Jiang Qian, Qin Yazhen, Lai Yueyun, Jiang Hao, Shi Hongxia
Peking University People's Hospital, Peking University Institute of Hematology, Beijing 100044, China.
Zhonghua Xue Ye Xue Za Zhi. 2016 Jan;37(1):7-13. doi: 10.3760/cma.j.issn.0253-2727.2016.01.002.
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.
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.
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).
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.
基于BCR-ABL突变检测，评估达沙替尼作为慢性髓性白血病（CML）伊马替尼耐药患者二线或三线酪氨酸激酶抑制剂（TKI）的疗效。
122例CML患者接受达沙替尼治疗，其中83例伊马替尼耐药，39例伊马替尼和尼罗替尼均耐药，慢性期（CP）55例，加速期（AP）21例，急变期（BP）46例。在基线时通过Sanger测序对BCR-ABL激酶结构域进行突变筛查，排除携带达沙替尼高度耐药突变（T315I/A、F317L/V/C和V299L）的患者。定期评估血液学、细胞遗传学和分子反应，并分析无进展生存期（PFS）和总生存期（OS）率。患者达沙替尼治疗失败后进行BCR-ABL突变检测。
CP患者中，完全血液学缓解（CHR）率、完全细胞遗传学缓解（CCyR）率、主要分子反应（MMR）率和分子反应4.5（MR4.5）率分别为92.7%、53.7%、29.6%和14.8%。4年PFS率和OS率分别为84.4%和89.5%。AP患者中，HR和CCyR率分别为81.0%和35.0%；3年PFS率和OS率分别为56.1%和59.3%。BP患者中，HR和CCyR率分别为63.0%和21.4%；1年PFS率和OS率分别为43.6%和61.8%。达沙替尼作为二线TKI或三线TKI时结果相似。75例对达沙替尼耐药的患者中，37例（48.7%）出现新突变，T315I（59.5%）是最常见的突变类型。达沙替尼治疗前已携带突变的患者与基线无突变患者的反应和结局相似。然而，他们发生与达沙替尼耐药相关的额外突变的可能性更高（65.7%对34.1%，P=0.006）。
达沙替尼被证明对伊马替尼或/和尼罗替尼耐药的CML患者有效，尤其是在CP和AP队列中。在达沙替尼治疗前和治疗期间应强调BCR-ABL突变筛查和监测的重要性。
