title: Prognosis for patients with CML and >10% BCR-ABL1 after 3 months of imatinib depends on the rate of BCR-ABL1 decline.
abstract: In chronic myeloid leukemia (CML) patients, a breakpoint cluster region-Abelson (BCR-ABL1) value >10% at 3 months of therapy is statistically associated with poorer outcome, yet many of these patients still achieve satisfactory outcomes. We investigated 528 first-line imatinib-treated patients to determine whether patients with the poorest outcome can be better discriminated at 3 months. All outcomes were significantly superior for the 410 patients with BCR-ABL1 ≤10% at 3 months (P < .001). However, the poorest outcomes among the 95 evaluable patients with BCR-ABL1 >10% at 3 months were identified by the rate of BCR-ABL1 decline from baseline, assessed by estimating the number of days over which BCR-ABL1 halved. Patients with BCR-ABL1 halving time <76 days (n = 74) had significantly superior outcomes compared with patients whose BCR-ABL1 values did not halve by 76 days (n = 21; 4-year overall survival, 95% vs 58%, P = .0002; progression-free survival, 92% vs 63%, P = .008; failure-free survival, 59% vs 6%, P < .0001; and major molecular response, 54% vs 5%, P = .008). By multivariate analysis, the halving time was an independent predictor of outcome in this poor risk group. Our study highlighted that the rate of BCR-ABL1 decline may be a critical prognostic discriminator of the patients with very poor outcome among those >10% at 3 months. The International Randomized IFN vs STI571 (IRIS) trial was registered at http://www.clinicaltrials.gov as #NCT00006343. The Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) trial was registered at http://www.clinicaltrials.gov as #NCT00124748. The Therapeutic Intensification in DE-novo Leukaemia (TIDEL) I trial was registered at http://www.ANZCTR.org.au as #ACTRN12607000614493. The TIDEL II trial was registered at http://www.ANZCTR.org.au as #ACTRN12607000325404.
authors.affiliation: Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia; School of Medicine, and School of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia; School of Pharmacy and Medical Science, University of South Adelaide, Adelaide, Australia;
authors.forename: Susan
authors.initials: S
authors.lastname: Branford
authors.affiliation: Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia; School of Medicine, and Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia; Australasian Leukaemia and Lymphoma Group, East Melbourne, Australia;
authors.forename: David T
authors.initials: DT
authors.lastname: Yeung
authors.affiliation: Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia; School of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia;
authors.forename: Wendy T
authors.initials: WT
authors.lastname: Parker
authors.affiliation: Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia;
authors.forename: Nicola D
authors.initials: ND
authors.lastname: Roberts
authors.affiliation: Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia;
authors.forename: Leanne
authors.initials: L
authors.lastname: Purins
authors.affiliation: Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia;
authors.forename: Jodi A
authors.initials: JA
authors.lastname: Braley
authors.affiliation: Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia;
authors.forename: Haley K
authors.initials: HK
authors.lastname: Altamura
authors.affiliation: Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia;
authors.forename: Alexandra L
authors.initials: AL
authors.lastname: Yeoman
authors.affiliation: Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia;
authors.forename: Jasmina
authors.initials: J
authors.lastname: Georgievski
authors.affiliation: Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia;
authors.forename: Bronte A
authors.initials: BA
authors.lastname: Jamison
authors.affiliation: Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia;
authors.forename: Stuart
authors.initials: S
authors.lastname: Phillis
authors.affiliation: Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia;
authors.forename: Zoe
authors.initials: Z
authors.lastname: Donaldson
authors.affiliation: Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia;
authors.forename: Mary
authors.initials: M
authors.lastname: Leong
authors.affiliation: Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia;
authors.forename: Linda
authors.initials: L
authors.lastname: Fletcher
authors.affiliation: Australasian Leukaemia and Lymphoma Group, East Melbourne, Australia; Department of Haematology, Peter MacCallum Cancer Centre, East Melbourne, Australia; University of Melbourne, Parkville, Australia;
authors.forename: John F
authors.initials: JF
authors.lastname: Seymour
authors.affiliation: Australasian Leukaemia and Lymphoma Group, East Melbourne, Australia; University of Melbourne, Parkville, Australia; Department of Haematology, Austin Hospital, Melbourne, Australia;
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Grigg
authors.affiliation: School of Medicine, and Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia; Australasian Leukaemia and Lymphoma Group, East Melbourne, Australia; Department of Haematology, Flinders University and Medical Centre, Bedford Park, Australia; and.
authors.forename: David M
authors.initials: DM
authors.lastname: Ross
authors.affiliation: School of Medicine, and Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia; Australasian Leukaemia and Lymphoma Group, East Melbourne, Australia; Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, Australia.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Hughes
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000627:therapeutic use*; D011379:Prognosis; D011743:Pyrimidines / Q000627:therapeutic use*; D012074:Remission Induction; D015996:Survival Rate; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl