Treatment of chronic myeloid leukemia in blast crisis
- Robert S Negrin, MD
Robert S Negrin, MD
- Section Editor — Bone Marrow Transplantation
- Professor of Medicine
- Stanford University School of Medicine
- Charles A Schiffer, MD
Charles A Schiffer, MD
- Professor of Medicine and Oncology
- Barbara Ann Karmanos Cancer Institute
- Wayne State University School of Medicine
Chronic myeloid leukemia (CML) is a myeloproliferative disorder associated with the Philadelphia chromosome t(9;22)(q34;q11) and the BCR-ABL fusion gene. This genetic abnormality results in the formation of a unique gene product (BCR-ABL), which results in a constitutively active tyrosine kinase. It is this deregulated tyrosine kinase that is implicated in the development of CML and is the target of current therapies. (See "Molecular genetics of chronic myeloid leukemia".)
Imatinib mesylate was the first tyrosine kinase inhibitor (TKI) used in the treatment of CML. Since then, several other TKIs have been developed for the treatment of patients with CML, most notably dasatinib, nilotinib, bosutinib, and ponatinib. (See "Clinical use of tyrosine kinase inhibitors for chronic myeloid leukemia".)
CML has historically been a triphasic disease. Approximately 85 to 90 percent of patients present in a chronic stable phase. Without treatment, this inevitably progresses to a more aggressive, accelerated phase, and then culminates in a very difficult to treat blast crisis. With advances in the treatment of chronic phase CML, fewer patients (approximately 6 percent at five years) are progressing to accelerated phase and blast crisis. In addition, 10 to 15 percent of patients will initially present in accelerated phase or blast crisis.
The treatment of CML in blast crisis is discussed here. The treatment of CML in chronic or accelerated phase is discussed separately, as is the use of hematopoietic cell transplantation (HCT). (See "Treatment of chronic myeloid leukemia in accelerated phase" and "Overview of the treatment of chronic myeloid leukemia" and "Initial treatment of chronic myeloid leukemia in chronic phase" and "Treatment of chronic myeloid leukemia in chronic phase after failure of initial therapy" and "Hematopoietic cell transplantation in chronic myeloid leukemia".)
In approximately 30 percent of cases, blast crisis in CML is of the lymphoid (ie, acute lymphoblastic leukemia [ALL]), rather than the myeloid (ie, acute myeloid leukemia [AML]) phenotype. TKIs can be incorporated into a treatment plan for these and other patients with Philadelphia chromosome positive ALL. This is discussed separately. (See "Induction therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults", section on 'TKI plus chemotherapy'.)To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Jabbour E, Kantarjian H, O'Brien S, et al. Sudden blastic transformation in patients with chronic myeloid leukemia treated with imatinib mesylate. Blood 2006; 107:480.
- Alimena G, Breccia M, Latagliata R, et al. Sudden blast crisis in patients with Philadelphia chromosome-positive chronic myeloid leukemia who achieved complete cytogenetic remission after imatinib therapy. Cancer 2006; 107:1008.
- Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 2002; 100:2292.
- Talpaz M, Silver RT, Druker BJ, et al. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood 2002; 99:1928.
- Swerdlow SH, Campo E, Harris NL, et al. WHO classification of Tumors of Haematopoietic and Lymphoid Tissues, IARC Press, Lyon 2008.
- Strati P, Kantarjian H, Thomas D, et al. HCVAD plus imatinib or dasatinib in lymphoid blastic phase chronic myeloid leukemia. Cancer 2014; 120:373.
- Vignetti M, Fazi P, Cimino G, et al. Imatinib plus steroids induces complete remissions and prolonged survival in elderly Philadelphia chromosome-positive patients with acute lymphoblastic leukemia without additional chemotherapy: results of the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) LAL0201-B protocol. Blood 2007; 109:3676.
- Sacchi S, Kantarjian HM, O'Brien S, et al. Chronic myelogenous leukemia in nonlymphoid blastic phase: analysis of the results of first salvage therapy with three different treatment approaches for 162 patients. Cancer 1999; 86:2632.
- Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 2001; 344:1038.
- Sawyers CL, Hochhaus A, Feldman E, et al. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood 2002; 99:3530.
- Kantarjian HM, Cortes J, O'Brien S, et al. Imatinib mesylate (STI571) therapy for Philadelphia chromosome-positive chronic myelogenous leukemia in blast phase. Blood 2002; 99:3547.
- Fruehauf S, Topaly J, Buss EC, et al. Imatinib combined with mitoxantrone/etoposide and cytarabine is an effective induction therapy for patients with chronic myeloid leukemia in myeloid blast crisis. Cancer 2007; 109:1543.
- Armand P, Kim HT, Logan BR, et al. Validation and refinement of the Disease Risk Index for allogeneic stem cell transplantation. Blood 2014; 123:3664.
- Lange T, Günther C, Köhler T, et al. High levels of BAX, low levels of MRP-1, and high platelets are independent predictors of response to imatinib in myeloid blast crisis of CML. Blood 2003; 101:2152.
- Baccarani M, Saglio G, Goldman J, et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2006; 108:1809.
- Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2010; 362:2260.
- Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 2010; 362:2251.
- Gurion R, Gafter-Gvili A, Vidal L, et al. Has the time for first-line treatment with second generation tyrosine kinase inhibitors in patients with chronic myelogenous leukemia already come? Systematic review and meta-analysis. Haematologica 2013; 98:95.
- Jabbour E, Kantarjian HM, Saglio G, et al. Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION). Blood 2014; 123:494.
- Silver RT, Talpaz M, Sawyers CL, et al. Four years of follow-up of 1027 patients with late chronic phase, accelerated phase, or blast crisis chronic myeloid leukemia treated with imatinib in three large phase II trials (abstract). Blood 2004; 104:abstract 23.
- Wolff NC, Richardson JA, Egorin M, Ilaria RL Jr. The CNS is a sanctuary for leukemic cells in mice receiving imatinib mesylate for Bcr/Abl-induced leukemia. Blood 2003; 101:5010.
- le Coutre P, Kreuzer KA, Pursche S, et al. Pharmacokinetics and cellular uptake of imatinib and its main metabolite CGP74588. Cancer Chemother Pharmacol 2004; 53:313.
- Bujassoum S, Rifkind J, Lipton JH. Isolated central nervous system relapse in lymphoid blast crisis chronic myeloid leukemia and acute lymphoblastic leukemia in patients on imatinib therapy. Leuk Lymphoma 2004; 45:401.
- Leis JF, Stepan DE, Curtin PT, et al. Central nervous system failure in patients with chronic myelogenous leukemia lymphoid blast crisis and Philadelphia chromosome positive acute lymphoblastic leukemia treated with imatinib (STI-571). Leuk Lymphoma 2004; 45:695.
- Rytting ME, Wierda WG. Central nervous system relapse in two patients with chronic myelogenous leukemia in myeloid blastic phase on imatinib mesylate therapy. Leuk Lymphoma 2004; 45:1623.
- Cortes J, Rousselot P, Kim DW, et al. Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood 2007; 109:3207.
- Cortes J, Kim DW, Raffoux E, et al. Efficacy and safety of dasatinib in imatinib-resistant or -intolerant patients with chronic myeloid leukemia in blast phase. Leukemia 2008; 22:2176.
- Saglio G, Hochhaus A, Goh YT, et al. 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 2010; 116:3852.
- Giles FJ, Kantarjian HM, le Coutre PD, et al. Nilotinib is effective in imatinib-resistant or -intolerant patients with chronic myeloid leukemia in blastic phase. Leukemia 2012; 26:959.
- http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203341lbl.pdf (Accessed on September 05, 2012).
- http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf?et_cid=30657199&et_rid=463648356&linkid=http%3a%2f%2fwww.accessdata.fda.gov%2fdrugsatfda_docs%2flabel%2f2012%2f203469lbl.pdf (Accessed on December 17, 2012).
- Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med 2013; 369:1.
- http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/203469s007s008lbl.pdf (Accessed on January 22, 2014).
- http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm370971.htm (Accessed on October 15, 2013).
- http://www.fda.gov/Drugs/DrugSafety/ucm379554.htm (Accessed on January 14, 2014).
- Baccarani M, Cortes J, Pane F, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol 2009; 27:6041.
- Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 2013; 122:872.
- Axdorph U, Stenke L, Grimfors G, et al. Intensive chemotherapy in patients with chronic myelogenous leukaemia (CML) in accelerated or blastic phase--a report from the Swedish CML Group. Br J Haematol 2002; 118:1048.
- Valent JN, Schiffer CA. Prevalence of large granular lymphocytosis in patients with chronic myelogenous leukemia (CML) treated with dasatinib. Leuk Res 2011; 35:e1.
- Kantarjian HM, O'Brien S, Cortes JE, et al. Imatinib mesylate therapy for relapse after allogeneic stem cell transplantation for chronic myelogenous leukemia. Blood 2002; 100:1590.
- DeAngelo DJ, Hochberg EP, Alyea EP, et al. Extended follow-up of patients treated with imatinib mesylate (gleevec) for chronic myelogenous leukemia relapse after allogeneic transplantation: durable cytogenetic remission and conversion to complete donor chimerism without graft-versus-host disease. Clin Cancer Res 2004; 10:5065.
- O'Hare T, Eide CA, Deininger MW. Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia. Blood 2007; 110:2242.
- Soverini S, Hochhaus A, Nicolini FE, et al. 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 LeukemiaNet. Blood 2011; 118:1208.
- DEFINITION OF BLAST CRISIS
- EVALUATION UPON TRANSFORMATION
- REMISSION INDUCTION
- Lymphoid blast crisis
- Myeloid blast crisis
- Choice of TKI
- - Imatinib
- - Dasatinib
- - Nilotinib
- - Bosutinib
- - Ponatinib
- RESPONSE EVALUATION
- POST-REMISSION THERAPY
- Assessing HCT eligibility
- Eligible for HCT
- Ineligible for HCT
- TREATMENT AFTER FAILURE OF INITIAL THERAPY
- CLINICAL TRIALS
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS