James P. Wilmot Cancer Center, University of Rochester, NY 14642, USA.
Blood. 2010 Apr 1;115(13):2578-85. doi: 10.1182/blood-2009-08-236471. Epub 2009 Nov 17.
Certain malignant B cells rely on B-cell receptor (BCR)-mediated survival signals. Spleen tyrosine kinase (Syk) initiates and amplifies the BCR signal. In in vivo analyses of B-cell lymphoma cell lines and primary tumors, Syk inhibition induces apoptosis. These data prompted a phase 1/2 clinical trial of fostamatinib disodium, the first clinically available oral Syk inhibitor, in patients with recurrent B-cell non-Hodgkin lymphoma (B-NHL). Dose-limiting toxicity in the phase 1 portion was neutropenia, diarrhea, and thrombocytopenia, and 200 mg twice daily was chosen for phase 2 testing. Sixty-eight patients with recurrent B-NHL were then enrolled in 3 cohorts: (1) diffuse large B-cell lymphoma (DLBCL), (2) follicular lymphoma (FL), and (3) other NHL, including mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), mucosa-associated lymphoid tissue lymphoma, lymphoplasmacytic lymphomas, and small lymphocytic leukemia/chronic lymphocytic leukemia (SLL/CLL). Common toxicities included diarrhea, fatigue, cytopenias, hypertension, and nausea. Objective response rates were 22% (5 of 23) for DLBCL, 10% (2 of 21) for FL, 55% (6 of 11) for SLL/CLL, and 11% (1/9) for MCL. Median progression-free survival was 4.2 months. Disrupting BCR-induced signaling by inhibiting Syk represents a novel and active therapeutic approach for NHL and SLL/CLL. This trial was registered at www.clinicaltrials.gov as #NCT00446095.
某些恶性 B 细胞依赖 B 细胞受体 (BCR) 介导的存活信号。脾酪氨酸激酶 (Syk) 启动并放大 BCR 信号。在 B 细胞淋巴瘤细胞系和原发性肿瘤的体内分析中，Syk 抑制诱导细胞凋亡。这些数据促使进行了 fostamatinib disodium 的 1/2 期临床试验，该药物是首个临床可用的口服 Syk 抑制剂，用于复发性 B 细胞非霍奇金淋巴瘤 (B-NHL) 患者。1 期部分的剂量限制毒性为中性粒细胞减少症、腹泻和血小板减少症，选择每天两次 200mg 进行 2 期测试。随后，68 名复发性 B-NHL 患者被纳入 3 个队列：(1)弥漫性大 B 细胞淋巴瘤 (DLBCL)，(2)滤泡性淋巴瘤 (FL)，和 (3)其他 NHL，包括套细胞淋巴瘤 (MCL)、边缘区淋巴瘤 (MZL)、黏膜相关淋巴组织淋巴瘤、淋巴浆细胞性淋巴瘤和小淋巴细胞白血病/慢性淋巴细胞白血病 (SLL/CLL)。常见的毒性包括腹泻、疲劳、血细胞减少、高血压和恶心。DLBCL 的客观缓解率为 22%（23 例中的 5 例），FL 为 10%（21 例中的 2 例），SLL/CLL 为 55%（11 例中的 6 例），MCL 为 11%（9 例中的 1 例）。中位无进展生存期为 4.2 个月。通过抑制 Syk 阻断 BCR 诱导的信号转导代表了 NHL 和 SLL/CLL 的一种新的、有效的治疗方法。该试验在 www.clinicaltrials.gov 上注册，编号为 #NCT00446095。
