Blakkisrud Johan, Løndalen Ayca, Dahle Jostein, Turner Simon, Holte Harald, Kolstad Arne, Stokke Caroline
Department of Diagnostic Physics, Oslo University Hospital, Oslo, Norway.
Department of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway.
J Nucl Med. 2017 Jan;58(1):55-61. doi: 10.2967/jnumed.116.180471. Epub 2016 Sep 1.
Red marrow (RM) is often the primary organ at risk in radioimmunotherapy; irradiation of marrow may induce short- and long-term hematologic toxicity. Lu-lilotomab satetraxetan is a novel anti-CD37 antibody-radionuclide conjugate currently in phase 1/2a. Two predosing regimens have been investigated, one with 40 mg of unlabeled lilotomab antibody (arm 1) and one without (arm 2). The aim of this work was to compare RM-absorbed doses for the two arms and to correlate absorbed doses with hematologic toxicity.
Eight patients with relapsed CD37+ indolent B-cell non-Hodgkin lymphoma were included for RM dosimetry. Hybrid SPECT and CT images were used to estimate the activity concentration in the RM of L2-L4. Pharmacokinetic parameters were calculated after measurement of the Lu-lilotomab satetraxetan concentration in blood samples. Adverse events were graded according to the Common Terminology Criteria for Adverse Events, version 4.0.
The mean absorbed doses to RM were 0.9 mGy/MBq for arm 1 (lilotomab+) and 1.5 mGy/MBq for arm 2 (lilotomab-). There was a statistically significant difference between arms 1 and 2 (Student t test, P = 0.02). Total RM-absorbed doses ranged from 67 to 127 cGy in arm 1 and from 158 to 207 cGy in arm 2. For blood, the area under the curve was higher with lilotomab predosing than without (P = 0.001), whereas the volume of distribution and the clearance of Lu-lilotomab satetraxetan was significantly lower (P = 0.01 and P = 0.03, respectively). Patients with grade 3/4 thrombocytopenia had received significantly higher radiation doses to RM than patients with grade 1/2 thrombocytopenia (P = 0.02). A surrogate, non-imaging-based, method underestimated the RM dose and did not show any correlation with toxicity.
Predosing with lilotomab reduces the RM-absorbed dose for Lu-lilotomab satetraxetan patients. The decrease in RM dose could be explained by the lower volume of distribution. Hematologic toxicity was more severe for patients receiving higher absorbed radiation doses, indicating that adverse events possibly can be predicted by the calculation of absorbed dose to RM from SPECT/CT images.
红骨髓（RM）通常是放射免疫治疗中的主要风险器官；骨髓照射可能会引发短期和长期血液学毒性。鲁利妥单抗萨特曲妥坦是一种新型抗CD37抗体 - 放射性核素偶联物，目前处于1/2a期试验阶段。已研究了两种给药前方案，一种使用40mg未标记的利妥单抗抗体（第1组），另一种不使用（第2组）。这项工作的目的是比较两组的红骨髓吸收剂量，并将吸收剂量与血液学毒性相关联。
纳入8例复发的CD37 +惰性B细胞非霍奇金淋巴瘤患者进行红骨髓剂量测定。使用混合SPECT和CT图像估计L2 - L4红骨髓中的活性浓度。在测量血样中鲁利妥单抗萨特曲妥坦浓度后计算药代动力学参数。根据不良事件通用术语标准4.0版对不良事件进行分级。
第1组（有利妥单抗）红骨髓的平均吸收剂量为0.9mGy/MBq，第2组（无利妥单抗）为1.5mGy/MBq。第1组和第2组之间存在统计学显著差异（Student t检验，P = 0.02）。第1组红骨髓的总吸收剂量范围为67至127cGy，第2组为158至207cGy。对于血液，给药前使用利妥单抗时曲线下面积高于未使用时（P = 0.001），而鲁利妥单抗萨特曲妥坦的分布容积和清除率则显著更低（分别为P = 0.01和P = 0.03）。3/4级血小板减少症患者接受的红骨髓辐射剂量显著高于1/2级血小板减少症患者（P = 0.02）。一种基于非成像的替代方法低估了红骨髓剂量，且未显示出与毒性的任何相关性。
给药前使用利妥单抗可降低鲁利妥单抗萨特曲妥坦患者的红骨髓吸收剂量。红骨髓剂量的降低可以通过较低的分布容积来解释。接受较高吸收辐射剂量的患者血液学毒性更严重，这表明通过SPECT/CT图像计算红骨髓吸收剂量可能可以预测不良事件。
