Philadelphia-positive patients who already harbor imatinib-resistant Bcr-Abl kinase domain mutations have a higher likelihood of developing additional mutations associated with resistance to second- or third-line tyrosine kinase inhibitors

• Published in: Blood 2009-09, Vol.114 (10), p.2168-2171
• Main Authors: Soverini, Simona, Gnani, Alessandra, Colarossi, Sabrina, Castagnetti, Fausto, Abruzzese, Elisabetta, Paolini, Stefania, Merante, Serena, Orlandi, Ester, de Matteis, Silvia, Gozzini, Antonella, Iacobucci, Ilaria, Palandri, Francesca, Gugliotta, Gabriele, Papayannidis, Cristina, Poerio, Angela, Amabile, Marilina, Cilloni, Daniela, Rosti, Gianantonio, Baccarani, Michele, Martinelli, Giovanni
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Antineoplastic agents; Benzamides; Biological and medical sciences; Chemotherapy; Dasatinib; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Female; Fusion Proteins, bcr-abl - antagonists & inhibitors; Fusion Proteins, bcr-abl - genetics; Hematologic and hematopoietic diseases; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - enzymology; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Middle Aged; Mutation - drug effects; Pharmacology. Drug treatments; Piperazines - administration & dosage; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - enzymology; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Protein Kinase Inhibitors - administration & dosage; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - genetics; Pyrimidines - administration & dosage; Recurrence; Thiazoles - administration & dosage
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2009-01-197186

Dasatinib and nilotinib are tyrosine kinase inhibitors (TKIs) developed to overcome imatinib resistance in Philadelphia-positive leukemias. To assess how Bcr-Abl kinase domain mutation status evolves during sequential therapy with these TKIs and which mutations may further develop and impair their efficacy, we monitored the mutation status of 95 imatinib-resistant patients before and during treatment with dasatinib and/or nilotinib as second or third TKI. We found that 83% of cases of relapse after an initial response are associated with emergence of newly acquired mutations. However, the spectra of mutants conferring resistance to dasatinib or nilotinib are small and nonoverlapping, except for T315I. Patients already harboring mutations had higher likelihood of relapse associated with development of further mutations compared with patients who did not harbor mutations (23 of 51 vs 8 of 44, respectively, for patients who relapsed on second TKI; 13 of 20 vs 1 of 6, respectively, for patients who relapsed on third TKI).