Background/Objectives: Peptide Receptor Radionuclide Therapy (PRRT) is approved for patients with inoperable, progressive and/or metastatic well-differentiated NETs. Before the approval of Lutathera®, locally manufactured177Lu-HA-DOTATATE was used on a regular basis in clinical routine. The aim of this study was (1) to compare the hematotoxicity of locally manufactured177Lu-HA-DOTATATE with Lutathera®in GEP-NET patients and (2) to compare the recommended treatment interval of 8 weeks between each cycle to a prolonged scheme of up to 11 weeks for both177Lu-HA-DOTATATE and Lutathera®. Methods: The included patients with GEP NETs (n= 46) received four cycles of PRRT, either177Lu-HA-DOTATATE or Lutathera®, and were divided into four subgroups. The subgroups were treated with either locally manufactured177Lu-HA-DOTATATE or Lutathera®and were stratified into a mean application interval of 8 (HA8weeks,n= 10/Lutathera8weeks,n= 16) or 11 weeks (HAadapted,n= 10/Lutatheraadapted,n= 10). To evaluate therapy associated hemato- and nephrotoxicity, patients underwent two laboratory follow-up examinations (follow-up 1—between 2./3. therapy cycle; follow-up 2—after the termination of the 4. therapy cycle) and were then compared to pre-PRRT laboratory results. To assess hematological and renal recovery trends, blood values and parameters of kidney function were collected up to 58.9 weeks after PRRT completion. Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) were used for grading hematological parameters. Results: The occurrence of high-grade adverse events (CTCAE grade 3/4) after PRRT was moderate, with 1/10 (10%) grade 4 lymphocytopenia in the Lutatheraadaptedgroup, while overall, 20/46 (43.5%) patients had grade 3 lymphocytopenia. Grade 3 thrombocytopenia occurred in 1/10 (10%) patients of the HAadaptedgroup. Absolute and percentage changes in the kidney function (creatinine, TER) remained constant during PRRT in all subgroups. All four subgroups showed a significant decrease in absolute blood value changes for PLT counts, WBC counts, neutrophil granulocytes and lymphocytes between, prior to and after PRRT (p< 0.05, each). Regarding percentage changes in laboratory parameters, only the HAadaptedand the HA8weeksgroups had significant decreases in WBC (p< 0.03, each) and PLT counts (p< 0.04, each) while there was no significant degradation of any other hematological parameter in any of the subgroups. Only patients with longer treatment intervals under177Lu-HA-DOTATATE therapy showed a statistically significant correlation in the long-term recovery analysis concerning the PLT counts (r = 0.6,p< 0.0001). Other blood and kidney values showed no significant correlation in the long-term analysis in the other subgroups. Conclusion: Comparing the hematotoxicity in patients that were treated with locally manufactured177Lu-HA-DOTATATE with patients that were treated with Lutathera®and assessing different treatment intervals in both groups (8 vs. 11 weeks), revealed that there is overall a low to moderate incidence of significant changes in hematological and renal parameters directly after PRRT. Recovery trends of hematological and renal parameters after 1 year suggest that patients treated with locally manufactured177Lu-HA-DOTATATE might benefit from a longer treatment interval of 11 weeks regarding their PLT counts. Given the risk of developing hematological diseases such as therapy-related myeloid neoplasms years after PRRT, longer observational periods after PRRT will be crucial.
背景/目的：肽受体放射性核素治疗（PRRT）已获批用于治疗无法手术、进展性和/或转移性高分化神经内分泌肿瘤患者。在Lutathera®获批之前，临床常规中常使用本地生产的¹⁷⁷Lu-HA-DOTATATE。本研究旨在：（1）比较本地生产的¹⁷⁷Lu-HA-DOTATATE与Lutathera®在胃肠胰神经内分泌肿瘤患者中的血液毒性；（2）针对¹⁷⁷Lu-HA-DOTATATE和Lutathera®两种药物，比较推荐的8周治疗间隔方案与延长至11周的治疗方案。方法：纳入的胃肠胰神经内分泌肿瘤患者（n=46）接受四个周期的PRRT治疗（使用¹⁷⁷Lu-HA-DOTATATE或Lutathera®），并分为四个亚组。各亚组分别接受本地生产的¹⁷⁷Lu-HA-DOTATATE或Lutathera®治疗，并按平均给药间隔8周（HA8周组，n=10/Lutathera8周组，n=16）或11周（HA调整组，n=10/Lutathera调整组，n=10）进行分层。为评估治疗相关的血液毒性和肾毒性，患者接受两次实验室随访检查（随访1——第2/3治疗周期之间；随访2——第4治疗周期结束后），并与PRRT前的实验室结果进行比较。为评估血液学和肾功能恢复趋势，收集了PRRT完成后58.9周内的血液指标和肾功能参数。采用《不良事件通用术语标准》5.0版对血液学参数进行分级。结果：PRRT后高级别不良事件（CTCAE 3/4级）发生率中等，其中Lutathera调整组出现1/10例（10%）4级淋巴细胞减少症，而总体上有20/46例（43.5%）患者出现3级淋巴细胞减少症。HA调整组有1/10例（10%）患者出现3级血小板减少症。所有亚组在PRRT期间肾功能（肌酐、总排泄率）的绝对值和百分比变化保持稳定。四个亚组在PRRT治疗前、治疗期间及治疗后，血小板计数、白细胞计数、中性粒细胞和淋巴细胞的绝对血液值变化均显著下降（p<0.05）。在实验室参数的百分比变化方面，仅HA调整组和HA8周组的白细胞计数（p<0.03）和血小板计数（p<0.04）显著下降，而其他亚组的任何血液学参数均未出现显著恶化。仅在¹⁷⁷Lu-HA-DOTATATE治疗中采用较长治疗间隔的患者，其血小板计数的长期恢复分析显示出统计学显著相关性（r=0.6，p<0.0001）。其他亚组的长期分析中，其他血液和肾脏指标未显示显著相关性。结论：比较接受本地生产¹⁷⁷Lu-HA-DOTATATE治疗的患者与接受Lutathera®治疗患者的血液毒性，并评估两组不同治疗间隔（8周 vs. 11周）的效果，结果显示PRRT后血液学和肾脏参数发生显著变化的总体发生率低至中等。血液学和肾脏参数在1年后的恢复趋势表明，接受本地生产¹⁷⁷Lu-HA-DOTATATE治疗的患者可能从11周的较长治疗间隔中获益，特别是在血小板计数方面。考虑到PRRT数年后可能发生治疗相关髓系肿瘤等血液疾病的风险，PRRT后更长的观察期至关重要。
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