cowan-Jacob
  4. Medizinische Fakultat Mannheim der Universitat Heidelberg III. Medizinische Klinik, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.

    • Andreas Hochhaus
  5. Dana-Farber Cancer Institute, Department of Medical Oncology, 44 Binney Street, Boston, Massachusetts 02115, USA.

    • James D. Griffin


  1. Search for Ellen Weisberg in:

  2. Search for Paul W. Manley in:

  3. Search for Sandra W. Cowan-Jacob in:

  4. Search for Andreas Hochhaus in:

  5. Search for James D. Griffin in:

Competing interests

Paul W. Manley and Sandra W. Cowan-Jacob are employees of Novartis pharma AG, Switzerland. Andreas Hochhaus receives research funding from Novartis, Bristol-Myers Squibb, Wyeth, Merck and Innovive.

Corresponding author

Correspondence to James D. Griffin.


Gatekeeper residue

The gatekeeper is a residue located at the back of the ATP-binding site, the properties of which (size, charge and hydrophobicity) regulate the binding of inhibitors.

Cap region

A region at the N terminus of wild-type ABL, which has a role in keeping the kinase in an inactive state.


PI3K is a heterodimer that is made up of a regulatory (p85) subunit (which BCR-ABL interacts with), and a catalytic (p110) subunit.

Focal adhesion

A cell-to-substrate adhesion structure that anchors the ends of actin microfilaments (stress fibres) and mediates strong attachment to the extracellular matrix.

Cytogenetic remission

Complete cytogenetic remission is the absence of metaphase cells positive for the BCR-ABL rearrangement (or Philadelphia chromosome positive cells). Partial cytogenetic remission is the presence of 35% of metaphase cells positive for the BCR-ABL rearrangement (or Philadelphia chromosome positive cells).

Haematological remission

Complete haematological remission is the achievement of a normal white blood cell (WBC) and platelet count, and no signs and symptoms of CML. Partial haematological remission is a decrease in the WBC count to less than 50% of pretreatment levels.

Chronic phase

An early phase of CML characterized by variable duration. Patients often lack symptoms, or are mildly symptomatic; if left untreated, this will progress to an accelerated phase.

Accelerated phase

Occurs between chronic phase and blast crisis. Characterized by 10–19% myeloblasts and >20% basophils in blood or bone marrow and cytogenetic evolution; increasing splenomegaly, platelet count or white blood cell count also occurs in patients who are unresponsive to treatment.

Blast phase

The final phase of CML (also known as blast crisis), which is similar to an acute leukaemia (poor prognosis). Characterized by >20% myeloblasts or lymphoblasts in blood or bone marrow.


Swelling of tissues that results from the accumulation of excess lymph fluid.

Pleural effusion

Accumulation of excess fluid in the fluid-filled space that surrounds the lungs.

Pulmonary oedema

Accumulation of fluid in the alveoli and interstitial spaces of the lungs.

Pericardial effusion

Accumulation of fluid inside the sac covering the heart.

Autoactivation site

Region within the kinase domain activation loop that, when phosphorylated by the kinase itself, results in the activation of the protein.

About this article

Publication history



Further reading