Skip to main content

Advertisement

SpringerLink
Log in

Management of chronic myeloid leukemia in blast crisis

  • Review Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Abstract

Due to the high efficacy of BCR-ABL tyrosine kinase inhibition (TKI) in chronic phase (CP) chronic myeloid leukemia (CML), the frequency of blast crisis (BC) is greatly reduced compared to the pre-TKI era. However, TKI treatment of BC has only marginally improved the number of favorable responses, including remissions, which for the most part have only been transitory. Occasionally, they provide a therapeutic window to perform an allogeneic stem cell transplantation (allo-SCT). The challenge remains to improve management of BC with the limited options available. We review and summarize articles pertaining to the treatment of BC CML published after 2002. Additionally, we will discuss whether there is a need for a new definition of BC and/or treatment failure.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Tardieu S, Brun-Strang C, Berthaud P et al (2005) Management of chronic myeloid leukemia in France: a multicentered cross-sectional study on 538 patients. Pharmacoepidemiol Drug Saf 14:545–553

    Article  PubMed  Google Scholar 

  2. Mottalib MA, Sultana TA, Khalil MI et al (2014) Phase distribution of chronic myeloid leukemia in Bangladesh. BMC Res Notes 7:142

    Article  PubMed Central  PubMed  Google Scholar 

  3. Ahmed R, Naqi N, Hussain I et al (2009) Presentating phases of chronic myeloid leukaemia. J Coll Phys Surg Pak 19:469–472

    Google Scholar 

  4. Lindoerfer D, Hoffmann VS, Rosti G et al (2014) The EUTOS population-based registry: evaluation of baseline characteristics and first treatment choices of 3045 newly diagnosed chronic myeloid leukemia (CML) patients from 20 European countries. Haematologica. epub ahead of print: Abstract

  5. Hochhaus A, Kim D-W, Shah NP et al (2013) Four-Year (Yr) Follow-Up Of Patients (Pts) With Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP) Receiving Dasatinib Or Imatinib: Efficacy Based On Early Response. Blood. 122: Abstract 653

  6. Saußele S, Kalmanti L, Lauseker M, Dietz C, Heinrich L, Schwerdtfeger R, Kolb HJ, Gratwohl A, Krause SW, Falge C, Dengler J, Kanz L, Stegelmann F, Pfreundschuh M, Spiekermann K, Buchert A, Neubauer A, Ehninger G, Hossfeld DK, Heimpel H, Müller MC, Fabarius A, Hochhaus A, Pfirrmann M, Hasford J, Hehlmann R (2014) Management and outcome of CML-blast crisis: results from the randomized CML study IV. Haematologica 99:P275

    Google Scholar 

  7. Hughes TP, Saglio G, Kantarjian HM et al (2013) Early molecular response predicts outcomes in patients with chronic myeloid leukemia in chronic phase treated with frontline nilotinib or imatinib. Blood 123:1353–1360

    Article  PubMed  Google Scholar 

  8. Hehlmann R (2012) How I treat CML blast crisis. Blood 120:737–747

    Article  CAS  PubMed  Google Scholar 

  9. Hehlmann R, Heimpel H, Hasford J et al (1993) Randomized comparison of busulfan and hydroxyurea in chronic myelogenous leukemia: Prolongation of survival by hydroxyurea. Blood 82:398–407

    CAS  PubMed  Google Scholar 

  10. Hehlmann R, Heimpel H, Hasford J et al (1994) Randomized comparison of interferon-alpha with busulfan and hydroxyurea in chronic myelogenous leukemia. The German CML study group. Blood 84:4064–4077

    CAS  PubMed  Google Scholar 

  11. Hehlmann R, Berger U, Pfirrmann M et al (2003) Randomized comparison of interferon alpha and hydroxyurea with hydroxyurea monotherapy in chronic myeloid leukemia (CML-study II): prolongation of survival by the combination of interferon alpha and hydroxyurea. Leukemia 17:1529–1537

    Article  CAS  PubMed  Google Scholar 

  12. Hehlmann R, Lauseker M, Jung-Munkwitz S et al (2011) Tolerability-adapted imatinib 800 mg/d versus 400 mg/d versus 400 mg/d plus interferon-alpha in newly diagnosed chronic myeloid leukemia. J Clin Oncol 29:1634–1642

    Article  CAS  PubMed  Google Scholar 

  13. Hehlmann R, Müller MC, Lauseker M et al (2014) Deep molecular response (MR4.5) is reached by the majority of imatinib-treated patients, predicts survival, and is achieved faster by optimized high-dose imatinib—results from the randomized CML-study IV. J Clin Oncol 32:415–423

    Article  PubMed  Google Scholar 

  14. Hughes TP, Branford S (2009) Monitoring disease response to tyrosine kinase inhibitor therapy in CML. ASH Educ Program Book 2009:477–487

    Google Scholar 

  15. Karanas A, Silver RT (1968) Characteristics of the terminal phase of chronic granulocytic leukemia. Blood 32:445–459

    CAS  PubMed  Google Scholar 

  16. Cortes JE, Talpaz M, O’Brien S et al (2006) Staging of chronic myeloid leukemia in the imatinib era: an evaluation of the World Health Organization proposal. Cancer 106:1306–1315

    Article  CAS  PubMed  Google Scholar 

  17. Silver RT (2009) The blast phase of chronic myeloid leukaemia. Best Pract Res Clin Haematol 22:387–394

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  19. Vardiman JW, Harris NL, Brunning RD (2002) The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 100:2292–2302

    Article  CAS  PubMed  Google Scholar 

  20. Jabbour EJ, Hughes TP, Cortes JE et al (2014) Potential mechanisms of disease progression and management of advanced-phase chronic myeloid leukemia. Leuk Lymphoma 55:1451–1462

    Article  CAS  PubMed  Google Scholar 

  21. Nicolini FE, Morisset S, Hochhaus A et al (2010) The presence of the BCR ABL T315I mutation in chronic phase chronic myelogenous leukemia resistant to tyrosine kinase inhibitors profoundly compromises overall survival and progression free survival preliminary results of a matched pair analysts. Blood 116:1396–1397

    Article  Google Scholar 

  22. Kihara R, Nagata Y, Kiyoi H et al (2014) Comprehensive analysis of genetic alterations and their prognostic impacts in adult acute myeloid leukemia patients. Leukemia 28:1586–1595

    Article  CAS  PubMed  Google Scholar 

  23. Greenberg PL, Tuechler H, Schanz J et al (2012) Revised international prognostic scoring system for myelodysplastic syndromes. Blood 120:2454–2465

    Article  CAS  PubMed  Google Scholar 

  24. Sandberg AA, Hossfeld DK, Ezdinli EZ, Crosswhite LH (1971) Chromosomes and causation of human cancer and leukemia. VI. Blastic phase, cellular origin, and th Ph1 in CML. Cancer 27:176–185

    Article  CAS  PubMed  Google Scholar 

  25. Fabarius A, Leitner A, Hochhaus A et al (2011) Impact of additional cytogenetic aberrations at diagnosis on prognosis of CML: long-term observation of 1151 patients from the randomized CML Study IV. Blood 118:6760–6768

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  27. Bacher U, Haferlach T, Hiddemann W et al (2005) Additional clonal abnormalities in Philadelphia-positive ALL and CML demonstrate a different cytogenetic pattern at diagnosis and follow different pathways at progression. Cancer Genet Cytogenet 157:53–61

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  29. Radich JP (2007) The biology of CML blast crisis. Hematol Am Soc Hematol Educ Program 2007:384–391

    Article  Google Scholar 

  30. Melo JV, Barnes DJ (2007) Chronic myeloid leukaemia as a model of disease evolution in human cancer. Nat Rev Cancer 7:441–453

    Article  CAS  PubMed  Google Scholar 

  31. Calabretta B, Perrotti D (2004) The biology of CML blast crisis. Blood 103:4010–4022

    Article  CAS  PubMed  Google Scholar 

  32. Koptyra M, Falinski R, Nowicki MO et al (2006) BCR/ABL kinase induces self-mutagenesis via reactive oxygen species to encode imatinib resistance. Blood 108:319–327

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Cervantes F, Rozman M, Rosell J et al (1990) A study of prognostic factors in blast crisis of Philadelphia chromosome-positive chronic myelogenous leukaemia. Br J Haematol 76:27–32

    Article  CAS  PubMed  Google Scholar 

  34. Wadhwa J, Szydlo RM, Apperley JF et al (2002) Factors affecting duration of survival after onset of blastic transformation of chronic myeloid leukemia. Blood 99:2304–2309

    Article  CAS  PubMed  Google Scholar 

  35. Palandri F, Castagnetti F, Testoni N et al (2008) Chronic myeloid leukemia in blast crisis treated with imatinib 600 mg: outcome of the patients alive after a 6-year follow-up. Haematologica 93:1792–1796

    Article  CAS  PubMed  Google Scholar 

  36. Silver RT, Cortes J, Waltzman R et al (2009) Sustained durability of responses and improved progression-free and overall survival with imatinib treatment for accelerated phase and blast crisis chronic myeloid leukemia: long-term follow-up of the STI571 0102 and 0109 trials. Haematologica 94:743–744

    Article  PubMed Central  PubMed  Google Scholar 

  37. Sureda A, Carrasco M, de Miguel M et al (2003) Imatinib mesylate as treatment for blastic transformation of Philadelphia chromosome positive chronic myelogenous leukemia. Haematologica 88:1213–1220

    CAS  PubMed  Google Scholar 

  38. Sawyers CL, Hochhaus A, Feldman E et al (2002) Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood 99:3530–3539

    Article  CAS  PubMed  Google Scholar 

  39. Kantarjian HM, Cortes J, O’Brien S et al (2002) Imatinib mesylate (STI571) therapy for Philadelphia chromosome–positive chronic myelogenous leukemia in blast phase. Blood 99:3547–3553

    Article  CAS  PubMed  Google Scholar 

  40. Druker B (2001) Signal transduction inhibition: results from phase I clinical trials in chronic myeloid leukemia. Semin Hematol 38:9–14

    Article  CAS  PubMed  Google Scholar 

  41. Talpaz M, Shah NP, Kantarjian H et al (2006) Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. NEngl J Med 354:2531–2541

    Article  CAS  PubMed  Google Scholar 

  42. Cortes J, Kim DW, Raffoux E et al (2008) Efficacy and safety of dasatinib in imatinib-resistant or -intolerant patients with chronic myeloid leukemia in blast phase. Leukemia 22:2176–2183

    Article  CAS  PubMed  Google Scholar 

  43. Saglio G, Hochhaus A, Goh YT et al (2010) Dasatinib in imatinib-resistant or imatinib-intolerant chronic myeloid leukemia in blast phase after 2 years of follow-up in a phase 3 study: efficacy and tolerability of 140 milligrams once daily and 70 milligrams twice daily. Cancer 116:3852–3861

    Article  CAS  PubMed  Google Scholar 

  44. Kantarjian H, Giles F, Wunderle L et al (2006) Nilotinib (AMN107), a novel, highly active, selective BCR-ABL tyrosine kinase inhibitor in patients with Philadelphia-Chromosome (Ph) positive chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL) who are resistant to imatinib mesylate therapy. N.Engl.J Med. 2542-2551

  45. Giles FJ, Kantarjian HM, le Coutre PD et al (2012) Nilotinib is effective in imatinib-resistant or -intolerant patients with chronic myeloid leukemia in blastic phase. Leukemia 26:959–962

    Article  CAS  PubMed  Google Scholar 

  46. Gambacorti-Passerini C, Cortes JE, Khoury HJ et al (2010) Safety and efficacy of bosutinib in patients with AP and BP CML and ph + ALL following resistance/intolerance to imatinib and other TKIs: update from study SKI-200. ASCO Meet Abstracts 28:6509

    Google Scholar 

  47. Cortes JE, Kim DW, Pinilla-Ibarz J et al (2013) A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med 369:1783–1796

    Article  CAS  PubMed  Google Scholar 

  48. Kim D-W, Pinilla-Ibarz J, le Coutre PD et al (2013) Ponatinib In Patients (pts) With Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph + ALL) Resistant Or Intolerant To Dasatinib Or Nilotinib, Or With The T315I BCR-ABL Mutation: 2-Year Follow-Up Of The PAC. 122: 650-650

  49. Hehlmann R, Saussele S (2008) Treatment of chronic myeloid leukemia in blast crisis. Haematol Hematol J 93:1765–1769

    Article  CAS  Google Scholar 

  50. Fruehauf S, Topaly J, Buss EC et al (2007) Imatinib combined with mitoxantrone/etoposide and cytarabine is an effective induction therapy for patients with chronic myeloid leukemia in myeloid blast crisis. Cancer 109:1543–1549

    Article  CAS  PubMed  Google Scholar 

  51. Oki Y, Kantarjian HM, Gharibyan V et al (2007) Phase II study of low-dose decitabine in combination with imatinib mesylate in patients with accelerated or myeloid blastic phase of chronic myelogenous leukemia. Cancer 109:899–906

    Article  CAS  PubMed  Google Scholar 

  52. Quintas-Cardama A, Kantarjian H, Garcia-Manero G et al (2007) A pilot study of imatinib, low-dose cytarabine and idarubicin for patients with chronic myeloid leukemia in myeloid blast phase. Leuk Lymphoma 48:283–289

    Article  CAS  PubMed  Google Scholar 

  53. Cortes J, Jabbour E, Daley GQ et al (2007) Phase 1 study of lonafarnib (SCH 66336) and imatinib mesylate in patients with chronic myeloid leukemia who have failed prior single-agent therapy with imatinib. Cancer 110:1295–1302

    Article  CAS  PubMed  Google Scholar 

  54. Fang B, Li N, Song Y et al (2010) Standard-dose imatinib plus low-dose homoharringtonine and granulocyte colony-stimulating factor is an effective induction therapy for patients with chronic myeloid leukemia in myeloid blast crisis who have failed prior single-agent therapy with imatinib. Ann Hematol 89:1099–1105

    Article  CAS  PubMed  Google Scholar 

  55. Rea D, Legros L, Raffoux E et al (2006) High-dose imatinib mesylate combined with vincristine and dexamethasone (DIV regimen) as induction therapy in patients with resistant Philadelphia-positive acute lymphoblastic leukemia and lymphoid blast crisis of chronic myeloid leukemia. Leukemia 20:400–403

    Article  CAS  PubMed  Google Scholar 

  56. Deau B, Nicolini FE, Guilhot J et al (2011) The addition of daunorubicin to imatinib mesylate in combination with cytarabine improves the response rate and the survival of patients with myeloid blast crisis chronic myelogenous leukemia (AFR01 study). Leukemia Research 35:777–782

    Article  CAS  PubMed  Google Scholar 

  57. Milojkovic D, Ibrahim A, Reid A et al (2012) Efficacy of combining dasatinib and FLAG-IDA for patients with chronic myeloid leukemia in blastic transformation. Haematol Hematol J 97:473–474

    Article  CAS  Google Scholar 

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Ghez D, Micol JB, Pasquier F et al (2013) Clinical efficacy of second generation tyrosine kinase inhibitor and 5-azacytidine combination in chronic myelogenous leukaemia in myeloid blast crisis. Eur J Cancer 49:3666–3670

    Article  CAS  PubMed  Google Scholar 

  60. Benjamini O, Dumlao TL, Kantarjian H et al (2014) Phase II trial of hyper CVAD and dasatinib in patients with relapsed Philadelphia chromosome positive acute lymphoblastic leukemia or blast phase chronic myeloid leukemia. Am J Hematol 89:282–287

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  61. Jiang H, Xu LP, Liu DH et al (2014) Allogeneic hematopoietic SCT in combination with tyrosine kinase inhibitor treatment compared with TKI treatment alone in CML blast crisis. Bone Marrow Transplant 49:1146

    Article  CAS  PubMed  Google Scholar 

  62. Schmid C, Schleuning M, Ledderose G et al (2005) Sequential regimen of chemotherapy, reduced-intensity conditioning for allogeneic stem-cell transplantation, and prophylactic donor lymphocyte transfusion in high-risk acute myeloid leukemia and myelodysplastic syndrome. J Clin Oncol 23:5675–5687

    Article  PubMed  Google Scholar 

  63. Jain N, van Besien K (2011) Chronic myelogenous leukemia: role of stem cell transplant in the imatinib era. Hematol Oncol Clin North Am 25:1025–1048

    Article  PubMed Central  PubMed  Google Scholar 

  64. Passweg JR, Baldomero H, Gratwohl A et al (2012) The EBMT activity survey: 1990–2010. Bone Marrow Transplant 47:906–923

    Article  CAS  PubMed  Google Scholar 

  65. Perotti A, Locatelli A, Sessa C et al (2010) Phase IB study of the mTOR inhibitor ridaforolimus with capecitabine. J Clin Oncol 28:4554–4561

    Article  CAS  PubMed  Google Scholar 

  66. Panjarian S, Iacob RE, Chen S et al (2013) Enhanced SH3/linker interaction overcomes Abl kinase activation by gatekeeper and myristic acid binding pocket mutations and increases sensitivity to small molecule inhibitors. J Biol Chem 288:6116–6129

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  67. Zhang J, Adrian FJ, Jahnke W et al (2010) Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors. Nature 463:501–506

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  68. Adrian FJ, Ding Q, Sim T et al (2006) Allosteric inhibitors of Bcr-abl-dependent cell proliferation. Nat Chem Biol 2:95–102

    Article  CAS  PubMed  Google Scholar 

  69. Held SA, Heine A, Mayer KT et al (2013) Advances in immunotherapy of chronic myeloid leukemia CML. Curr Cancer Drug Targets 13:768–774

    Article  CAS  PubMed  Google Scholar 

  70. McDermott DF, Atkins MB (2013) PD-1 as a potential target in cancer therapy. Cancer Med 2:662–673

    PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

This work was supported by the German CML Study Group which is supported by the Deutsche Krebshilfe (Nr. 106642); Deutsches Kompetenznetz für Akute und Chronische Leukämien (BMBF 01GI0270); Deutsche José-Carreras Leukämiestiftung (DJCLS H09/01f, H06/04v) the European LeukemiaNet (LSHC-CT-2004-503216); also supported in part by the Judy and William Higgins Trust of the Cancer Research and Treatment Fund, Inc., New York, NY, USA.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. III. Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg, Pettenkoferstr. 22, 68169, Mannheim, Germany

    S. Saußele

  2. Myeloproliferative Neoplasm Center, Division of Hematology-Oncology, Weill Cornell Medical College, New York, NY, USA

    Richard T. Silver

Authors
  1. S. Saußele
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Richard T. Silver
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S. Saußele.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Saußele, S., Silver, R.T. Management of chronic myeloid leukemia in blast crisis. Ann Hematol 94 (Suppl 2), 159–165 (2015). https://doi.org/10.1007/s00277-015-2324-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-015-2324-0

Keywords

Search

Navigation