DeNardo G L, DeNardo S J, Shen S, DeNardo D A, Mirick G R, Macey D J, Lamborn K R
University of California Davis Medical Center, Sacramento, USA.
J Nucl Med. 1999 Aug;40(8):1317-26.
Lym-1, a monoclonal antibody that preferentially targets malignant lymphocytes, has induced therapeutic responses in patients with non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL) when labeled with 131I. Responders had statistically significant prolongation of survival compared with nonresponders. The nonmyeloablative, maximum tolerated dose for each of two doses of 131I-Lym-1 was 3.7 GBq/m2 (total 7.4 GBq/m2 [100 mCi/m2, total 200 mCi/m2]) of body surface area. The purpose of this study was to determine the pharmacokinetics and radiation dosimetry for the initial 131I-Lym-1 therapy dose in patients with NHL and CLL and to compare tumor dosimetry with 131I-Lym-1 dosing and other patient parameters.
Fifty-one patients with stage 3 or 4 lymphoma were treated with 131I-Lym-1 (0.74-8.04 GBq [20-217 mCi]) in either a maximum tolerated dose (MTD) or low-dose (LD) trial. Total Lym-1 given to each patient was sufficient in all instances to exceed the threshold required for stable pharmacokinetics. Quantitative imaging and physical examination, including caliper and CT measurement of tumor size and analysis of blood, urine and feces, were performed for a period of 7 to 10 d after infusion to assess pharmacokinetics and radiation dosimetry. Clinical records were reviewed to obtain data required for comparative assessments.
The concentration (%ID/g) and biologic half-time of 131-Lym-1 in tumor were about twice those in normal tissues, although tumor half-time was similar to that of the thyroid. Pharmacokinetics were similar for patients in the MTD and LD trials, and for NHL and CLL patients in the LD trial, except that the latter group had less tumor concentration of 131I. Mean tumor radiation dose per unit of administered 131I was 1.0 Gy/GBq (3.7 rad/mCi) for patients with NHL whether in MTD or LD trials, about nine times greater than that for body or marrow. Tumor radiation dose was less and liver radiation dose was more in patients with CLL. Otherwise, radiation dosimetry was, on average, remarkably similar among groups of patients and among individual patients. Pharmacokinetics and dosimetry did not appear to be influenced by the amount of 131I or Lym-1 within the ranges administered. Tumor concentration of 131I and radiation dose per gigabecquerel were inversely related to tumor size but did not seem to be related to histologic grade or type, tumor burden or therapeutic response.
The therapeutic index of 131I-Lym-1 was favorable, although the index for patients with CLL was less than that for patients with NHL. Pharmacokinetics and radiation dosimetry were, on average, remarkably similar among patients and groups of patients in different trials.
Lym-1是一种优先靶向恶性淋巴细胞的单克隆抗体，用131I标记后已在非霍奇金淋巴瘤（NHL）和慢性淋巴细胞白血病（CLL）患者中诱导出治疗反应。与无反应者相比，有反应者的生存期在统计学上有显著延长。两剂131I-Lym-1的非清髓性最大耐受剂量为每平方米体表面积3.7 GBq（总计7.4 GBq/m2 [100 mCi/m2，总计200 mCi/m2]）。本研究的目的是确定NHL和CLL患者初始131I-Lym-1治疗剂量的药代动力学和辐射剂量学，并将肿瘤剂量学与131I-Lym-1给药及其他患者参数进行比较。
51例3期或4期淋巴瘤患者在最大耐受剂量（MTD）或低剂量（LD）试验中接受131I-Lym-1（0.74 - 8.04 GBq [20 - 217 mCi]）治疗。在所有情况下，给予每位患者的Lym-1总量足以超过稳定药代动力学所需的阈值。输注后7至10天进行定量成像和体格检查，包括用卡尺和CT测量肿瘤大小以及分析血液、尿液和粪便，以评估药代动力学和辐射剂量学。查阅临床记录以获取比较评估所需的数据。
131-Lym-1在肿瘤中的浓度（%ID/g）和生物半衰期约为正常组织中的两倍，尽管肿瘤半衰期与甲状腺相似。MTD和LD试验中的患者以及LD试验中的NHL和CLL患者的药代动力学相似，只是后一组的131I肿瘤浓度较低。无论是MTD还是LD试验，NHL患者每给予1 GBq 131I的平均肿瘤辐射剂量为1.0 Gy/GBq（3.7 rad/mCi），约为身体或骨髓的九倍。CLL患者的肿瘤辐射剂量较低而肝脏辐射剂量较高。否则，平均而言，不同患者组和个体患者之间的辐射剂量学非常相似。在所给药的范围内，药代动力学和剂量学似乎不受131I或Lym-1量的影响。131I的肿瘤浓度和每吉贝可勒尔的辐射剂量与肿瘤大小呈负相关，但似乎与组织学分级或类型、肿瘤负荷或治疗反应无关。
131I-Lym-1的治疗指数良好，尽管CLL患者的指数低于NHL患者。在不同试验中，患者和患者组之间的药代动力学和辐射剂量学平均而言非常相似。
