Treatment of chronic myeloid leukemia in chronic phase after failure of initial therapy
- 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), resulting in the BCR-ABL fusion gene. This genetic abnormality results in the formation of a unique gene product (BCR-ABL), which is a constitutively active tyrosine kinase. It is this deregulated tyrosine kinase that is implicated in the development of CML. (See "Molecular genetics of chronic myeloid leukemia".)
The majority of patients with CML present in a relatively indolent phase termed chronic phase and are treated initially with a BCR-ABL tyrosine kinase inhibitor (TKI), such as imatinib, dasatinib, or nilotinib. Side effects are generally mild, but there are some patients who must discontinue the drug due to intolerance. In addition, second line therapy is required for the patient who has a suboptimal response (primary resistance) or relapses after an initial response (secondary resistance) to a TKI.
The treatment of patients with chronic phase CML who are intolerant of or have a primary or secondary resistance to a TKI will be reviewed here. The initial treatment of chronic phase CML and specific details regarding the pharmacology of TKIs are discussed separately. (See "Initial treatment of chronic myeloid leukemia in chronic phase" and "Overview of the treatment of chronic myeloid leukemia" and "Clinical use of tyrosine kinase inhibitors for chronic myeloid leukemia".)
DEFINING INTOLERANCE AND RESISTANCE
Intolerance — Long term studies of BCR-ABL tyrosine kinase inhibitors (TKIs) have shown that side effects are usually mild and most patients can continue treatment without interruption. When more severe symptoms do develop, the majority resolve rapidly within a few days after stopping the TKI for a brief "drug holiday." Often, the drug can then be restarted at the same dose without a recurrence of the side effects. Less than 5 percent of patients treated with a TKI will be unable to tolerate long term treatment. The side effects of TKIs and their management are discussed in detail separately. (See "Clinical use of tyrosine kinase inhibitors for chronic myeloid leukemia".)
While the TKIs have some side effect profiles in common, there are some notable variations. Common side effects include myelosuppression, gastrointestinal complaints, fatigue, headache, rash, and peripheral and periorbital edema (most notably with imatinib). Imatinib has been rarely associated with severe heart failure; dasatinib and nilotinib are associated with QT prolongation; nilotinib can occasionally cause pancreatitis; and dasatinib may cause pleural effusions and rarely pulmonary hypertension, as well as gastrointestinal bleeding probably related to an effect on platelet function. Bosutinib can cause significant diarrhea during the first one to two months of treatment, as well as transient elevations of transaminases.
- 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.
- http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf (Accessed on April 27, 2011).
- Shah NP. Medical management of CML. Hematology Am Soc Hematol Educ Program 2007; :371.
- Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 2013; 122:872.
- O'Dwyer ME, Mauro MJ, Blasdel C, et al. Clonal evolution and lack of cytogenetic response are adverse prognostic factors for hematologic relapse of chronic phase CML patients treated with imatinib mesylate. Blood 2004; 103:451.
- Kantarjian HM, Talpaz M, O'Brien S, et al. Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. Blood 2003; 101:473.
- Kantarjian H, Talpaz M, O'Brien S, et al. Prediction of initial cytogenetic response for subsequent major and complete cytogenetic response to imatinib mesylate therapy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia. Cancer 2003; 97:2225.
- Soverini S, Martinelli G, Rosti G, 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 2005; 23:4100.
- Noens L, van Lierde MA, De Bock R, et al. Prevalence, determinants, and outcomes of nonadherence to imatinib therapy in patients with chronic myeloid leukemia: the ADAGIO study. Blood 2009; 113:5401.
- Marin D, Bazeos A, Mahon FX, et al. Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol 2010; 28:2381.
- Dusetzina SB, Winn AN, Abel GA, et al. Cost sharing and adherence to tyrosine kinase inhibitors for patients with chronic myeloid leukemia. J Clin Oncol 2014; 32:306.
- Larson RA, Druker BJ, Guilhot F, et al. Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study. Blood 2008; 111:4022.
- Picard S, Titier K, Etienne G, et al. Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood 2007; 109:3496.
- Cortes JE, Egorin MJ, Guilhot F, et al. Pharmacokinetic/pharmacodynamic correlation and blood-level testing in imatinib therapy for chronic myeloid leukemia. Leukemia 2009; 23:1537.
- Efficace F, Baccarani M, Rosti G, et al. Investigating factors associated with adherence behaviour in patients with chronic myeloid leukemia: an observational patient-centered outcome study. Br J Cancer 2012; 107:904.
- Larson RA. Therapeutic monitoring of drug plasma concentrations and improved clinical outcomes in CML. Clin Adv Hematol Oncol 2009; 7:S3.
- Singh N, Kumar L, Meena R, Velpandian T. Drug monitoring of imatinib levels in patients undergoing therapy for chronic myeloid leukaemia: comparing plasma levels of responders and non-responders. Eur J Clin Pharmacol 2009; 65:545.
- Milojkovic D, Apperley JF, Gerrard G, et al. Responses to second-line tyrosine kinase inhibitors are durable: an intention-to-treat analysis in chronic myeloid leukemia patients. Blood 2012; 119:1838.
- Porkka K, Koskenvesa P, Lundán T, et al. Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia. Blood 2008; 112:1005.
- Cortes JE, Hochhaus A, le Coutre PD, et al. Minimal cross-intolerance with nilotinib in patients with chronic myeloid leukemia in chronic or accelerated phase who are intolerant to imatinib. Blood 2011; 117:5600.
- Jabbour E, Jones D, Kantarjian HM, et al. Long-term outcome of patients with chronic myeloid leukemia treated with second-generation tyrosine kinase inhibitors after imatinib failure is predicted by the in vitro sensitivity of BCR-ABL kinase domain mutations. Blood 2009; 114:2037.
- Hughes T, Saglio G, Branford S, et al. Impact of baseline BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic phase. J Clin Oncol 2009; 27:4204.
- Jabbour E, Branford S, Saglio G, et al. Practical advice for determining the role of BCR-ABL mutations in guiding tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia. Cancer 2011; 117:1800.
- Kantarjian H, Pasquini R, Hamerschlak N, et al. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial. Blood 2007; 109:5143.
- Shah NP, Kantarjian HM, Kim DW, et al. Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia. J Clin Oncol 2008; 26:3204.
- Hochhaus A, Kantarjian HM, Baccarani M, et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood 2007; 109:2303.
- Hochhaus A, Baccarani M, Deininger M, et al. Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia 2008; 22:1200.
- Shah NP, Guilhot F, Cortes JE, et al. Long-term outcome with dasatinib after imatinib failure in chronic-phase chronic myeloid leukemia: follow-up of a phase 3 study. Blood 2014; 123:2317.
- Shah NP, Tran C, Lee FY, et al. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 2004; 305:399.
- Müller MC, Cortes JE, Kim DW, et al. Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations. Blood 2009; 114:4944.
- 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.
- Kantarjian HM, Giles F, Gattermann N, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood 2007; 110:3540.
- Kantarjian HM, Giles FJ, Bhalla KN, et al. Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results. Blood 2011; 117:1141.
- Giles FJ, le Coutre PD, Pinilla-Ibarz J, et al. Nilotinib in imatinib-resistant or imatinib-intolerant patients with chronic myeloid leukemia in chronic phase: 48-month follow-up results of a phase II study. Leukemia 2013; 27:107.
- Nicolini FE, Turkina A, Shen ZX, et al. Expanding Nilotinib Access in Clinical Trials (ENACT): an open-label, multicenter study of oral nilotinib in adult patients with imatinib-resistant or imatinib-intolerant Philadelphia chromosome-positive chronic myeloid leukemia in the chronic phase. Cancer 2012; 118:118.
- Hughes TP, Lipton JH, Spector N, et al. Deep molecular responses achieved in patients with CML-CP who are switched to nilotinib after long-term imatinib. Blood 2014; 124:729.
- 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.
- Jabbour E, Kantarjian H, Jones D, et al. Characteristics and outcomes of patients with chronic myeloid leukemia and T315I mutation following failure of imatinib mesylate therapy. Blood 2008; 112:53.
- Puttini M, Coluccia AM, Boschelli F, 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 2006; 66:11314.
- http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203341lbl.pdf (Accessed on September 05, 2012).
- Cortes JE, Kantarjian HM, Brümmendorf TH, et al. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood 2011; 118:4567.
- Gambacorti-Passerini C, Brümmendorf TH, Kim DW, et al. Bosutinib efficacy and safety in chronic phase chronic myeloid leukemia after imatinib resistance or intolerance: Minimum 24-month follow-up. Am J Hematol 2014; 89:732.
- Kantarjian HM, Cortes JE, Kim DW, et al. Bosutinib safety and management of toxicity in leukemia patients with resistance or intolerance to imatinib and other tyrosine kinase inhibitors. Blood 2014; 123:1309.
- 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, Kantarjian H, Shah NP, et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med 2012; 367:2075.
- 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.
- Lipton JH, Chuah C, Guerci-Bresler A, et al. Ponatinib versus imatinib for newly diagnosed chronic myeloid leukaemia: an international, randomised, open-label, phase 3 trial. Lancet Oncol 2016; 17:612.
- Druker BJ. Circumventing resistance to kinase-inhibitor therapy. N Engl J Med 2006; 354:2594.
- Jabbour E, Kantarjian HM, Jones D, et al. Imatinib mesylate dose escalation is associated with durable responses in patients with chronic myeloid leukemia after cytogenetic failure on standard-dose imatinib therapy. Blood 2009; 113:2154.
- Kantarjian H, Pasquini R, Lévy V, et al. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia resistant to imatinib at a dose of 400 to 600 milligrams daily: two-year follow-up of a randomized phase 2 study (START-R). Cancer 2009; 115:4136.
- Jabbour E, Kantarjian H, O'Brien S, et al. Predictive factors for outcome and response in patients treated with second-generation tyrosine kinase inhibitors for chronic myeloid leukemia in chronic phase after imatinib failure. Blood 2011; 117:1822.
- Milojkovic D, Nicholson E, Apperley JF, et al. Early prediction of success or failure of treatment with second-generation tyrosine kinase inhibitors in patients with chronic myeloid leukemia. Haematologica 2010; 95:224.
- 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.
- Shah NP, Cortes JE, Schiffer CA, et al. Four-year follow-up of patients with chronic-phase chronic myeloid leukemia (CP-CML) receiving 100 mg of dasatinib once daily. J Clin Oncol 2010; 28:490s.
- Shah NP, Kim DW, Kantarjian H, et al. Potent, transient inhibition of BCR-ABL with dasatinib 100 mg daily achieves rapid and durable cytogenetic responses and high transformation-free survival rates in chronic phase chronic myeloid leukemia patients with resistance, suboptimal response or intolerance to imatinib. Haematologica 2010; 95:232.
- Velev N, Cortes J, Champlin R, et al. Stem cell transplantation for patients with chronic myeloid leukemia resistant to tyrosine kinase inhibitors with BCR-ABL kinase domain mutation T315I. Cancer 2010; 116:3631.
- Nicolini FE, Basak GW, Soverini S, et al. Allogeneic stem cell transplantation for patients harboring T315I BCR-ABL mutated leukemias. Blood 2011; 118:5697.
- 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.
- Branford S, Kim DW, Soverini S, et al. Initial molecular response at 3 months may predict both response and event-free survival at 24 months in imatinib-resistant or -intolerant patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase treated with nilotinib. J Clin Oncol 2012; 30:4323.
- Garg RJ, Kantarjian H, O'Brien S, et al. The use of nilotinib or dasatinib after failure to 2 prior tyrosine kinase inhibitors: long-term follow-up. Blood 2009; 114:4361.
- Giles FJ, Abruzzese E, Rosti G, et al. Nilotinib is active in chronic and accelerated phase chronic myeloid leukemia following failure of imatinib and dasatinib therapy. Leukemia 2010; 24:1299.
- Khoury HJ, Cortes JE, Kantarjian HM, et al. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood 2012; 119:3403.
- 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 J, Lipton JH, Rea D, et al. Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation. Blood 2012; 120:2573.
- Cortes J, Digumarti R, Parikh PM, et al. Phase 2 study of subcutaneous omacetaxine mepesuccinate for chronic-phase chronic myeloid leukemia patients resistant to or intolerant of tyrosine kinase inhibitors. Am J Hematol 2013; 88:350.
- 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.
- DEFINING INTOLERANCE AND RESISTANCE
- PATIENTS INELIGIBLE FOR HCT
- Choice of TKI
- Increased dose imatinib
- PATIENTS ELIGIBLE FOR HCT
- MONITORING DISEASE STATUS
- PATIENTS WHO HAVE FAILED ON MORE THAN ONE TKI
- Use of another TKI
- CLINICAL TRIALS
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS