用于非霍奇金淋巴瘤分次放射免疫治疗的67Cu-2IT-BAT-LYM-1的最大耐受剂量：一项初步研究。

Maximum tolerated dose of 67Cu-2IT-BAT-LYM-1 for fractionated radioimmunotherapy of non-Hodgkin's lymphoma: a pilot study.

作者信息

Denardo G L, Denardo S J, Kukis D L, O'Donnell R T, Shen S, Goldstein D S, Kroger L A, Salako Q, Denardo D A, Mirick G R, Mausner L F, Srivastava S C, Meares C F

机构信息

Department of Internal Medicine, University of California Davis Medical Center, Sacramento 95816, USA.

出版信息

Anticancer Res. 1998 Jul-Aug;18(4B):2779-88.

DOI:

PMID:9713461

Abstract

PURPOSE

Lym-1, a monoclonal antibody (MoAb) that preferentially targets malignant lymphocytes, has induced therapeutic responses in patients with non-Hodgkin's lymphoma (NHL) when labeled with iodine-131 (131I). Radiometal labeled antibodies provide a higher tumor radiation dose than the corresponding 131I labeled antibodies. Based on the strategy of fractionating the total radiation dose, this study was designed to define the maximum tolerated dose (MTD) of the first 2, of a maximum of 4, doses of 67Cu-2IT-BAT-Lym-1 given 4 weeks apart. Additionally, toxicity, radiation dosimetry and efficacy were assessed.

MATERIALS AND METHODS

Patients had Ann Arbor stage IVB NHL, resistant to standard therapy, including multiple chemotherapy regimens. Each dose of 67Cu-2IT-BAT-Lym-1 was given after a preload of unmodified Lym-1. A 10 mCi imaging dose of 67Cu-2IT-BAT-Lym-1 was given in order to assess pharmacokinetics and radiation dosimetry prior to therapy. Based on the MTD for 131I-Lym-1 and comparative dosimetry for 131I-Lym-1 and 67Cu-2IT-BAT-Lym-1, the trial was initiated at 60 millicuries per square meter of body surface area (mCi/m2) in cohorts of 3 patients.

RESULTS

A single cohort of patients proved sufficient to define the MTD as 60 mCi/m2 for each of the first 2 doses of 67Cu-2IT-BAT-Lym-1. The dose-limiting toxicities were grade 3-4 thrombocytopenia and neutropenia. Neutropenic sepsis and bleeding did not occur. Mean radiation dose contributed to the bone marrow by 67Cu in the body and blood was 0.2 (range, 0.2 to 0.3) rads/mCi. Copper-67 incorporated into ceruloplasmin contributed 25% of the dose to marrow from blood. Non-hematologic toxicities did not exceed grade 2. The three patients had substantial tumor regression even after imaging doses of 67Cu-2IT-BAT-Lym-1. After therapy, one response was complete with a duration of 12 months. Radiation doses to tumors in this patient varied from 7.0-21.9 rads/mCi or 5420-7000 total rads from the course of therapy.

CONCLUSION

67Cu-2IT-BAT-Lym-1 provided good imaging, favorable radiation dosimetry and a remarkably high therapeutic index (ratio of tumor to marrow radiation doses). The non-myeloablative MTD for each of 2 doses was 60 mCi/m2.

摘要

目的

Lym-1是一种单克隆抗体（MoAb），优先靶向恶性淋巴细胞，用碘-131（131I）标记后可在非霍奇金淋巴瘤（NHL）患者中诱导治疗反应。放射性金属标记的抗体比相应的131I标记的抗体提供更高的肿瘤辐射剂量。基于将总辐射剂量分割的策略，本研究旨在确定67Cu-2IT-BAT-Lym-1最大4剂中前2剂的最大耐受剂量（MTD），每剂间隔4周给药。此外，还评估了毒性、辐射剂量学和疗效。

材料与方法

患者患有Ann Arbor IVB期NHL，对包括多种化疗方案在内的标准治疗耐药。每剂67Cu-2IT-BAT-Lym-1均在未修饰的Lym-1预负荷后给药。给予10 mCi的67Cu-2IT-BAT-Lym-1显像剂量，以在治疗前评估药代动力学和辐射剂量学。基于131I-Lym-1的MTD以及131I-Lym-1和67Cu-2IT-BAT-Lym-1的比较剂量学，试验以每平方米体表面积60毫居里（mCi/m2）开始，每组3例患者。

结果

一组患者足以确定67Cu-2IT-BAT-Lym-1前2剂每剂的MTD为60 mCi/m2。剂量限制性毒性为3-4级血小板减少和中性粒细胞减少。未发生中性粒细胞减少性败血症和出血。体内67Cu和血液对骨髓的平均辐射剂量为0.2（范围0.2至0.3）拉德/毫居里。结合到铜蓝蛋白中的铜-67对血液中骨髓剂量的贡献为25%。非血液学毒性未超过2级。这3例患者即使在接受67Cu-2IT-BAT-Lym-1显像剂量后也有显著的肿瘤消退。治疗后，1例患者完全缓解，持续时间为12个月。该患者肿瘤的辐射剂量在7.0-21.9拉德/毫居里之间，或整个治疗过程中总辐射剂量为5420-7000拉德。