Loncastuximab tesirine, an anti-CD19 antibody-drug conjugate, in relapsed/refractory B-cell acute lymphoblastic leukemia
Loncastuximab tesirine, an anti-CD19 antibody-drug conjugate, in relapsed/refractory B-cell acute lymphoblastic leukemia
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DOI：
10.1182/bloodadvances.2019000767
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发表时间：
2020-02-11
期刊：
影响因子：
7.5
通讯作者：
Wieduwilt, Matthew J.
中科院分区：
文献类型：
--
作者：
Jain, Nitin;Stock, Wendy;Wieduwilt, Matthew J.
复发性或难治性（R/R）B细胞急性淋巴细胞白血病（B-ALL）仍然是一个治疗挑战。Loncastuximab tesirine是一种针对CD 19的抗体-药物偶联物，CD 19是一种在许多B细胞恶性肿瘤中表达的抗原。这项开放标签、单组、剂量递增、剂量扩展研究评估了loncastuximab tesirine在成人R/R B-ALL患者中的安全性、耐受性、药代动力学（PK）、免疫原性和初步临床活性。共入组35例患者，中位年龄为55岁（范围：20-80岁），中位既往治疗为3种（范围：1-15）。所有患者均接受了至少1次15 - 150 μ g/kg/3周一次（Q3 W; n = 30）或50 μ g/kg/周IV输注（n = 5）。常见的治疗后出现的不良事件（TEAE）为恶心（42.9%）、发热性中性粒细胞减少（37.1%）和可逆性肝功能检查异常。85.7%的患者报告了≥ 3级TEAE，最常见的是发热性中性粒细胞减少症和其他血液学异常以及可逆性肝功能检查异常。无治疗相关死亡。4例患者（11.4%）发生2级输注相关反应，1例患者（150 mg/kg Q3 W）发生剂量限制性毒性高胆红素血症，在6天内消退，未采取进一步措施。未达到最大耐受剂量。3例患者达到完全缓解，30、120和150 mg/kg Q3 W组各1例。PK研究显示患者间存在显著差异，靶向介导的药物分布似乎有助于时间和剂量依赖性分布。未发生临床相关抗药抗体形成。试验在剂量递增阶段因药物累积缓慢而终止。
Relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) remains a therapeutic challenge. Loncastuximab tesirine is an antibody-drug conjugate against CD19, an antigen expressed in many B-cell malignancies. This open-label, single-arm, dose-escalation, dose-expansion study assessed the safety, tolerability, pharmacokinetics (PKs), immunogenicity, and preliminary clinical activity of loncastuximab tesirine in adults with R/R B-ALL. A total of 35 patients were enrolled, with a median age of 55 years (range, 20-80) and a median of 3 prior therapies (range, 1-15). All patients received at least 1 IV infusion of loncastuximab tesirine at 15 to 150 mu g/kg once every 3 weeks (Q3W; n = 30) or 50 mu g/kg IV weekly (n = 5). Common treatment-emergent adverse events (TEAEs) were nausea (42.9%), febrile neutropenia (37.1%), and reversible liver test abnormalities. Grade >= 3 TEAEs were reported in 85.7% patients, most commonly febrile neutropenia and other hematologic abnormalities and reversible liver test abnormalities. There were no treatment-related deaths. Four patients (11.4%) had grade 2 infusion-related reactions, and 1 patient (150 mg/kg Q3W) had a dose-limiting toxicity of hyperbilirubinemia that resolved within 6 days without further action. The maximum tolerated dose was not reached. Three patients achieved complete responses, 1 each at 30, 120, and 150 mg/kg Q3W. PK studies showed marked interpatient variability, with target-mediated drug disposition seeming to contribute to time- and dose-dependent disposition. No clinically relevant anti-drug-antibody formation occurred. The trial was terminated in the dose-escalation phase because of slow accrual.