BCR-ABL突变检测指导下的达沙替尼治疗伊马替尼耐药的慢性髓性白血病疗效分析

OBJECTIVE: To evaluate the efficiency of dasatinib as the second- or third-line tyrosine kinase inhibitor (TKI) in imatinib-resistant patients with chronic myeloid leukemia (CML) based on BCR-ABL mutation detection. METHODS: 122 CML patients received dasatinib treatment, including 83 with imatinib-resistance and 39 with both imatinib- and nilotinib-resistance, 55 in the chronic-phase (CP), 21 in the accelerated-phase (AP) and 46 in the blast-phase (BP). Those harboring dasatinib highly-resistant mutations (T315I/A, F317L/V/C and V299L) were excluded based on BCR-ABL kinase domain mutation screening by Sanger sequencing at baseline. Hematologic, cytogenetic and molecular responses were evaluated regularly, and rates of progression-free-survival (PFS) and overall survival (OS) were analyzed. BCR-ABL mutation detection was performed once the patients failed on dasatinib. RESULTS: In the CP patients, the rates of complete hematological response (CHR), complete cytogenetic response (CCyR), major molecular response (MMR) and molecular response 4.5 (MR4.5) were 92.7%, 53.7%, 29.6% and 14.8%, respectively. 4-year PFS and OS rates were 84.4% and 89.5%, respectively. In the AP patients, HR and CCyR rates were 81.0% and 35.0%; and 3-year PFS and OS rates were 56.1% and 59.3%, respectively. In the BP patients, HR and CCyR rates were 63.0% and 21.4%; and 1-year PFS and OS rates were 43.6% and 61.8%, respectively. Outcomes were similar when dasatinib was used as the second-line TKI or the third-line TKI. Of the 75 patients who were resistant to dasatinib, 37 (48.7%) developed new mutation(s), and T315I (59.5%) was the most common mutation type. The patients who already harbored mutation(s) before dasatinib therapy achieved similar responses and outcomes to those with no mutation at baseline. However, they had higher likelihood of developing additional mutations associated with resistance to dasatinib (65.7% vs 34.1%, P=0.006). CONCLUSION: Dasatinib was proved to be effective in the treatment of imatinib- or/and nilotinib-resistant CML patients, especially in both CP and AP cohorts. The significance of BCR-ABL mutation screening and monitoring should be highlighted before and during dasatinib therapy.