Supplementary Material for: Increased Spleen Volume in Hepatocellular Carcinoma Patients Treated with Atezolizumab plus Bevacizumab in Comparison to Lenvatinib: A Retrospective Analysis

<b><i>Introduction:</i></b> We previously reported 2 cases of esophageal varices rupture during atezolizumab and bevacizumab (Atez/Bev) treatment, in which the spleen volume gradually increased. The aim of this retrospective study is to compare the chronological change in spleen volume of patients treated with Atez/Bev and lenvatinib (LEN). <b><i>Methods:</i></b> Seventy-two patients (Atez/Bev group, <i>n</i> = 26; LEN group, <i>n</i> = 46) were included in this retrospective study. The splenic parenchyma area was measured based on CT imaging. We used mixed-effect regression models with random intercepts to test the difference in the rate of change in spleen volume between the Atez/Bev and LEN groups. <b><i>Results:</i></b> The median age of the Atez/Bev and LEN groups was 74.0 (71.0–82.0) and 72.0 (67.5–76.0), respectively. About 80% patients were male. The mALBI grade was classified as 1, 2a, 2b, and 3 in 10 (38.5%), 6 (23.1%), 10 (38.5%), and zero (0.0%) patients, respectively, in the Atez/Bev group and 21 (45.7%), 9 (19.6%), 15 (32.6%), and 1 (2.2%) patient in the LEN group (<i>p</i> = 0.9). The median baseline neutrophil-to-lymphocyte ratio (NLR) was 2.61 (1.80–3.41) in the Atez/Bev group and 2.71 (1.76–3.67) in the LEN group (<i>p</i> = 1.0). The median baseline spleen volume was 185 (132–246) cm³ in the Atez/Bev group and 231 (150–355) cm³ in the LEN group. The spleen volume gradually increased during Atez/Bev treatment (2.41 cm³ per week), while it was mostly consistent during LEN treatment (0.32 cm³ per week). Among patients with mALBI grade 2b or 3, the spleen volume increased in the Atez/Bev group (2.99 cm³ per week) and slightly decreased in the LEN group (0.82 cm³ per week), without statistical significance (<i>p</i> = 0.07). Among patients with a baseline NLR of &gt;2.68, the spleen volume increased at a rate of 2.57 cm³ per week in the Atez/Bev group and decreased at a rate of 1.18 cm³ per week in the LEN group. The difference in the slope of the two groups was statistically significant (<i>p</i> = 0.04). <b><i>Discussion/Conclusion:</i></b> Atez/Bev treatment could result in an increased spleen volume. Caution is required when managing patients treated with Atez/Bev, especially those with a high NLR.

**引言**：本团队此前曾报道2例接受阿替利珠单抗（atezolizumab）联合贝伐珠单抗（Atez/Bev）治疗期间发生食管静脉曲张破裂出血的病例，该类患者的脾脏体积呈逐渐增大趋势。本回顾性研究旨在对比接受Atez/Bev方案与仑伐替尼（lenvatinib，LEN）治疗的患者脾脏体积的时序变化特征。
**方法**：本回顾性研究共纳入72例患者，其中Atez/Bev组26例，LEN组46例。基于计算机断层扫描（CT）影像测量患者的脾实质面积。本研究采用带有随机截距的混合效应回归模型，对比Atez/Bev组与LEN组患者脾脏体积的变化速率差异。
**结果**：Atez/Bev组与LEN组患者的中位年龄分别为74.0岁（四分位距：71.0~82.0岁）与72.0岁（四分位距：67.5~76.0岁）。两组中约80%的患者为男性。Atez/Bev组的改良ALBI分级（mALBI grade）为1级、2a级、2b级、3级的患者例数分别为10例（38.5%）、6例（23.1%）、10例（38.5%）与0例（0.0%）；LEN组对应例数分别为21例（45.7%）、9例（19.6%）、15例（32.6%）与1例（2.2%），组间差异无统计学意义（p=0.9）。Atez/Bev组与LEN组患者的基线中位中性粒细胞与淋巴细胞比值（NLR）分别为2.61（四分位距：1.80~3.41）与2.71（四分位距：1.76~3.67），组间差异无统计学意义（p=1.0）。两组患者的基线中位脾脏体积分别为185 cm³（四分位距：132~246 cm³）与231 cm³（四分位距：150~355 cm³）。接受Atez/Bev方案治疗的患者脾脏体积呈逐渐增大趋势（每周增加2.41 cm³），而接受LEN治疗的患者脾脏体积基本保持稳定（每周变化0.32 cm³）。在改良ALBI分级为2b级或3级的患者中，Atez/Bev组脾脏体积呈增加趋势（每周增加2.99 cm³），LEN组则略有下降（每周减少0.82 cm³），组间差异无统计学意义（p=0.07）。在基线NLR＞2.68的患者中，Atez/Bev组脾脏体积以每周2.57 cm³的速率增加，LEN组则以每周1.18 cm³的速率降低，两组的变化斜率差异具有统计学意义（p=0.04）。
**讨论与结论**：Atez/Bev方案治疗可导致脾脏体积增大。临床管理接受该方案治疗的患者时需格外谨慎，尤其是基线NLR升高的患者。