Lymphoma-Sink Effect in Marginal Zone Lymphoma Based on CXCR4-Targeted Molecular Imaging

Abstract

Purpose: Recent 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.

Procedures: We 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 (SUV_mean) were derived. MZL manifestations were also segmented to determine the maximum and peak standardized uptake values SUV (SUV_max/peak) and volumetric parameters, including lymphoma volume (LV), and fractional lymphoma activity (FLA, defined as LV*SUV_mean of 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.

Results: We recorded the following median SUV_mean in 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 SUV_max (ρ ≤ 0.21, P ≥ 0.07), SUV_peak (ρ ≤ 0.20, P ≥ 0.09), LV (ρ ≤ 0.13, P ≥ 0.27), nor FLA (ρ ≤ 0.15, P ≥ 0.33).

Conclusions: Investigating 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.

Keywords: C-X-C motif chemokine receptor; CXCR4; Lymphoma sink; PET; Radioligand therapy; Theranostics; Tumor sink; [68Ga]Ga-PentixaFor.

Fig. 1

Scatter plots of lymphoma-derived fractional lymphoma activity (FLA) and mean standardized uptake values (SUV_mean) in normal (heart (a), bone marrow (b), liver (c), spleen (d), kidneys (e)) Squares are partially overlaid. No significance was reached

Fig. 2

Maximum intensity projections of [⁶⁸Ga]Ga-PentixaFor PET/CT in patients with low (a lymphoma volume, 1.7 cm³), intermediate (b lymphoma volume, 66.2 cm³) and high (c lymphoma volume, 361.5 cm³) lymphoma load. Red arrows indicate lymphoma manifestations. Visually, no obvious differences in normal organ uptake are apparent between different patients, supporting the notion that in patients with high lymphoma manifestation burden, uptake in normal organs does not drop. H = Heart, L = Liver, K = Kidney, S = Spleen, BM = bone marrow