Phase II study of dasatinib in relapsed or refractory chronic lymphocytic leukemia.
Phase II study of dasatinib in relapsed or refractory chronic lymphocytic leukemia.
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DOI：
10.1158/1078-0432.ccr-10-2879
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发表时间：
2011-05-01
期刊：
影响因子：
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通讯作者：
Brown JR
中科院分区：
文献类型：
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作者：
Amrein PC;Attar EC;Takvorian T;Hochberg EP;Ballen KK;Leahy KM;Fisher DC;Lacasce AS;Jacobsen ED;Armand P;Hasserjian RP;Werner L;Neuberg D;Brown JR
在体外用达沙替尼处理的CLL细胞通过抑制林恩激酶而发生凋亡。因此，在这项研究中，我们测试了达沙替尼在复发性CLL患者中的活性。如果患者记录了CLL/SLL，并且既往至少一次含氟达拉滨方案治疗失败，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每日140 mg。入组了15例患者，中位年龄为59岁，中位既往治疗方案为3种。所有患者均接受了氟达拉滨治疗，5例为氟达拉滨难治性。15例中有11例（73%）具有高风险del（11 q）或del（17 p）细胞遗传学。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级中性粒细胞减少和血小板减少。根据NCI-WG标准，15例患者中有3例达到部分缓解（20%; 90% CI 6-44）。在其余12例患者中，5例通过体格检查发现淋巴结反应，1例患者出现淋巴结和淋巴细胞反应，但伴有重度骨髓抑制。药效学研究表明，达沙替尼给药后3-6小时内，外周血CLL细胞发生凋亡，与syk 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。
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 2 trial if they had documented CLL/SLL and had failed at least one 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 3–6 hours after dasatinib administration, associated with downregulation of syk mRNA. Dasatinib as a single agent has activity in relapsed and refractory CLL.