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Results from an international phase 2 study of the anti-CD22 immunotoxin moxetumomab pasudotox in relapsed or refractory childhood B-lineage acute lymphoblastic leukemia.

Anti-CD22 免疫毒素 moxetumoab pasudotox 治疗复发或难治性儿童 B 系急性淋巴细胞白血病的国际 2 期研究结果。

  • 影响因子:2.28
  • DOI:10.1002/pbc.28112
  • 作者列表:"Shah NN","Bhojwani D","August K","Baruchel A","Bertrand Y","Boklan J","Dalla-Pozza L","Dennis R","Hijiya N","Locatelli F","Martin PL","Mechinaud F","Moppett J","Rheingold SR","Schmitt C","Trippett TM","Liang M","Balic K","Li X","Vainshtein I","Yao NS","Pastan I","Wayne AS
  • 发表时间:2020-01-15
Abstract

BACKGROUND:In a multicenter phase 1 study of children with relapsed/refractory acute lymphoblastic leukemia (ALL), moxetumomab pasudotox, an anti-CD22 immunotoxin, demonstrated a manageable safety profile and preliminary evidence of clinical activity. A phase 2 study further evaluated efficacy. PROCEDURE:This international, multicenter, phase 2 study enrolled children with relapsed/refractory B-cell precursor ALL who received moxetumomab pasudotox 40 µg/kg intravenously every other day, for six doses per 21-day cycle. The primary objective was to evaluate the complete response (CR) rate. Secondary objectives included safety, pharmacokinetics, and immunogenicity evaluations. RESULTS:Thirty-two patients (median age, 10 years) were enrolled at 16 sites; 30 received study drug and were evaluable for safety; 28 were evaluable for response. The objective response rate was 28.6%, with three patients (10.7%) achieving morphologic CR, and five patients (17.9%) achieving partial response. Disease progression occurred in 11 patients (39.3%). Ten patients (33.3%) experienced at least one treatment-related serious adverse event, including capillary leak syndrome (CLS; n = 6), hemolytic uremic syndrome (HUS; n = 4), and treatment-related death (n = 1) from pulmonary edema. No differences were observed in inflammatory markers in patients who did or did not develop CLS or HUS. CONCLUSIONS:Despite a signal for clinical activity, this phase 2 study was terminated at interim analysis for a CR rate that did not reach the stage 1 target. Preclinical data suggest enhanced efficacy of moxetumomab pasudotox via continuous infusion or in combination regimens; thus, further studies designed to optimize the efficacy and safety of moxetumomab pasudotox in pediatric ALL may be warranted.

摘要

背景: 在一项针对儿童复发/难治性急性淋巴细胞白血病 (ALL) 的多中心 1 期研究中,moxetumomab pasudotox,一种 anti-CD22 免疫毒素,显示了可管理的安全性特征和临床活性的初步证据。2 期研究进一步评价疗效。 程序: 这项国际、多中心、 2 期研究招募了接受 moxetumomab pasudotox 40 µ g/kg 每隔一天静脉注射的复发/难治性 B 细胞前体 ALL 儿童, 对于每 21 天周期的六个剂量。主要目的是评价完全缓解率 (CR)。次要目标包括安全性、药代动力学和免疫原性评价。 结果: 32 例患者 (中位年龄,10 岁) 在 16 个地点入组; 30 例接受研究药物,可评价安全性; 28 例可评价反应。客观缓解率为 28.6%,3 例 (10.7%) 达到形态学 CR,5 例 (17.9%) 达到部分缓解。疾病进展 11 例 (39.3%)。10 例患者 (33.3%) 经历了至少一次治疗相关的严重不良事件,包括毛细血管渗漏综合征 (CLS; n = 6),溶血性尿毒症综合征 (HUS; n = 4), 和治疗相关的肺水肿死亡 (n = 1)。在发生或未发生 CLS 或 HUS 的患者中,未观察到炎症标志物的差异。 结论: 尽管有临床活动的信号,但由于未达到 1 期目标的 CR 率,本 2 期研究在中期分析时终止。临床前数据表明 moxetumoab pasudotox 通过持续输注或联合方案增强疗效; 因此,可能需要进一步研究旨在优化 moxetumoab pasudotox 在儿科 ALL 中的疗效和安全性。

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