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

• Published in: Clinics (São Paulo, Brazil) Vol. 70; no. 8; pp. 550 - 555
• Main Authors: Ribeiro, Beatriz Felicio, Miranda, Eliana C M, de Albuquerque, Dulcinéia Martins, Delamain, Márcia T, Oliveira-Duarte, Gislaine, Almeida, Maria Helena, Vergílio, Bruna, da Silveira, Rosana Antunes, Oliveira-Duarte, Vagner, Lorand-Metze, Irene, De Souza, Carmino A, Pagnano, Katia B B
• Format: Journal Article
• Language: English; Portuguese
• Published: Brazil Elsevier España, S.L.U 01.08.2015; Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo; Faculdade de Medicina / USP; Elsevier España
• Subjects: Adolescent; Adult; Aged; Antineoplastic Agents - therapeutic use; Bone Marrow Examination; Clinical Science; CML; Dasatinib; Dasatinib - therapeutic use; Disease-Free Survival; Drug Resistance - drug effects; Female; Fusion Proteins, bcr-abl - genetics; Humans; Kaplan-Meier Estimate; Karyotyping; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Male; MEDICINE, GENERAL & INTERNAL; Middle Aged; Mutation; Nilotinib; Protein Kinase Inhibitors - therapeutic use; Protein-Tyrosine Kinases - antagonists & inhibitors; Pyrimidines - therapeutic use; Real-Time Polymerase Chain Reaction; Third-line TKI treatment; Time Factors; Treatment Outcome; Young Adult; Nilotinib; Dasatinib; CML; Third-line TKI treatment
• ISSN: 1807-5932; 1980-5322; 1980-5322
• DOI: 10.6061/clinics/2015(08)04

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. 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. 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. 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.