title: Initial molecular response at 3 months may predict both response and event-free survival at 24 months in imatinib-resistant or -intolerant patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase treated with nilotinib.
abstract: OBJECTIVE
  The association between initial molecular response and longer-term outcomes with nilotinib was examined.
  
  
  METHODS
  Patients with imatinib-resistant or -intolerant chronic myeloid leukemia in chronic phase from the phase II nilotinib registration study with available postbaseline BCR-ABL1 transcript assessments were included (N = 237).
  
  
  RESULTS
  BCR-ABL1 transcript levels (International Scale [IS]) at 3 months correlated with complete cytogenetic response (CCyR) by 24 months. Patients with BCR-ABL1 (IS) of > 1% to ≤ 10% at 3 months with nilotinib had higher cumulative incidence of CCyR by 24 months than patients with BCR-ABL1 (IS) of > 10% (53% v 16%). BCR-ABL1 (IS) at 3 months predicted major molecular response (MMR) by 24 months. Cumulative incidence of MMR by 24 months for patients with BCR-ABL1 (IS) of > 0.1% to ≤ 1%, > 1% to ≤ 10%, and > 10% was 65%, 27%, and 9%, respectively. These differences were observed for patients with or without baseline BCR-ABL1 mutations and for those with imatinib resistance or intolerance. Estimated event-free survival (EFS) rates at 24 months decreased with higher transcript levels at 3 months; patients with BCR-ABL1 (IS) of ≤ 1% had an estimated 24-month EFS rate of 82%, compared with 70% for patients with BCR-ABL1 (IS) of > 1% to ≤ 10% and 48% for patients with BCR-ABL1 (IS) of > 10%.
  
  
  CONCLUSIONS
  Patients with BCR-ABL1 (IS) of > 10% at 3 months had a lower cumulative incidence of CCyR and MMR and lower rates of EFS versus patients with BCR-ABL1 (IS) of ≤ 10%. Prospective studies may determine whether close monitoring or alternative therapies are warranted for patients with minimal initial molecular response.
authors.affiliation: Centre for Cancer Biology, SA Pathology, University of Adelaide, Australia. susan.branford@health.sa.gov.au
authors.forename: Susan
authors.initials: S
authors.lastname: Branford
authors.forename: Dong-Wook
authors.initials: DW
authors.lastname: Kim
authors.forename: Simona
authors.initials: S
authors.lastname: Soverini
authors.forename: Ariful
authors.initials: A
authors.lastname: Haque
authors.forename: Yaping
authors.initials: Y
authors.lastname: Shou
authors.forename: Richard C
authors.initials: RC
authors.lastname: Woodman
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.forename: Giovanni
authors.initials: G
authors.lastname: Martinelli
authors.forename: Jerald P
authors.initials: JP
authors.lastname: Radich
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Saglio
authors.forename: Andreas
authors.initials: A
authors.lastname: Hochhaus
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Hughes
authors.forename: Martin C
authors.initials: MC
authors.lastname: Müller
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides / Q000627:therapeutic use*; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010879:Piperazines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012074:Remission Induction; D015996:Survival Rate; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D012333:RNA, Messenger; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib