Sequential cytarabine and alpha-particle immunotherapy with bismuth-213-lintuzumab (HuM195) for acute myeloid leukemia.
Sequential cytarabine and alpha-particle immunotherapy with bismuth-213-lintuzumab (HuM195) for acute myeloid leukemia.
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DOI：
10.1158/1078-0432.ccr-10-0382
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发表时间：
2010-11-01
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影响因子：
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通讯作者：
Jurcic JG
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作者：
Rosenblat TL;McDevitt MR;Mulford DA;Pandit-Taskar N;Divgi CR;Panageas KS;Heaney ML;Chanel S;Morgenstern A;Sgouros G;Larson SM;Scheinberg DA;Jurcic JG
Lintuzumab （HuM195）是一种人源化抗cd33抗体，靶向髓性白血病细胞，对急性髓性白血病（AML）具有适度的单药活性。为了提高抗体的效力而不产生β-发射体相关的非特异性细胞毒性，将α粒子发射放射性核素铋-213 （213Bi）偶联到林妥珠单抗上。该I/II期试验旨在确定第一个靶向α-发射器213Bi-lintuzumab在部分细胞减少化疗后的最大耐受剂量（MTD）和抗白血病效果。31例新诊断（n = 13）或复发/难治性（n = 18） AML患者（中位年龄67岁，范围37-80岁）接受阿糖胞苷200mg /m2/天治疗5天，随后接受213Bi-lintuzumab 18.5-46.25 MBq/kg治疗。213Bi-lintuzumab的MTD为37 MB/kg；骨髓抑制持续35天是剂量限制。髓外毒性主要局限于≤2级的事件，包括输注相关反应。5例（16%）患者出现短暂的3/4级肝功能异常。接受MTD治疗的21例患者中有2例（10%）发生治疗相关死亡。在所有剂量水平下，骨髓原细胞均显著减少。中位反应持续时间为6个月（范围2-12）。生物分布和药代动力学研究表明，在用阿糖胞苷部分减少细胞后，213Bi-lintuzumab可使CD33位点饱和。序贯给药阿糖胞苷和213Bi-lintuzumab是可耐受的，并可在AML患者中产生缓解。
Lintuzumab (HuM195), a humanized anti-CD33 antibody, targets myeloid leukemia cells and has modest single-agent activity against acute myeloid leukemia (AML). To increase the antibody’s potency without the nonspecific cytotoxicity associated with β-emitters, the α particle-emitting radionuclide bismuth-213 (213Bi) was conjugated to lintuzumab. This phase I/II trial was conducted to determine the maximum tolerated dose (MTD) and antileukemic effects of 213Bi-lintuzumab, the first targeted α-emitter, after partially cytoreductive chemotherapy. Thirty-one patients with newly diagnosed (n = 13) or relapsed/refractory (n = 18) AML (median age, 67 years; range, 37–80) were treated with cytarabine 200 mg/m2/day for 5 days followed by 213Bi-lintuzumab 18.5–46.25 MBq/kg. The MTD of 213Bi-lintuzumab was 37 MB/kg; myelosuppression lasting > 35 days was dose-limiting. Extramedullary toxicities were primarily limited to ≤ grade 2 events, including infusion-related reactions. Transient grade 3/4 liver function abnormalities were seen in 5 patients (16%). Treatment-related deaths occurred in 2 of 21 patients (10%) who received the MTD. Significant reductions in marrow blasts were seen at all dose levels. The median response duration was 6 months (range, 2–12). Biodistribution and pharmacokinetic studies suggested that saturation of available CD33 sites by 213Bi-lintuzumab was achieved after partial cytoreduction with cytarabine. Sequential administration of cytarabine and 213Bi-lintuzumab is tolerable and can produce remissions in patients with AML.