Excellent outcomes of 2G-TKI therapy after imatinib failure in chronic phase CML patients

Second-generation tyrosine kinase inhibitors (2G-TKIs) dasatinib and nilotinib produced historical rates of about 50% complete cytogenetic response (CCyR) and about 40% major molecular response (MMR) in chronic myeloid leukaemia (CML) patients failing imatinib. Direct comparisons between dasatinib and nilotinib are lacking, and few studies addressed the dynamics of deep molecular response (DMR) in a “real-life” setting. We retrospectively analyzed 163 patients receiving dasatinib (n = 95) or nilotinib (n = 68) as second-line therapy after imatinib. The two cohorts were comparable for disease's characteristics, although there was a higher rate of dasatinib use in imatinib-resistant and of nilotinib in intolerant patients. Overall, 75% patients not in CCyR and 60% patients not in MMR at 2G-TKI start attained this response. DMR was achieved by 61 patients (37.4%), with estimated rate of stable DMR at 5 years of 24%. After a median follow-up of 48 months, 60% of patients persisted on their second-line treatment. Rates and kinetics of cytogenetic and molecular responses, progression-free and overall survival were similar for dasatinib and nilotinib. In a “real-life” setting, dasatinib and nilotinib resulted equally effective and safe after imatinib failure, determining high rates of CCyR and MMR, and a significant chance of stable DMR, a prerequisite for treatment discontinuation.

[1]  A. Salihoglu,et al.  Third-line treatment with second-generation tyrosine kinase inhibitors (dasatinib or nilotinib) in patients with chronic myeloid leukemia after two prior TKIs: real-life data on a single center experience along with the review of the literature , 2018, Hematology.

[2]  T. Brümmendorf,et al.  Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10-year survival results of the randomized CML study IV and impact of non-CML determinants , 2017, Leukemia.

[3]  R. Latagliata,et al.  Impact of exclusion criteria for the DASISION and ENESTnd trials in the front‐line treatment of a ‘real‐life’ patient population with chronic myeloid leukaemia , 2017, Hematological oncology.

[4]  G. Joseph,et al.  Nilotinib versus dasatinib as second-line therapy in patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase who are resistant or intolerant to imatinib: a cost-effectiveness analysis based on real-world data , 2017, Journal of medical economics.

[5]  Francisco Cervantes,et al.  Long‐Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia , 2017, The New England journal of medicine.

[6]  M. Breccia,et al.  Second line small molecule therapy options for treating chronic myeloid leukemia , 2017, Expert opinion on pharmacotherapy.

[7]  H. Kantarjian,et al.  A propensity score matching analysis of dasatinib and nilotinib as a frontline therapy for patients with chronic myeloid leukemia in chronic phase , 2016, Cancer.

[8]  Paul W Dickman,et al.  Life Expectancy of Patients With Chronic Myeloid Leukemia Approaches the Life Expectancy of the General Population. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  T. Hughes,et al.  Moving treatment-free remission into mainstream clinical practice in CML. , 2016, Blood.

[10]  H. Kantarjian,et al.  Dasatinib in imatinib‐resistant or ‐intolerant chronic‐phase, chronic myeloid leukemia patients: 7‐year follow‐up of study CA180‐034 , 2016, American journal of hematology.

[11]  M. Baccarani,et al.  European LeukemiaNet recommendations for the management and avoidance of adverse events of treatment in chronic myeloid leukaemia , 2016, Leukemia.

[12]  H. Kantarjian,et al.  CME Information: Chronic Myeloid Leukemia: 2016 update on diagnosis, therapy and monitoring , 2016 .

[13]  N. Cordani,et al.  Chronic myeloid leukemia: Second‐line drugs of choice , 2016, American journal of hematology.

[14]  H. Kantarjian,et al.  Use of second- and third-generation tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia: an evolving treatment paradigm. , 2015, Clinical lymphoma, myeloma & leukemia.

[15]  A. Hochhaus,et al.  Causes of resistance and treatment choices of second- and third-line treatment in chronic myelogenous leukemia patients , 2015, Annals of Hematology.

[16]  T. Brümmendorf,et al.  Long-term outcome with dasatinib after imatinib failure in chronic-phase chronic myeloid leukemia: follow-up of a phase 3 study. , 2014, Blood.

[17]  Francisco Cervantes,et al.  European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. , 2013, Blood.

[18]  J. Griffin,et al.  Comparing nilotinib with dasatinib as second-line therapies in patients with chronic myelogenous leukemia resistant or intolerant to imatinib – a retrospective chart review analysis , 2013, Current medical research and opinion.

[19]  Y. Kanda,et al.  Investigation of the freely available easy-to-use software ‘EZR' for medical statistics , 2012, Bone Marrow Transplantation.

[20]  Simona Soverini,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. , 2011, Blood.

[21]  M. Baccarani,et al.  Choosing the best second-line tyrosine kinase inhibitor in imatinib-resistant chronic myeloid leukemia patients harboring Bcr-Abl kinase domain mutations: how reliable is the IC₅₀? , 2011, The oncologist.

[22]  E. Jabbour,et al.  Management of adverse events associated with tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia , 2011, Leukemia.

[23]  M. Baccarani,et al.  Dasatinib and nilotinib in imatinib-resistant Philadelphia-positive chronic myelogenous leukemia: a ‘head-to-head comparison’ , 2010, Leukemia & lymphoma.

[24]  D. Marin,et al.  Early prediction of success or failure of treatment with second-generation tyrosine kinase inhibitors in patients with chronic myeloid leukemia , 2010, Haematologica.

[25]  Imona,et al.  Choosing the Best Second-Line Tyrosine Kinase Inhibitor in Imatinib-Resistant Chronic Myeloid Leukemia Patients Harboring Bcr-Abl Kinase Domain Mutations: How Reliable Is the IC 50 ? , 2017 .

[26]  J. Radich,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 , 2013, Leukemia.

[27]  M. Pitt,et al.  Dasatinib and nilotinib for imatinib-resistant or -intolerant chronic myeloid leukaemia: a systematic review and economic evaluation. , 2012, Health technology assessment.