Division of Hematology, Ohio State University, Columbus, Ohio.
Cancer. 2011 Jun 1;117(11):2442-51. doi: 10.1002/cncr.25792. Epub 2010 Dec 14.
In vitro studies in mantle cell lymphoma (MCL) cell lines and patient-derived cells have demonstrated synergistic apoptosis with combined rituximab and bortezomib (R-bortezomib) compared with single-agent bortezomib. Therefore, the authors of this report evaluated R-bortezomib in a preclinical model and in a phase 2 clinical trial.
A Hu-MCL-severe combined immunodeficiency (SCID) model engrafted with the Jeko cell line was treated with R-bortezomib, bortezomib, or rituximab. Twenty-five patients with relapsed follicular lymphoma (n = 11) and MCL (n = 14) received 375 mg/m(2) rituximab on Days 1 and 8 and 1.3 to 1.5 mg/m(2) bortezomib on Days 1, 4, 8, and 11 every 21 days for a median of 3 cycles (range, 1-5 cycles).
R-bortezomib resulted in a statistically significant improvement in overall survival in Hu-MCL-SCID mice. In the clinical trial, the overall response rate was 40% in all 25 patients, 55% in patients with follicular lymphoma, and 29% in patients with MCL. The estimated 2-year progression-free survival (PFS) rate was 24% (95% confidence interval [CI], 10%-53%) in all patients and 60% (95% CI, 20%-85%) in responding patients. Thirteen patients (52%) developed grade 3 neurotoxicity, which consisted of constipation/ileus, sensory or motor neuropathy, or orthostatic hypotension. Patients who were heterozygous for the CD32a (Fcγ receptor IIa) 131 histidine (H) to arginine (R) polymorphism had a significantly decreased PFS (P = .009) after R-bortezomib compared with HH and RR homozygotes.
R-bortezomib had significant activity in patients with relapsed or refractory follicular lymphoma and MCL, although an unexpectedly high incidence of grade 3 neurologic toxicity was a potential limiting factor with this combination.
在套细胞淋巴瘤（MCL）细胞系和患者来源的细胞中的体外研究表明，与单药硼替佐米相比，联合利妥昔单抗和硼替佐米（R-硼替佐米）可产生协同凋亡作用。因此，本研究报告的作者在临床前模型和 2 期临床试验中评估了 R-硼替佐米。
用人源化 MCL-严重联合免疫缺陷（SCID）模型植入 Jeko 细胞系，并用 R-硼替佐米、硼替佐米或利妥昔单抗治疗。25 例复发滤泡性淋巴瘤（n=11）和 MCL（n=14）患者接受 375mg/m²利妥昔单抗，于第 1 天和第 8 天，以及 1.3-1.5mg/m²硼替佐米，于第 1、4、8 和 11 天，每 21 天一次，中位数为 3 个周期（范围，1-5 个周期）。
R-硼替佐米可使 Hu-MCL-SCID 小鼠的总生存期得到统计学显著改善。在临床试验中，25 例患者的总体缓解率为 40%，滤泡性淋巴瘤患者为 55%，MCL 患者为 29%。所有患者的估计 2 年无进展生存率（PFS）为 24%（95%置信区间[CI]，10%-53%），应答患者为 60%（95%CI，20%-85%）。13 例患者（52%）发生 3 级神经毒性，包括便秘/肠梗阻、感觉或运动神经病或直立性低血压。与 HH 和 RR 纯合子相比，CD32a（Fcγ 受体 IIa）131 组氨酸（H）到精氨酸（R）多态性杂合子的患者在接受 R-硼替佐米后 PFS 明显降低（P=0.009）。
R-硼替佐米在复发或难治性滤泡性淋巴瘤和 MCL 患者中具有显著活性，尽管这种联合用药的 3 级神经毒性发生率高，这可能是一个限制因素。
