title: Treatment with dasatinib or nilotinib in chronic myeloid leukemia patients who failed to respond to two previously administered tyrosine kinase inhibitors--a single center experience.
abstract: OBJECTIVE
  To evaluate hematological, cytogenetic and molecular responses as well as the overall, progression-free and event-free survivals of chronic myeloid leukemia patients treated with a third tyrosine kinase inhibitor after failing to respond to imatinib and nilotinib/dasatinib.
  
  
  METHODS
  Bone marrow karyotyping and real-time quantitative polymerase chain reaction were performed at baseline and at 3, 6, 12 and 18 months after the initiation of treatment with a third tyrosine kinase inhibitor. Hematologic, cytogenetic and molecular responses were defined according to the European LeukemiaNet recommendations. BCR-ABL1 mutations were analyzed by Sanger sequencing.
  
  
  RESULTS
  We evaluated 25 chronic myeloid leukemia patients who had been previously treated with imatinib and a second tyrosine kinase inhibitor. Nine patients were switched to dasatinib, and 16 patients were switched to nilotinib as a third-line therapy. Of the chronic phase patients (n=18), 89% achieved a complete hematologic response, 13% achieved a complete cytogenetic response and 24% achieved a major molecular response. The following BCR-ABL1 mutations were detected in 6/14 (43%) chronic phase patients: E255V, Y253H, M244V, F317L (2) and F359V. M351T mutation was found in one patient in the accelerated phase of the disease. The five-year overall, progression-free and event-free survivals were 86, 54 and 22% (p<0.0001), respectively, for chronic phase patients and 66%, 66% and 0% (p<0.0001), respectively, for accelerated phase patients. All blast crisis patients died within 6 months of treatment. Fifty-six percent of the chronic phase patients lost their hematologic response within a median of 23 months.
  
  
  CONCLUSIONS
  Although the responses achieved by the third tyrosine kinase inhibitor were not sustainable, a third tyrosine kinase inhibitor may be an option for improving patient status until a donor becomes available for transplant. Because the long-term outcome for these patients is poor, the development of new therapies for resistant chronic myeloid leukemia patients is necessary.
authors.affiliation: Centro de Hematologia e Hemoterapia, Universidade de Campinas, Campinas, SP, Brazil.
authors.forename: Beatriz Felicio
authors.initials: BF
authors.lastname: Ribeiro
authors.affiliation: Centro de Hematologia e Hemoterapia, Universidade de Campinas, Campinas, SP, Brazil.
authors.forename: Eliana C M
authors.initials: EC
authors.lastname: Miranda
authors.affiliation: Centro de Hematologia e Hemoterapia, Universidade de Campinas, Campinas, SP, Brazil.
authors.forename: Dulcinéia Martins de
authors.initials: DM
authors.lastname: Albuquerque
authors.affiliation: Centro de Hematologia e Hemoterapia, Universidade de Campinas, Campinas, SP, Brazil.
authors.forename: Márcia T
authors.initials: MT
authors.lastname: Delamain
authors.affiliation: Centro de Hematologia e Hemoterapia, Universidade de Campinas, Campinas, SP, Brazil.
authors.forename: Gislaine
authors.initials: G
authors.lastname: Oliveira-Duarte
authors.affiliation: Centro de Hematologia e Hemoterapia, Universidade de Campinas, Campinas, SP, Brazil.
authors.forename: Maria Helena
authors.initials: MH
authors.lastname: Almeida
authors.affiliation: Centro de Hematologia e Hemoterapia, Universidade de Campinas, Campinas, SP, Brazil.
authors.forename: Bruna
authors.initials: B
authors.lastname: Vergílio
authors.affiliation: Centro de Hematologia e Hemoterapia, Universidade de Campinas, Campinas, SP, Brazil.
authors.forename: Rosana Antunes da
authors.initials: RA
authors.lastname: Silveira
authors.affiliation: Centro de Hematologia e Hemoterapia, Universidade de Campinas, Campinas, SP, Brazil.
authors.forename: Vagner
authors.initials: V
authors.lastname: Oliveira-Duarte
authors.affiliation: Centro de Hematologia e Hemoterapia, Universidade de Campinas, Campinas, SP, Brazil.
authors.forename: Irene
authors.initials: I
authors.lastname: Lorand-Metze
authors.affiliation: Centro de Hematologia e Hemoterapia, Universidade de Campinas, Campinas, SP, Brazil.
authors.forename: Carmino A
authors.initials: CA
authors.lastname: De Souza
authors.affiliation: Centro de Hematologia e Hemoterapia, Universidade de Campinas, Campinas, SP, Brazil.
authors.forename: Katia B B
authors.initials: KB
authors.lastname: Pagnano
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001856:Bone Marrow Examination; D000069439:Dasatinib / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004351:Drug Resistance / Q000187:drug effects*; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D006801:Humans; D053208:Kaplan-Meier Estimate; D007621:Karyotyping; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000627:therapeutic use*; D060888:Real-Time Polymerase Chain Reaction; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; C581634:BCR-ABL1 fusion protein, human; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib; D000069439:Dasatinib