Faderl Stefan, Rai Kanti, Gribben John, Byrd John C, Flinn Ian W, O'Brien Susan, Sheng Shihong, Esseltine Dixie-Lee, Keating Michael J
Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Cancer. 2006 Sep 1;107(5):916-24. doi: 10.1002/cncr.22097.
Therapeutic options are limited and the prognosis is poor for patients with fludarabine-refractory B-cell chronic lymphocytic leukemia (CLL). Bortezomib induces apoptosis in vitro in CLL cells, both alone and in combination, including in cells resistant to fludarabine or other agents. The aim of the current randomized, open-label, Phase II study was to investigate the clinical activity of bortezomib in patients with fludarabine-refractory B-cell CLL. Twenty-two patients with histologically confirmed B-cell CLL were treated with bortezomib at doses of 1.0 mg/m2, 1.3 mg/m2, or 1.5 mg/m2 on Days 1, 4, 8, and 11 of a 21-day treatment cycle for a maximum of 9 cycles. None of 19 patients evaluable for response achieved complete remission or partial response; however, signs of biologic activity based on disease site responses (e.g., reduction in lymphocytosis, splenomegaly, and lymphadenopathy) were observed. In the 1.5 mg/m2 dose group, a higher proportion of patients had stable disease, and a lower proportion had progressive disease compared with the 2 lower-dose groups. Eleven patients, all in the 2 higher dose groups, experienced Grade 3/4 adverse events (AEs) (according to National Cancer Institute Common Toxicity Criteria [version 2.0]); 2 patients experienced Grade 4 neutropenia. Grade 3 hematologic AEs included anemia, neutropenia, thrombocytopenia, and hemolytic anemia; Grade 3 nervous system AEs included aphasia; peripheral neuropathy, not otherwise specified; and peripheral sensory neuropathy. Although no objective responses were achieved in patients with fludarabine-refractory B-cell CLL, single-agent bortezomib demonstrated biologic activity. In view of the evidence for its activity, further exploration of bortezomib in combination with other agents is warranted.
对于氟达拉滨难治性B细胞慢性淋巴细胞白血病（CLL）患者，治疗选择有限且预后较差。硼替佐米在体外可诱导CLL细胞凋亡，无论是单独使用还是联合使用，包括对氟达拉滨或其他药物耐药的细胞。当前这项随机、开放标签的II期研究旨在调查硼替佐米对氟达拉滨难治性B细胞CLL患者的临床活性。22例经组织学确诊为B细胞CLL的患者，在21天治疗周期的第1、4、8和11天接受硼替佐米治疗，剂量分别为1.0mg/m²、1.3mg/m²或1.5mg/m²，最多治疗9个周期。19例可评估疗效的患者均未达到完全缓解或部分缓解；然而，基于疾病部位反应（如淋巴细胞增多、脾肿大和淋巴结病减轻）观察到了生物活性迹象。在1.5mg/m²剂量组中，与两个低剂量组相比，病情稳定的患者比例更高，病情进展的患者比例更低。11例患者（均在两个高剂量组）发生了3/4级不良事件（根据美国国立癌症研究所通用毒性标准[第2.0版]）；2例患者发生4级中性粒细胞减少。3级血液学不良事件包括贫血、中性粒细胞减少、血小板减少和溶血性贫血；3级神经系统不良事件包括失语症；未另行说明的周围神经病变；以及周围感觉神经病变。尽管氟达拉滨难治性B细胞CLL患者未取得客观缓解，但单药硼替佐米显示出生物活性。鉴于其活性证据，有必要进一步探索硼替佐米与其他药物联合使用的情况。
