Massachusetts General Hospital Cancer Center, Medical Oncology and Department of Biostatistics, Dana-Farber Cancer Institute, Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Clin Cancer Res. 2011 May 1;17(9):2977-86. doi: 10.1158/1078-0432.CCR-10-2879. Epub 2011 Mar 14.
Chronic lymphocytic leukemia (CLL) cells treated with dasatinib in vitro undergo apoptosis via inhibition of Lyn kinase. Thus, in this study we tested the activity of dasatinib in patients with relapsed CLL.
Patients were eligible for this phase II trial if they had documented CLL/SLL and had failed at least 1 prior therapy with a fludarabine-containing regimen and if they required therapy according to NCI-WG criteria. The starting dose of dasatinib was 140 mg daily.
Fifteen patients were enrolled, with a median age of 59 and a median of 3 prior regimens. All patients had received fludarabine, and 5 were fludarabine-refractory. Eleven of the 15 (73%) had high risk del(11q) or del(17p) cytogenetics. The primary toxicity was myelosuppression, with grade 3 or 4 neutropenia and thrombocytopenia in 10 and 6 patients, respectively. Partial responses by NCI-WG criteria were achieved in 3 of the 15 patients (20%; 90% CI: 6-44). Among the remaining 12 patients, 5 had nodal responses by physical exam, and 1 patient had a nodal and lymphocyte response but with severe myelosuppression. Pharmacodynamic studies indicated apoptosis in peripheral blood CLL cells within 3 to 6 hours after dasatinib administration, associated with downregulation of Syk (spleen tyrosine kinase) mRNA.
Dasatinib as a single agent has activity in relapsed and refractory CLL.
体外培养的慢性淋巴细胞白血病（CLL）细胞经达沙替尼治疗后通过抑制 Lyn 激酶发生细胞凋亡。因此，在这项研究中，我们检测了达沙替尼在复发性 CLL 患者中的活性。
如果患者有 CLL/SLL 的记录且在含有氟达拉滨的方案中至少经历过一次治疗失败，并且根据 NCI-WG 标准需要治疗，则有资格参加这项 II 期试验。达沙替尼的起始剂量为 140mg/天。
共入组 15 例患者，中位年龄为 59 岁，中位既往治疗方案为 3 种。所有患者均接受过氟达拉滨治疗，5 例为氟达拉滨难治性。15 例患者中有 11 例（73%）具有高危 del(11q)或 del(17p)细胞遗传学异常。主要毒性为骨髓抑制，分别有 10 例和 6 例患者发生 3 级或 4 级中性粒细胞减少症和血小板减少症。根据 NCI-WG 标准，15 例患者中有 3 例（20%；90%CI：6-44）获得部分缓解。在其余 12 例患者中，5 例患者经体格检查有淋巴结反应，1 例患者有淋巴结和淋巴细胞反应，但伴有严重骨髓抑制。药效学研究表明，达沙替尼给药后 3 至 6 小时外周血 CLL 细胞发生凋亡，与 Syk（脾酪氨酸激酶）mRNA 下调相关。
达沙替尼作为单一药物在复发性和难治性 CLL 中具有活性。
