Chronic Myeloid Leukemia - Prognostic Value of Mutations

  • Kaleem, Bushra (Haematology, Medical Sciences, National Institute of Blood Diseases and Bone Marrow Transplantation) ;
  • Shahab, Sadaf (Haematology, Medical Sciences, National Institute of Blood Diseases and Bone Marrow Transplantation) ;
  • Ahmed, Nuzhat (Haematology, Medical Sciences, National Institute of Blood Diseases and Bone Marrow Transplantation) ;
  • Shamsi, Tahir Sultan (Haematology, Medical Sciences, National Institute of Blood Diseases and Bone Marrow Transplantation)
  • Published : 2015.12.03


Chronic myeloid leukemia (CML) is a stem cell disorder characterized by unrestricted proliferation of the myeloid series that occurs due to the BCR-ABL fusion oncogene as a result of reciprocal translocation t(9;22) (q34;q11). This discovery has made this particular domain a target for future efforts to cure CML. Imatinib revolutionized the treatment options for CML and gave encouraging results both in case of safety as well as tolerability profile as compared to agents such as hydroxyurea or busulfan given before Imatinib. However, about 2-4% of patients show resistance and mutations have been found to be one of the reasons for its development. European Leukemianet gives recommendations for BCR-ABL mutational analysis along with other tyrosine kinase inhibitors (TKIs) that should be administered according to the mutations harbored in a patient. The following overview gives recommendations for monitoring patients on the basis of their mutational status.


Chronic myeloid leukemia;BCR-ABL mutations;tyrosine kinase inhibitors


  1. Corbin AS, La Rosee P, Stoffregen EP, Druker BJ, Deininger MW (2003). Several Bcr-Abl kinase domain mutants associated with imatinib mesylate resistance remain sensitive to imatinib. Blood, 101, 4611-14.
  2. Deininger MW, McGreevey L, Willis S, et al (2004). Detection of ABL kinase domain mutations with denaturing highperformance liquid chromatography. Leukemia, 18, 864-71.
  3. Deininger M (2005). Resistance to imatinib, mechanisms and management. J Natl Compr Canc Netw. 3, 757-68.
  4. Elias J, Hagop K, Dan J, et al (2008). Characteristics and outcomes of patients with chronic myeloid leukemia and T315I mutation following failure of imatinib mesylate therapy. Blood, 112, 53-5.
  5. Elias J, Andreas H, Jorge C, Paul La R, Hagop MK (2010). Choosing the best treatment strategy for chronic myeloid leukemia patients resistant to imatinib, weighing the efficacy and safety of individual drugs with BCR-ABL mutations and patient history. Leukemia, 24, 6-12.
  6. Elias J, Susan B, Giuseppe S, et al (2011). Practical Advice for Determining the Role of BCR-ABL Mutations in Guiding Tyrosine Kinase Inhibitor Therapy in Patients with Chronic Myeloid Leukemia. Cancer, 117, 1800-11.
  7. Fausel C (2007). Targeted chronic myeloid leukemia therapy, Seeking a cure. Am J Health Syst Pharm, 64, 9-15.
  8. Gorre ME, Mohammed M, Ellwood K, et al (2001). Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science, 293, 876-80.
  9. Hantschel O, Nagar B, Guettler S, et al (2003). A myristoyl/phosphotyrosine switch regulates c-Abl. Cell, 112, 845-57.
  10. Gulzar B, Ashaqullah B, Aadil W, et al (2012). Polymorphic variation in glutathione-s-transferase genes and risk of chronic myeloid leukaemia in the kashmiri population. Asian Pac J Cancer Prev, 13, 69-73
  11. Hagop K, Charles S, Andreas H, et al (2002). Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med, 346, 645-52.
  12. Hochhaus A, Kreil S, Corbin AS, et al (2002). Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia, 16, 2190-96.
  13. Hughes T, Branford S (2006). Molecular monitoring of BCRABL as a guide to clinical management in chronic myeloid leukaemia. Blood Rev, 20, 29-41
  14. Hughes T (2006). Abl kinase inhibitor therapy for CML, baseline assessments and response monitoring. Hematol Am Soc Hematol Educ Program, 211-18.
  15. Hughes T, Deininger M, Hochhaus A, et al (2006). 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.
  16. Hehlmann R, Hochhaus A, Baccarani M (2007). European LeukemiaNet. Chronic myeloid leukaemia. Lancet, 370, 342-50.
  17. Alderborn A, Kristofferson A, Hammerling U (2000). Determination of single-nucleotide polymorphisms by real-time pyrophosphate DNA sequencing. Genome Res, 10, 1249-58.
  18. Apperley JF (2007). Part I, mechanisms of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol, 8, 1018-29.
  19. Branford S, Rudzki Z, Walsh S, et al (2002). High frequency of point mutations clustered within the ATP binding region of BCR/ABL in CML and Ph-positive ALL patients who develop imatinib (STI571) resistance. Blood, 99, 3472-75.
  20. Branford S, Rudzki Z, Walsh S, et al (2003). Detection of BCRABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood, 102, 276-83.
  21. Branford S, Hughes T (2006). Detection of BCR-ABL mutations and resistance to imatinib mesylate. Methods Mol Med, 125, 93-106.
  22. Baccarani M, Cortes J, Pane F, et al (2009). Chronic myeloid leukemia, an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol, 27, 6041-51
  23. Bjorkholm M, Ohm L, Eloranta S, et al (2011). Success story of targeted therapy in chronic myeloid leukemia, a populationbased study of patients diagnosed in Sweden from 1973 to 2008. J Clin Oncol, 29, 2514-20.
  24. Baccarani M, Deininger MW, Rosti G, et al (2013). European LeukemiaNet 2013 recommendations for the management of chronic myeloid leukemia. Blood, 122, 885-92.
  25. Corbin AS, Buchdunger E, Pascal F, Druker BJ (2002). Analysis of the structural basis of specificity of inhibition of the Abl kinase by STI571. J Biol Chem, 277, 32214-19.
  26. Hochhaus A, Erben P, Ernst T, Mueller MC (2007). Resistance to targeted therapy in chronic myelogenous leukemia. Semin Hematol, 44, 15-24.
  27. Hagop MK, Jorge C, Paul LR, Andreas H (2010). Optimizing therapy for patients with chronic myelogenous leukemia in Chronic Phase. Cancer, 116, 1419-30.
  28. Irving JA, O'Brien S, Lennard AL (2004). Use of denaturing HPLC for detection of mutations in the BCR-ABL kinase domain in patients resistant to imatinib. Clin Chem, 50, 1233-37
  29. Ian JG, Mary MacP, Thomas B (2006). Kinase domain mutants of Bcr-Abl exhibit altered transformation potency, kinase activity, and substrate utilization, irrespective of sensitivity to imatinib. Molecular Cellular Biol, 26, 6082-93
  30. Jabbour E, Kantarjian H, Jones D, et al (2006). Frequency and clinical significance of BCR-ABL mutations in patients with chronic myeloid leukemia treated with imatinib mesylate. Leukemia, 20, 1767-73.
  31. Jamshid SK, Hugues de L, Jane FA, et al (2008). Finding of kinase domain mutations in patients with chronic phase chronic myeloid leukemia responding to imatinib may identify those at high risk of disease progression. J Clin Oncol, 26, 4806-13.
  32. Jamshid SK, Todd WK, Philippe S, et al (2013). BCR-ABL1 compound mutations in tyrosine kinase inhibitor-resistant CML, frequency and clonal relationships. Blood, 121, 489-98.
  33. Kreuzer KA, Le Coutre P, Landt O, et al (2003). Preexistence and evolution of imatinib mesylate-resistant clones in chronic myelogenous leukemia detected by a PNA-based PCR clamping technique. Ann Hematol, 82, 284-96
  34. Khorashad JS, Anand M, Marin D, et al (2006). The presence of a BCR-ABL mutant allele in CML does not always explain clinical resistance to imatinib. Leukemia, 20, 658-63.
  35. Kantarjian H, O'Brien S, Jabbour E, et al (2012). Improved survival in chronic myeloid leukemia since the introduction of imatinib therapy, a single-institution historical experience. Blood, 119, 1981-87.
  36. Karunakar T, Lalitha G. Ponatinib (2013). Is a Pan-BCR-ABL Kinase Inhibitor, MD Simulations and SIE Study. Plos One, 8, 1-10.
  37. Lahaye T, Riehm B, Berger U, et al (2005). Response and resistance in 300 patients with BCR-ABL-positive leukemias treated with imatinib in a single center, a 4.5-year follow-up. Cancer, 103, 1659-69.
  38. Matti S, Peter RS, Alfred W (1990). The P-loop --a common motif in ATP- and GTP-binding proteins. Trends Biochem Sci, 15, 430-34.
  39. Michael JM (2006). Defining and managing imatinib resistance. Haematol, 1, 219-25.
  40. Michele B, Giuseppe S, John G, et al (2006). Evolving concepts in the management of chronic myeloid leukemia, recommendations from an expert panel on behalf of the European Leukemianet. Blood, 108, 1809-20.
  41. Meggyesi N, Kozma A, Halm G, et al (2011). Additional chromosome abnormalities, BCR-ABL tyrosine kinase domain mutations and clinical outcome in hungarian tyrosine kinase inhibitor-resistant chronic myelogenous leukemia patients. Acta Haematologica, 127, 34-42
  42. Michele B, Michael WD, Gianantonio R, et al (2013). European LeukemiaNet recommendations for the management of chronic myeloid leukemia, 2013. Blood, 122, 872-84.
  43. Michele B, Fausto C, Gabriele G, Francesca P, Gianantonio R (2014). Treatment Recommendations for Chronic Myeloid Leukemia. Mediterr J Hematol Infect Dis, 6.
  44. Nagar B, Hantschel O, Young MA, et al (2003). Structural basis for the autoinhibition of c-Abl tyrosine kinase. Cell, 112, 859-71
  45. Nikolas von B, Darren RV, Heiko van der K, et al (2005). A cell-based screen for resistance of Bcr-Abl-positive leukemia identifies the mutation pattern for PD166326, an alternative Abl kinase inhibitor. Blood, 105, 1652-59.
  46. Nicolini FE, Corm S, Le QH, et al (2006). 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, 1061-6.
  47. Nicolini FE, Hayette S, Corm S, et al (2007). Clinical outcome of 27 imatinib mesylate-resistant chronic myelogenous leukemia patients harboring a T315I BCR-ABL mutation. Haematologica, 92, 1238-41.
  48. National Comprehensive Cancer Network (NCCN) (2010). Clinical practice guidelines in oncology, chronic myelogenous leukemia. V.2.2010. fort washington, PA, NCCN.
  49. O'Hare T, Eide CA, Deininger MW (2007). Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia. Blood, 110, 2242-9.
  50. Pavlu J, Szydlo RM, Goldman JM, Apperley JF (2011). Three decades of transplantation for chronic myeloid leukemia, what have we learned? Blood, 117, 755-63.
  51. Pavan KB, Hagop K, Jorge EC, A Megan C, Elias J (2013). Management of imatinib-resistant patients with chronic myeloid leukemia. Therapeutic Advances Hematol, 4, 103-17.
  52. Roche-Lestienne C, Soenen-Cornu V, et al (2002). 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, 1014-8.
  53. Roche-LC, Lai JL, Darre S, Facon T, Preudhomme C (2003). A mutation conferring resistance to imatinib at the time of diagnosis of chronic myelogenous leukemia. N Engl J Med. 348, 2265-6.
  54. Ravandi F (2011). Managing philadelphia chromosome-positive acute lymphoblastic leukemia, role of tyrosine kinase inhibitors. Clin Lymphoma Myeloma Leuk, 11, 198-203.
  55. Schindler T, Bornmann W, Pellicena P (2000). Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science, 289, 1938-42.
  56. Shah NP, Nicoll JM, Nagar B, et al (2002). 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, 117-25
  57. Sorel N, Chazelas F, Brizard A, Chomel JC (2005). Doublegradient- denaturing-gradient gel electrophoresis for mutation screening of the BCR-ABL tyrosine kinase domain in chronic myeloid leukemia patients. Clin Chem. 51, 1263-66
  58. Simona S, Giovanni M, Gianantonio R, et al (2005). 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, 4100-9.
  59. Soverini S, Colarossi S, Gnani A, et al (2006). Contribution of Abl kinase domain mutations to imatinib resistance in different subsets of Philadelphia-positive patients, by the GIMEMA working party on chronic myeloid leukemia. Clin Cancer Res, 12, 7374-9
  60. Simona S, Sabrina C, Alessandra G, et al (2007). Resistance to dasatinib in Philadelphia-positive leukemia patients and the presence or the selection of mutations at residues 315 and 317 in the BCR-ABL kinase domain. Haematologica 92, 401-4.
  61. Shundong C, Delong L (2008). P-loop mutations and novel therapeutic approaches for imatinib failures in chronic myeloid leukemia. J Hematol Oncol, 1.
  62. Stephen GO'B, Francois G, John MG, et al (2010). International randomized study of interferon versus STI571 (IRIS) 7-year follow-up, sustained survival, low rate of transformation and increased rate of major molecular response (MMR) in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib (IM). Blood, 116, 3758-65.
  63. Saad ZUsmani, Shakeeb A Yunus, Yasser Jamal (2009). Overview of chronic myeloid leukemia patients in pakistan in the pre-imatanib, Era Asian Pac J Cancer Prev, 10, 1039-40
  64. Sarit A, Jeffery HL (2011). Monitoring response and resistance to treatment in chronic myeloid leukemia. Current Oncol, 18, 71-83
  65. Simona.S, Andreas H, Franck EN, et al (2011). BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors, recommendations from an expert panel on behalf of European Leukemia Net. Blood, 118, 1208-15.
  66. Shweta S, Sarjana D (2013). Imatinib mesylate resistance and mutations, An Indian experience. Indian J Med Paediatr Oncol, 34, 213-20
  67. Thomas E, Philipp E, Thomas S, et al (2005). Early detection of imminent hematologic relapse due to BCRABL kinase domain mutations in CML patients on imatinib therapy by D-HPLC. Blood, 106, 317-23
  68. Thomas E, Philipp E, Martin CM, et al (2008). Dynamics of BCR-ABL mutated clones prior to hematologic or cytogenetic resistance to imatinib. Haematologica, 93, 186-92
  69. Thomas E, Franz X, Oliver PA, et al (2009). A co-operative evaluation of different methods of detecting BCR-ABL kinase domain mutations in patients with chronic myeloid leukemia on second-line dasatinib or nilotinib therapy after failure of imatinib. Haematologica, 94, 1227-35.
  70. Talpaz M, Hehlmann R, Quintas-Cardama A, et al (2013). Re-emergence of interferon-$\alpha$ in the treatment of chronic myeloid leukemia. Leukemia, 27, 803-12
  71. Thoralf L, Thomas E, Franz XG, et al (2013). The quantitative level of T315I mutated BCR-ABL predicts for major molecular response to second-line nilotinib or dasatinib treatment in patients with chronic myeloid leukemia. Haematologica, 98, 714-7.
  72. Willis SG, Lange T, Demehri S, et al (2005). High sensitivity detection of BCR-ABL kinase domain mutations in imatinibnaive patients, correlation with clonal cytogenetic evolution but not response to therapy. Blood, 106, 2128-37.
  73. Yasser HE, Hossam KM, Fahmy TA, et al (2013). Abl Kinase Domain Mutations in Imatinib-treated Egyptian Patients with Chronic Myeloid Leukemia. Leukemia, 1, 1-7.
  74. Yuan-X, Juan Z, Yan-H, et al (2014). Clinical significance of BCR-ABL fusion gene subtypes in chronic myelogenous and acute lymphoblastic leukemias, Asian Pac J Cancer Prev, 15, 9961-6
  75. Zhou T, Commodore L, Huang WS, et al (2011). Structural mechanism of the Pan-BCR-ABL inhibitor ponatinib (AP24534), lessons for overcoming kinase inhibitor resistance. Chem Biol Drug Des, 77, 1-11.
  76. Zafar I, Aamer A, Mudassar I, et al (2013). Sensitive detection of pre-existing BCR-ABL kinase domain mutations in CD34+ cells of newly diagnosed chronic-phase chronic myeloid leukemia patients is associated with imatinib resistance, implications in the post-imatinib Era. Plos One, 8, 1-9.
  77. Zaidatul S, Sarina S, Rosline H, et al (2014). Low level of TERC gene amplification between chronic myeloid leukaemia patients resistant and respond to imatinib mesylate treatment. Asian Pac J Cancer Prev, 15, 1863-9.