title: Rapid initial decline in BCR-ABL1 is associated with superior responses to second-line nilotinib in patients with chronic-phase chronic myeloid leukemia.
abstract: BACKGROUND
  We evaluated BCR-ABL1 kinetics in patients treated with nilotinib and analyzed whether a dynamic model of changes in BCR-ABL1 levels over time could be used to predict long-term responses.
  
  
  METHODS
  Patients from the nilotinib registration trial (CAMN107A2101; registered at http://www.clinicaltrials.gov as NCT00109707) who had imatinib-resistant or -intolerant Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP) or accelerated phase with BCR-ABL1 > 10% (on the international scale [IS]) at baseline and, in the first 6 months, had at least three BCR-ABL1 transcript measurements and an average daily dose of at least 720 mg were included in this analysis (N = 123).
  
  
  RESULTS
  More than half of patients (65/123; 53%) had a slow monophasic response and the remainder (58/123; 47%) had a biphasic response, in which patients had a rapid initial decrease in BCR-ABL1 transcripts followed by a more gradual response. The biphasic response type strongly correlated with improved event-free survival (EFS). Data in the first 6 months of follow-up were sufficient to predict EFS at 24 months.
  
  
  CONCLUSIONS
  Unlike newly diagnosed patients with Ph+ CML-CP-in whom the majority had a biphasic response-approximately half of patients with imatinib-resistant or -intolerant CML had a slower, monophasic response. Second-line patients who did have a biphasic response had an EFS outlook similar to that of newly diagnosed patients treated with imatinib. Our model was comparable to using BCR-ABL1 (IS) ≤ 10% at 6 months as a threshold for predicting EFS.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Stein
authors.forename: Giovanni
authors.initials: G
authors.lastname: Martinelli
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Hughes
authors.forename: Martin C
authors.initials: MC
authors.lastname: Müller
authors.forename: Lan
authors.initials: L
authors.lastname: Beppu
authors.forename: Enrico
authors.initials: E
authors.lastname: Gottardi
authors.forename: Susan
authors.initials: S
authors.lastname: Branford
authors.forename: Simona
authors.initials: S
authors.lastname: Soverini
authors.forename: Richard C
authors.initials: RC
authors.lastname: Woodman
authors.forename: Andreas
authors.initials: A
authors.lastname: Hochhaus
authors.forename: Dong-Wook
authors.initials: DW
authors.lastname: Kim
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Saglio
authors.forename: Jerald P
authors.initials: JP
authors.lastname: Radich
mesh_terms: D002908:Chronic Disease; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005500:Follow-Up Studies; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D008962:Models, Theoretical; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D015996:Survival Rate
chemical_list: D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib
references.citation: Science. 2001 Aug 3;293(5531):876-80
references.pmid: 11423618
references.citation: Lancet Oncol. 2011 Sep;12(9):841-51
references.pmid: 21856226
references.citation: N Engl J Med. 1999 Jul 15;341(3):164-72
references.pmid: 10403855
references.citation: Stem Cells. 2006 Dec;24(12):2603-10
references.pmid: 16931775
references.citation: Blood. 2002 Mar 15;99(6):1928-37
references.pmid: 11877262
references.citation: J Pharmacokinet Pharmacodyn. 2001 Oct;28(5):481-504
references.pmid: 11768292
references.citation: J Clin Oncol. 2012 Jan 20;30(3):232-8
references.pmid: 22067393
references.citation: J Pharmacokinet Biopharm. 1981 Oct;9(5):635-51
references.pmid: 7334463
references.citation: Blood. 2012 Feb 2;119(5):1123-9
references.pmid: 22160483
references.citation: N Engl J Med. 2003 Mar 13;348(11):994-1004
references.pmid: 12637609
references.citation: Blood. 2012 Feb 23;119(8):1838-43
references.pmid: 22174159
references.citation: Blood. 2008 Oct 15;112(8):3330-8
references.pmid: 18684859
references.citation: Leukemia. 2009 Jun;23(6):1054-61
references.pmid: 19282833
references.citation: Clin Cancer Res. 2011 Nov 1;17(21):6812-21
references.pmid: 21903771
references.citation: Haematologica. 2010 Jun;95(6):900-7
references.pmid: 20007137
references.citation: Blood. 2009 Jun 18;113(25):6315-21
references.pmid: 19369233
references.citation: N Engl J Med. 2006 Dec 7;355(23):2408-17
references.pmid: 17151364
references.citation: Blood. 2011 Aug 4;118(5):1190-1
references.pmid: 21816838
references.citation: Proc Biol Sci. 2010 Jun 22;277(1689):1875-80
references.pmid: 20147328
references.citation: Leukemia. 2009 Sep;23(9):1628-33
references.pmid: 19641527
references.citation: Nature. 2005 Jun 30;435(7046):1267-70
references.pmid: 15988530
references.citation: Blood. 2012 Jul 12;120(2):291-4
references.pmid: 22645182
references.citation: J Clin Oncol. 2009 Dec 10;27(35):6041-51
references.pmid: 19884523
references.citation: Blood. 2012 May 3;119(18):4264-71
references.pmid: 22431575
references.citation: Blood. 2011 Jan 27;117(4):1141-5
references.pmid: 21098399
references.citation: Blood. 2002 May 15;99(10):3530-9
references.pmid: 11986204
references.citation: PLoS One. 2007 Oct 03;2(10):e990
references.pmid: 17912367
references.citation: Br J Haematol. 1991 Oct;79 Suppl 1:34-7
references.pmid: 1931706
references.citation: Blood. 2010 Nov 11;116(19):3758-65
references.pmid: 20679528
references.citation: J Clin Oncol. 2009 Sep 1;27(25):4204-10
references.pmid: 19652056
references.citation: J Clin Oncol. 2012 Dec 10;30(35):4323-9
references.pmid: 23109697
references.citation: Nat Med. 2006 Oct;12(10):1181-4
references.pmid: 17013383
references.citation: N Engl J Med. 2003 Oct 9;349(15):1423-32
references.pmid: 14534335
references.citation: Blood. 2007 Nov 15;110(10):3540-6
references.pmid: 17715389
references.citation: J Mol Diagn. 2007 Sep;9(4):421-30
references.pmid: 17690211
references.citation: J Clin Oncol. 2011 Apr 20;29(12):1634-42
references.pmid: 21422420
references.citation: N Engl J Med. 1999 Apr 29;340(17):1330-40
references.pmid: 10219069
references.citation: Blood. 2002 Sep 15;100(6):1965-71
references.pmid: 12200353