Supplementary Material for: Irradiation-Related Lymphopenia for Bone Metastasis from Hepatocellular Carcinoma

<b><i>Background/Aim:</i></b> In the era of immunotherapy, treatment-related lymphopenia (TRL) is gaining attention. In this study, TRL was investigated in patients with bone metastasis from hepatocellular carcinoma (HCC) treated with radiotherapy (RT). <b><i>Methods:</i></b> Clinical data of 302 patients receiving RT for 511 bone metastases from HCC between 2005 and 2018 were reviewed. Data on absolute lymphocyte count (ALC) from pre-RT to 12 months post-RT were collected. Severe TRL was defined as ALC &lt;500 cells/mm³ and evaluated using ALC 2 months after initiating RT. Factors associated with TRL were analyzed, which include the amount of active bone marrow within the RT field. The amount of active bone marrow included in the RT field was calculated as the product of the percentage of the bone compartment included in the RT field and the active bone marrow percentage of the bone compartment. <b><i>Results:</i></b> Overall, 33.4% of patients developed TRL 2 months after initiating RT. The mean ALC decreased after initiating RT and remained persistently low during 12 months of observation. Overall survival (OS) was significantly worse in patients with TRL than in those without (median OS: 3.7 vs. 6.5 months, <i>p</i> &lt; 0.001). In the prognostic factor analysis, TRL was an independent prognostic factor of OS (<i>p</i> = 0.036), along with known prognostic factors of HCC. The percentage of active bone marrow within the RT field was the only significant factor associated with TRL (<i>p</i> &lt; 0.001). <b><i>Conclusion:</i></b> TRL was observed in patients receiving RT for bone metastasis from HCC, and it was associated with poor survival. The percentage of active bone marrow within the RT field significantly affected TRL development. The results suggest that a new strategy is required to prevent TRL.

**背景与目的：** 在免疫治疗时代，治疗相关淋巴细胞减少症（treatment-related lymphopenia, TRL）正逐渐受到关注。本研究针对接受放疗（radiotherapy, RT）的肝细胞癌（hepatocellular carcinoma, HCC）骨转移患者的治疗相关淋巴细胞减少症展开了探究。
**方法：** 回顾性分析了2005年至2018年间，302例因肝细胞癌骨转移接受放疗的患者的临床资料，共计涉及511处骨转移灶。收集了患者放疗前至放疗后12个月的绝对淋巴细胞计数（absolute lymphocyte count, ALC）相关数据。重度治疗相关淋巴细胞减少症被定义为绝对淋巴细胞计数＜500个/mm³，并以放疗开始后2个月的绝对淋巴细胞计数作为评估依据。本研究分析了与治疗相关淋巴细胞减少症相关的影响因素，其中包括放疗野内的活性骨髓占比。放疗野内活性骨髓占比的计算方式为：放疗野所覆盖的骨组织占该骨室总容积的百分比，与该骨室的活性骨髓占比的乘积。
**结果：** 总体而言，33.4%的患者在放疗开始后2个月出现了治疗相关淋巴细胞减少症。患者的平均绝对淋巴细胞计数在放疗开始后出现下降，并在12个月的观察期内持续维持在较低水平。出现治疗相关淋巴细胞减少症的患者的总体生存期（overall survival, OS）显著差于未出现该症状的患者（中位总体生存期：3.7个月 vs. 6.5个月，*p* < 0.001）。在预后因素分析中，治疗相关淋巴细胞减少症与已知的肝细胞癌预后因素一同，成为总体生存期的独立预后因素（*p* = 0.036）。放疗野内的活性骨髓占比是与治疗相关淋巴细胞减少症相关的唯一显著影响因素（*p* < 0.001）。
**结论：** 本研究发现，接受放疗的肝细胞癌骨转移患者可出现治疗相关淋巴细胞减少症，且该症状与不良生存结局相关。放疗野内的活性骨髓占比对治疗相关淋巴细胞减少症的发生具有显著影响。研究结果提示，亟需开发全新的策略以预防治疗相关淋巴细胞减少症。