BCR-ABL激酶区突变在酪氨酸激酶抑制剂耐药慢性髓性白血病患者中的分布及其影响因素

OBJECTIVE: To explore BCR-ABL kinase domain mutation profiles and clinical variables associated with them in tyrosine kinase inhibitor (TKI)-resistant patients with chronic myeloid leukemia (CML). METHODS: Imatinib-, nilotinib-, and/or dasatinib-resistant patients with CML who screened BCR-ABL mutation (s) in Peking University People's Hospital between June 2001 and September 2019 were retrospectively reviewed. BCR-ABL mutation was analyzed by Sanger sequencing. Binary logistic regression model was built to identify independent clinical variables associated with developing BCR-ABL mutation (s). RESULTS: Data of 1 093 TKI-resistant cases in 804 patients who experienced resistance to imatinib (n=576, 52.7%), nilotinib (n=238, 21.8%), and dasatinib (n=279, 25.5%) were analyzed. In total, 291 (50.5%) imatinib-, 152 (63.9%) nilotinib-, and 160 (57.3%) dasatinib-resistant cases developed BCR-ABL mutation (s). T315I mutation was the most frequent mutation detected in imatinib-, nilotinib-, and dasatinib-resistant cases, accounting for 12.3%, 27.3%, and 34.1%, respectively. Y253F/H (7.5%) and F359V/C/I (5.6%) were the mutation detected in≥5% imatinib-resistant cases; F359V/C/I (12.2%), Y253F/H (11.8%), and E255K/V (10.5%) in nilotinib-resistant cases; and F317L/V/I/C (11.5%) and E255K/V (5.4%) in dasatinib-resistant cases. In multivariate analyses, no TKI dose reduction or discontinuation of TKI therapy was the common variable associated with developing BCR-ABL mutation (s). Other variables associated with developing BCR-ABL mutation (s) in imatinib-, nilotinib-, or dasatinib-resistant cases included male gender, younger age, no comorbidity, advanced phase before starting current TKI therapy, longer interval from diagnosis to starting current TKI therapy, acquired resistance, and TKI resistance due to progression to advanced phase or hematologic failure. In addition, interval from TKI failure to BCR-ABL mutation detection, starting initial TKI therapy to TKI failure, and starting current TKI therapy to TKI failure were associated with the frequency of developing BCR-ABL mutation. Dasatinib and nilotinib use and acquired resistance were identified to be associated with the development of T315I mutation in multivariate analyses. CONCLUSION: More than half of TKI-resistant CML patients developed BCR-ABL mutation (s) by Sanger sequencing. T315I mutation was the most frequently detected. Clinical variables significantly associated with developing BCR-ABL mutation (s) should be used not only as basis for the choice of subsequent TKIs but also the understanding of TKI-resistant mechanisms.