title: Nilotinib is associated with a reduced incidence of BCR-ABL mutations vs imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase.
abstract: In patients with chronic myeloid leukemia, BCR-ABL mutations contribute to resistance to tyrosine kinase inhibitor therapy. We examined the occurrence of treatment-emergent mutations and their impact on response in patients from the ENESTnd phase 3 trial. At the 3-year data cutoff, mutations were detected in approximately twice as many patients (21) on imatinib 400 mg once daily as on nilotinib (11 patients each on nilotinib 300 mg twice daily and nilotinib 400 mg twice daily). The majority of mutations occurred in patients with intermediate or high Sokal scores. Most mutations (14 [66.7%]) emerging during imatinib treatment were imatinib-resistant and nilotinib-sensitive. Incidence of the T315I mutation was low (found in 3, 2, and 3 patients on nilotinib 300 mg twice daily, nilotinib 400 mg twice daily, and imatinib, respectively) and mostly occurred in patients with high Sokal scores. Of the patients with emergent mutations, 1 of 11, 2 of 11, and 7 of 21 patients on nilotinib 300 mg twice daily, nilotinib 400 mg twice daily, and imatinib, respectively, progressed to accelerated phase/blast crisis (AP/BC) on treatment. Overall, nilotinib led to fewer treatment-emergent BCR-ABL mutations than imatinib and reduced rates of progression to AP/BC in patients with these mutations. (Clinicaltrials.gov NCT00471497).
authors.affiliation: Abteilung Hämatologie/Onkologie, Universitätsklinikum Jena, Jena, Germany. andreas.hochhaus@med.uni-jena.de
authors.forename: Andreas
authors.initials: A
authors.lastname: Hochhaus
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Saglio
authors.forename: Richard A
authors.initials: RA
authors.lastname: Larson
authors.forename: Dong-Wook
authors.initials: DW
authors.lastname: Kim
authors.forename: Gabriel
authors.initials: G
authors.lastname: Etienne
authors.forename: Gianantonio
authors.initials: G
authors.lastname: Rosti
authors.forename: Carmino
authors.initials: C
authors.lastname: De Souza
authors.forename: Mineo
authors.initials: M
authors.lastname: Kurokawa
authors.forename: Matt E
authors.initials: ME
authors.lastname: Kalaycio
authors.forename: Albert
authors.initials: A
authors.lastname: Hoenekopp
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Fan
authors.forename: Yaping
authors.initials: Y
authors.lastname: Shou
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Hughes
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D001549:Benzamides / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D001752:Blast Crisis / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004334:Drug Administration Schedule; D005500:Follow-Up Studies; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D005787:Gene Frequency; D006801:Humans; D000068877:Imatinib Mesylate; D015994:Incidence; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics*; D009154:Mutation / Q000187:drug effects*; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib