Subcutaneous Alemtuzumab in Fludarabine-Refractory Chronic Lymphocytic Leukemia: Clinical Results and Prognostic Marker Analyses From the CLL2H Study of the German Chronic Lymphocytic Leukemia Study Group
Subcutaneous Alemtuzumab in Fludarabine-Refractory Chronic Lymphocytic Leukemia: Clinical Results and Prognostic Marker Analyses From the CLL2H Study of the German Chronic Lymphocytic Leukemia Study Group
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DOI：
10.1200/jco.2008.21.1128
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发表时间：
2009-08-20
影响因子：
45.3
通讯作者：
Doehner, Hartmut
中科院分区：
文献类型：
--
作者：
Stilgenbauer, Stephan;Zenz, Thorsten;Doehner, Hartmut
目的II 期 CLL2H 试验评估皮下注射阿仑单抗治疗氟达拉滨难治性慢性淋巴细胞白血病 (CLL) 患者的安全性和有效性。评估了临床和生物标志物对结果的影响。患者和方法纳入了 109 名患者，其中 103 人接受了至少一剂阿仑单抗。剂量递增后，阿仑单抗以 30 mg 皮下注射，每周 3 次，持续长达 12 周。治疗期间每 4 周评估一次疗效，此后每季度评估一次。结果 总体缓解率为 34%（完全缓解，4%；部分缓解，30%）。中位无进展生存期为 7.7 个月，中位总生存期 (OS) 为 19.1 个月。 3 至 4 级中性粒细胞减少症、血小板减少症和贫血分别发生在 56%、57% 和 49% 的患者中。 3 至 4 级非巨细胞病毒和巨细胞病毒感染分别发生在 29% 和 8% 的患者中。注射部位皮肤反应一般较轻微。在由遗传参数定义的亚组中（特别是 17p 缺失、11q 缺失、突变 TP53 和未突变 VH），疗效没有显着差异，但在 β 2-微球蛋白 (β 2-MG) 和胸苷激酶 (TK) 升高的患者中疗效较差。在临床和生物学变量的多变量分析中，年龄、体力状态、β2-MG 和 TK 是 OS 的独立预后因素。 结论 皮下注射阿仑单抗与静脉注射阿仑单抗治疗氟达拉滨难治性 CLL 一样有效且安全。皮下给药应该是首选的给药途径，因为它有效、方便、改善了不良反应并节省了成本。与基于化疗的治疗相比，阿仑单抗治疗克服了 VH 突变状态、TP53 突变和基因组畸变的不良预后影响。
PurposeThe phase II CLL2H trial evaluated safety and efficacy of subcutaneous alemtuzumab in patients with fludarabine-refractory chronic lymphocytic leukemia (CLL). Clinical and biologic markers were evaluated for their impacts on outcome.Patients and MethodsOne hundred nine patients were enrolled, and 103 received at least one dose of alemtuzumab. After dose escalation, alemtuzumab was administered subcutaneously at 30 mg three times weekly for up to 12 weeks. Response was assessed every 4 weeks during treatment and quarterly thereafter.ResultsThe overall response rate was 34% (complete response, 4%; partial response, 30%). The median progression-free survival was 7.7 months, and the median overall survival ( OS) was 19.1 months. Grades 3 to 4 neutropenia, thrombocytopenia, and anemia occurred in 56%, 57%, and 49% of patients, respectively. Grades 3 to 4 noncytomegalovirus and cytomegalovirus infections occurred in 29% and 8% of patients, respectively. Injection-site skin reactions were generally mild. Efficacy did not vary significantly in subgroups defined by genetic parameters ( in particular, in 17p deletion, 11q deletion, mutated TP53, and unmutated VH), but efficacy was inferior in patients with increased beta 2-microglobulin (beta 2-MG) and thymidine kinase (TK). In multivariate analysis of clinical and biologic variables, age, performance status, beta 2-MG, and TK were independent prognostic factors for OS.ConclusionSubcutaneous alemtuzumab appears as effective and safe as intravenous alemtuzumab in fludarabine-refractory CLL. Subcutaneous administration should be the preferred delivery route because of its efficacy, convenience, improved adverse effect profile, and cost savings. In contrast to chemotherapy-based therapy, alemtuzumab treatment overcomes the adverse prognostic impact of VH mutation status, TP53 mutation, and genomic aberrations.