Olsen E, Duvic M, Frankel A, Kim Y, Martin A, Vonderheid E, Jegasothy B, Wood G, Gordon M, Heald P, Oseroff A, Pinter-Brown L, Bowen G, Kuzel T, Fivenson D, Foss F, Glode M, Molina A, Knobler E, Stewart S, Cooper K, Stevens S, Craig F, Reuben J, Bacha P, Nichols J
Duke University Medical Center, Durham, NC 27710, USA.
J Clin Oncol. 2001 Jan 15;19(2):376-88. doi: 10.1200/JCO.2001.19.2.376.
The objective of this phase III study was to determine the efficacy, safety, and pharmacokinetics of denileukin diftitox (DAB389IL-2, Ontak [Ligand Pharmaceuticals Inc, San Diego, CA]) in patients with stage Ib to IVa cutaneous T-cell lymphoma (CTCL) who have previously received other therapeutic interventions.
Patients with biopsy-proven CTCL that expressed CD25 on > or = 20% of lymphocytes were assigned to one of two dose levels (9 or 18 microg/kg/d) of denileukin diftitox administered 5 consecutive days every 3 weeks for up to 8 cycles. Patients were monitored for toxicity and clinical efficacy, the latter assessed by changes in disease burden and quality of life measurements. Antibody levels of antidenileukin diftitox and anti-interleukin-2 and serum concentrations of denileukin diftitox were also measured.
Overall, 30% of the 71 patients with CTCL treated with denileukin diftitox had an objective response (20% partial response; 10% complete response). The response rate and duration of response based on the time of the first dose of study drug for all responders (median of 6.9 months with a range of 2.7 to more than 46.1 months) were not statistically different between the two doses. Adverse events consisted of flu-like symptoms (fever/chills, nausea/vomiting, and myalgias/arthralgias), acute infusion-related events (hypotension, dyspnea, chest pain, and back pain), and a vascular leak syndrome (hypotension, hypoalbuminemia, edema). In addition, 61% of the patients experienced transient elevations of hepatic transaminase levels with 17% grade 3 or 4. Hypoalbuminemia occurred in 79%, including 15% with grade 3 or 4 changes. Tolerability at 9 and 18 microg/kg/d was similar, and there was no evidence of cumulative toxicity.
Denileukin diftitox has been shown to be a useful and important agent in the treatment of patients whose CTCL is persistent or recurrent despite other therapeutic interventions.
本III期研究的目的是确定地尼白介素-妥昔单抗（DAB389IL-2，商品名Ontak [Ligand制药公司，加利福尼亚州圣地亚哥]）对先前接受过其他治疗干预的Ib至IVa期皮肤T细胞淋巴瘤（CTCL）患者的疗效、安全性和药代动力学。
经活检证实为CTCL且淋巴细胞上CD25表达≥20%的患者被分配至地尼白介素-妥昔单抗的两个剂量水平之一（9或18μg/kg/天），每3周连续给药5天，最多8个周期。对患者进行毒性和临床疗效监测，临床疗效通过疾病负担变化和生活质量测量进行评估。还测量了抗地尼白介素-妥昔单抗和抗白介素-2的抗体水平以及地尼白介素-妥昔单抗的血清浓度。
总体而言，71例接受地尼白介素-妥昔单抗治疗的CTCL患者中有30%出现客观缓解（20%部分缓解；10%完全缓解）。基于首次给予研究药物的时间，所有缓解者的缓解率和缓解持续时间（中位6.9个月，范围2.7至超过46.1个月）在两个剂量组之间无统计学差异。不良事件包括类流感症状（发热/寒战、恶心/呕吐、肌痛/关节痛）、急性输液相关事件（低血压、呼吸困难、胸痛和背痛）以及血管渗漏综合征（低血压、低白蛋白血症、水肿）。此外，61%的患者出现肝转氨酶水平短暂升高，其中17%为3级或4级。79%的患者出现低白蛋白血症，其中15%有3级或4级变化。9μg/kg/天和18μg/kg/天的耐受性相似，且无累积毒性证据。
对于尽管接受了其他治疗干预但CTCL仍持续或复发的患者，地尼白介素-妥昔单抗已被证明是一种有用且重要的治疗药物。
