Multicentric Matched-Pair Analysis of Long-Term Hematotoxicity of Peptide Receptor Radionuclide Therapy in Patients Postsplenectomy

Peptide receptor radionuclide therapy (PRRT) with ¹⁷⁷Lu-DOTATATE is an approved treatment for metastatic neuroendocrine tumors (NETs). Although the therapy is effective, hematologic toxicity, particularly leukopenia, remains a significant concern. The spleen, which accumulates radiolabeled somatostatin analogs, may play a critical role in modulating this toxicity. This study investigates whether patients undergoing PRRT after splenectomy exhibit lower hematologic toxicity. <b>Methods:</b> This multicenter retrospective study included 68 patients with metastatic NETs treated with PRRT between 2009 and 2022. Splenectomized patients (<i>n</i> = 34) were matched to nonsplenectomized patients on the basis of age, sex, tumor location, grading, metastatic pattern, and treatment cycles. Hematologic parameters (leukocytes, lymphocytes, neutrophils, hemoglobin, and platelets) were assessed at baseline and 12 and 24 mo after PRRT. Hematotoxicity was graded using Common Terminology Criteria for Adverse Events. Statistical analyses included <i>t</i> test, Mann-Whitney <i>U</i> test, and Fisher exact test, with an α of 0.05 and Bonferroni adjustment applied. <b>Results:</b> Splenectomized patients had significantly lower rates of leukopenia, with a mean decline of 12.8% in leukocyte count at 24 mo versus 47.2% in nonsplenectomized patients (<i>P</i> < 0.001), and a higher median absolute leukocyte count (7.2 vs. 4.2 × 10³/mm³, <i>P</i> < 0.001). Leukopenia occurred in 2 splenectomized patients compared with 20 in the control group (<i>P</i> < 0.001). Lymphocyte decline was also less pronounced, with higher absolute counts at 24 mo. Platelet counts were consistently higher postsplenectomy, although relative changes over time were not significant. Neutrophil counts and hemoglobin levels remained comparable between groups. <b>Conclusion:</b> Splenectomy appears to reduce leukopenia and improve hematologic tolerability in NET patients undergoing PRRT, highlighting the spleen's role in leukocyte regulation. These patients may better tolerate intensified PRRT regimens, including additional cycles or reinduction, with minimal toxicity. This is particularly relevant for patients with pancreatic NETs, who frequently undergo splenectomy and face a poorer prognosis. Prospective studies are needed to further clarify the spleen's impact on PRRT-related hematotoxicity and guide treatment optimization.