title: Impact of baseline BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic phase.
abstract: OBJECTIVE
  Nilotinib is a second-generation tyrosine kinase inhibitor indicated for the treatment of patients with chronic myeloid leukemia (CML) in chronic phase (CP; CML-CP) and accelerated phase (AP; CML-AP) who are resistant to or intolerant of prior imatinib therapy. In this subanalysis of a phase II study of nilotinib in patients with imatinib-resistant or imatinib-intolerant CML-CP, the occurrence and impact of baseline and newly detectable BCR-ABL mutations were assessed.
  
  
  METHODS
  Baseline mutation data were assessed in 281 (88%) of 321 patients with CML-CP in the phase II nilotinib registration trial.
  
  
  RESULTS
  Among imatinib-resistant patients, the frequency of mutations at baseline was 55%. After 12 months of therapy, major cytogenetic response (MCyR) was achieved in 60%, complete cytogenetic response (CCyR) in 40%, and major molecular response (MMR) in 29% of patients without baseline mutations versus 49% (P = .145), 32% (P = .285), and 22% (P = .366), respectively, of patients with mutations. Responses in patients who harbored mutations with high in vitro sensitivity to nilotinib (50% inhibitory concentration [IC(50)] <or= 150 nM) or mutations with unknown nilotinib sensitivity were equivalent to those responses for patients without mutations (not significant). Patients with mutations that were less sensitive to nilotinib in vitro (IC(50) > 150 nM; Y253H, E255V/K, F359V/C) had less favorable responses, as 13%, 43%, and 9% of patients with each of these mutations, respectively, achieved MCyR; none achieved CCyR.
  
  
  CONCLUSIONS
  For most patients with imatinib resistance and with mutations, nilotinib offers a substantial probability of response. However, mutational status at baseline may influence response. Less sensitive mutations that occurred at three residues defined in this study, as well as the T315I mutation, may be associated with less favorable responses to nilotinib.
authors: Institute of Medical and Veterinary Science, Hanson Center for Cancer Research, Department of Hematology, Adelaide, 5000, Australia. Timothy.hughes@imvs.sa.gov.au
authors: Timothy
authors: T
authors: Hughes
authors: Giuseppe
authors: G
authors: Saglio
authors: Susan
authors: S
authors: Branford
authors: Simona
authors: S
authors: Soverini
authors: Dong-Wook
authors: DW
authors: Kim
authors: Martin C
authors: MC
authors: Müller
authors: Giovanni
authors: G
authors: Martinelli
authors: Jorge
authors: J
authors: Cortes
authors: Lan
authors: L
authors: Beppu
authors: Enrico
authors: E
authors: Gottardi
authors: Dongho
authors: D
authors: Kim
authors: Philipp
authors: P
authors: Erben
authors: Yaping
authors: Y
authors: Shou
authors: Ariful
authors: A
authors: Haque
authors: Neil
authors: N
authors: Gallagher
authors: Jerald
authors: J
authors: Radich
authors: Andreas
authors: A
authors: Hochhaus
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001315:Australia; D001549:Benzamides; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005060:Europe; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D000068877:Imatinib Mesylate; D007723:Korea; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D009154:Mutation; D010879:Piperazines / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C406060:abl-bcr fusion protein, human; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib