Treatment of chronic myeloid leukemia in accelerated phase
- 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/or the BCR-ABL1 fusion gene. This genetic abnormality results in the formation of a unique gene product (BCR-ABL1), 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 used in the treatment of CML. Since then, several other tyrosine kinase inhibitors have been developed and tested in 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. As advances are made 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. Interestingly, some patients progress to blast crisis without a clinically discernible accelerated phase. This is supported by an analysis of gene expression profiles in different stages of CML demonstrated relatively distinct patterns in chronic and blast phases without an identifiable "signature" of accelerated phase suggesting that CML is biologically more likely to be a "bi" rather than a triphasic disease .
The treatment of CML in accelerated phase is discussed here. The treatment of CML in chronic phase or blast crisis is discussed separately as is the use of hematopoietic cell transplantation. (See "Treatment of chronic myeloid leukemia in blast crisis" 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".)
DEFINITION OF ACCELERATED PHASE DISEASE
Varying definitions have been applied to the accelerated phase of CML (table 1) . The most frequently used criteria from the World Health Organization (WHO) define the accelerated phase in patients with CML by the presence of one or more of the following features:
- Radich JP, Dai H, Mao M, et al. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci U S A 2006; 103:2794.
- Cortes JE, Talpaz M, O'Brien S, et al. Staging of chronic myeloid leukemia in the imatinib era: an evaluation of the World Health Organization proposal. Cancer 2006; 106:1306.
- 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.
- Clift RA, Buckner CD, Thomas ED, et al. Marrow transplantation for patients in accelerated phase of chronic myeloid leukemia. Blood 1994; 84:4368.
- Gratwohl A, Hermans J, Goldman JM, et al. 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 1998; 352:1087.
- Ohanian M, Kantarjian HM, Quintas-Cardama A, et al. Tyrosine kinase inhibitors as initial therapy for patients with chronic myeloid leukemia in accelerated phase. Clin Lymphoma Myeloma Leuk 2014; 14:155.
- 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.
- Jiang Q, Xu LP, Liu DH, et al. Imatinib mesylate versus allogeneic hematopoietic stem cell transplantation for patients with chronic myelogenous leukemia in the accelerated phase. Blood 2011; 117:3032.
- 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.
- 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.
- Kantarjian HM, O'Brien S, Cortes JE, et al. Treatment of philadelphia chromosome-positive, accelerated-phase chronic myelogenous leukemia with imatinib mesylate. Clin Cancer Res 2002; 8:2167.
- Kantarjian H, Talpaz M, O'Brien S, et al. Survival benefit with imatinib mesylate therapy in patients with accelerated-phase chronic myelogenous leukemia--comparison with historic experience. Cancer 2005; 103:2099.
- 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.
- Kantarjian HM, Smith TL, O'Brien S, et al. Prolonged survival in chronic myelogenous leukemia after cytogenetic response to interferon-alpha therapy. The Leukemia Service. Ann Intern Med 1995; 122:254.
- Kantarjian HM, Keating MJ, Estey EH, et al. Treatment of advanced stages of Philadelphia chromosome-positive chronic myelogenous leukemia with interferon-alpha and low-dose cytarabine. J Clin Oncol 1992; 10:772.
- O'Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003; 348:994.
- Kantarjian HM, Cortes JE, O'Brien S, et al. Imatinib mesylate therapy in newly diagnosed patients with Philadelphia chromosome-positive chronic myelogenous leukemia: high incidence of early complete and major cytogenetic responses. Blood 2003; 101:97.
- O'Dwyer ME, Mauro MJ, Kurilik G, et al. The impact of clonal evolution on response to imatinib mesylate (STI571) in accelerated phase CML. Blood 2002; 100:1628.
- Rea D, Etienne G, Nicolini F, et al. First-line imatinib mesylate in patients with newly diagnosed accelerated phase-chronic myeloid leukemia. Leukemia 2012; 26:2254.
- Palandri F, Castagnetti F, Alimena G, et al. The long-term durability of cytogenetic responses in patients with accelerated phase chronic myeloid leukemia treated with imatinib 600 mg: the GIMEMA CML Working Party experience after a 7-year follow-up. Haematologica 2009; 94:205.
- 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.
- Fava C, Kantarjian HM, Jabbour E, et al. Failure to achieve a complete hematologic response at the time of a major cytogenetic response with second-generation tyrosine kinase inhibitors is associated with a poor prognosis among patients with chronic myeloid leukemia in accelerated or blast phase. Blood 2009; 113:5058.
- Kantarjian H, Cortes J, Kim DW, et al. Phase 3 study of dasatinib 140 mg once daily versus 70 mg twice daily in patients with chronic myeloid leukemia in accelerated phase resistant or intolerant to imatinib: 15-month median follow-up. Blood 2009; 113:6322.
- Apperley JF, Cortes JE, Kim DW, et al. Dasatinib in the treatment of chronic myeloid leukemia in accelerated phase after imatinib failure: the START a trial. J Clin Oncol 2009; 27:3472.
- Guilhot F, Apperley J, Kim DW, et al. Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood 2007; 109:4143.
- Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 2006; 354:2542.
- le Coutre P, Ottmann OG, Giles F, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia. Blood 2008; 111:1834.
- le Coutre PD, Giles FJ, Hochhaus A, et al. Nilotinib in patients with Ph+ chronic myeloid leukemia in accelerated phase following imatinib resistance or intolerance: 24-month follow-up results. Leukemia 2012; 26:1189.
- Bradeen HA, Eide CA, O'Hare T, 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 2006; 108:2332.
- von Bubnoff N, Manley PW, Mestan J, 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 2006; 108:1328.
- 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).
- 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).
- http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/203469s007s008lbl.pdf (Accessed on January 22, 2014).
- 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/2012/203585lbl.pdf?et_cid=30334780&et_rid=463648356&linkid=http%3a%2f%2fwww.accessdata.fda.gov%2fdrugsatfda_docs%2flabel%2f2012%2f203585lbl.pdf (Accessed on October 26, 2012).
- Cortes JE, Kantarjian HM, Rea D, et al. Final analysis of the efficacy and safety of omacetaxine mepesuccinate in patients with chronic- or accelerated-phase chronic myeloid leukemia: Results with 24 months of follow-up. Cancer 2015; 121:1637.