title: Long-term molecular and cytogenetic response and survival outcomes with imatinib 400 mg, imatinib 800 mg, dasatinib, and nilotinib in patients with chronic-phase chronic myeloid leukaemia: retrospective analysis of patient data from five clinical trials.
abstract: BACKGROUND
  Several tyrosine kinase inhibitors (TKIs) are available for treatment of patients with chronic myeloid leukaemia in chronic phase (CML-CP). We analysed long-term molecular and cytogenetic response and survival outcomes for four TKI modalities used as frontline therapy for CML-CP.
  
  
  METHODS
  In a retrospective cohort analysis, we included data from patients with CML-CP treated in prospective clinical trials with frontline TKI modalities at a single institution between July 31, 2000, and Sept 10, 2013. The main aim of the study was to determine whether achievement of complete cytogenetic response or major molecular response had similar prognostic implications irrespective of the frontline TKI modality used. We analysed each TKI modality for response assessment and analysed survival endpoints (event-free, failure-free, transformation-free, and overall survival) with the Kaplan-Meier method. Univariate and multivariate analyses were done with Cox proportional hazard regression.
  
  
  RESULTS
  Our analysis included 482 patients who were treated with imatinib 400 mg daily (n=68), imatinib 800 mg daily (n=200), dasatinib 50 mg twice daily or 100 mg daily (n=106), or nilotinib 400 mg twice daily (n=108). More patients receiving imatinib 800 mg or second-generation TKIs (ie, dasatinib or nilotinib) achieved complete cytogenetic response (58 [87%] of 67 for imatinib 400 mg vs 180 [90%] of 199 for imatinib 800 mg, vs 100 [96%] of 104 for dasatinib vs 99 [93%] of 107 for nilotinib), major molecular response (51 [76%] vs 171 [86%] vs 93 [90%] vs 97 [91%]), and 4·5 log or higher reduction in BCR-ABL transcripts (MR(4·5) response 38 [57%] vs 148 [74%] vs 76 [71%] vs 76 [71%]). This finding was consistent over time (3-60 months). 5-year event free survival significantly differed between the imatinib 400 mg group and the other TKI groups (imatinib 800 mg p=0·029, dasatinib p=0·003, nilotinib p=0·031). There was no significant difference in 5-year failure-free survival (p=0·32, p=0·075, p=0·332), transformation-free survival (p=0·053, p=0·038, p=0·493), or overall survival (p=0·563, p=0·162, p=0·981). Multivariate analysis showed that therapy with imatinib 800 mg (HR 0·51, 95% CI 0·29-0·88, p=0·016), dasatinib (0·28, 0·12-0·66, p=0·004), or nilotinib (0·42, 0·20-0·89, p=0·024) predicted for better event-free survival compared with imatinib 400 mg, but that failure-free, transformation-free, and overall survival were similar irrespective of the TKI used. 28 (41%) patients receiving imatinib 400 mg, 85 (43%) receiving imatinib 800 mg, 23 (21%) receiving dasatinib, and 27 (25%) receiving nilotinib discontinued treatment for any reason.
  
  
  CONCLUSIONS
  Treatment with imatinib 800 mg or the second-generation TKIs dasatinib or nilotinib resulted in superior and deeper responses than did standard-dose imatinib, which were maintained after 5 years of follow-up. Results with imatinib 800 mg were similar to those with second-generation TKIs, although more patients discontinued therapy.
  
  
  BACKGROUND
  MD Anderson Cancer Center, National Cancer Institute.
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Preetesh
authors.initials: P
authors.lastname: Jain
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Medical Oncology, University of Texas Southwestern Dallas, TX, USA.
authors.forename: Mona Lisa
authors.initials: ML
authors.lastname: Alattar
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Elias
authors.initials: E
authors.lastname: Jabbour
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Koji
authors.initials: K
authors.lastname: Sasaki
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Graciela
authors.initials: G
authors.lastname: Nogueras Gonzalez
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Dellasala
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Sherry
authors.initials: S
authors.lastname: Pierce
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Srdan
authors.initials: S
authors.lastname: Verstovsek
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: William
authors.initials: W
authors.lastname: Wierda
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Gautam
authors.initials: G
authors.lastname: Borthakur
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Farhad
authors.initials: F
authors.lastname: Ravandi
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: O'Brien
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: jcortes@mdanderson.org.
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D020732:Cytogenetic Analysis; D000069439:Dasatinib / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D000068877:Imatinib Mesylate / Q000008:administration & dosage / Q000627:therapeutic use*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D011743:Pyrimidines / Q000008:administration & dosage / Q000627:therapeutic use*; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C498826:nilotinib; D000069439:Dasatinib