PurposeRecent studies investigating a tumor-sink effect in solid tumors reported on decreasing uptake in normal organs in patients with higher tumor burden. This phenomenon, however, has not been evaluated yet for theranostic radiotracers applied to hematological neoplasms. As such, we aimed to determine a potential “lymphoma-sink effect” in patients with marginal zone lymphoma (MZL) imaged with C-X-C motif chemokine receptor (CXCR) 4-directed PET/CTs.ProceduresWe retrospectively analyzed 73 patients with MZL who underwent CXCR4-directed [68Ga]Ga-PentixaFor PET/CT. Normal unaffected organ uptake (heart, liver, spleen, bone marrow, kidneys) was quantified using volumes of interests (VOIs) and mean standardized uptake values (SUVmean) were derived. MZL manifestations were also segmented to determine the maximum and peak standardized uptake values SUV (SUVmax/peak) and volumetric parameters, including lymphoma volume (LV), and fractional lymphoma activity (FLA, defined as LV*SUVmeanof lymphoma burden). This approach resulted in 666 VOIs to capture the entire MZL manifestation load. We used Spearman’s rank correlations to determine associations between organ uptake and CXCR4-expressing lymphoma lesions.ResultsWe recorded the following median SUVmeanin normal organs: heart, 1.82 (range, 0.78–4.11); liver, 1.35 (range, 0.72–2.99); bone marrow, 2.36 (range, 1.12–4.83); kidneys, 3.04 (range, 2.01–6.37); spleen, 5.79 (range, 2.07–10.5). No relevant associations between organ radiotracer uptake and MZL manifestation were observed, neither for SUVmax(ρ ≤ 0.21,P≥ 0.07), SUVpeak(ρ ≤ 0.20,P≥ 0.09), LV (ρ ≤ 0.13,P≥ 0.27), nor FLA (ρ ≤ 0.15,P≥ 0.33).ConclusionsInvestigating a lymphoma-sink effect in patients with hematological neoplasms, we observed no relevant associations between lymphoma burden and uptake in normal organs. Those observations may have therapeutic implications, e.g., for “cold” SDF1-pathway disrupting or “hot,” CXCR4-directed radiolabeled drugs, as with higher lymphoma load, normal organ uptake seems to remain stable.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11307-023-01830-9.