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

C-X-C motif chemokine receptor 4 and its only known ligand SDF1 are crucially involved in stem cell mobilization and migration of CXCR4-positive bone marrow (BM) cells by following a gradient towards (neo-)angiogenic niches, finally leading to promotion of tumor-feeding vessels and metastatic spread [1]. For instance, in specimen of patients afflicted with marginal zone lymphoma (MZL), more than 90% revealed relevant CXCR4 expression and those ex-vivo findings then laid the proper groundwork for in-vivo imaging using CXCR4-directed [⁶⁸Ga]Ga-PentixaFor PET/CT [2, 3]. Further favoring a more wide-spread adoption in hemato-oncology, hematological neoplasms achieved substantially higher target-to-background ratios and maximum standardized uptake values (SUV_max) on a quantitative level when compared to most solid tumor entities [4]. As such, beyond enabling a more precise diagnostic read-out, CXCR4-targeted PET/CT may also allow to identify candidates for treatment with ß^-(minus)-emitting counterparts, e.g., [¹⁷⁷Lu]Lu-/[⁹⁰Y]Y-PentixaTher [5]. Of note, such a molecular imaging-based treatment strategy may then achieve both anti-lymphoma and desired myeloablative effects, thereby preparing for subsequent hematopoietic stem cell transplantation (HSCT) in addition to conditioning regimens [6, 7].

Increasing tumor load, however, may be linked to decreasing radiotracer accumulation in normal organs, possibly explained by a lower amount of tracer available to the normal organs in the presence of high tumor load. Such a tumor-sink effect has been described for solid tumors including prostate carcinoma (PC) imaged with prostate-specific membrane antigen (PSMA)-targeted PET [8]. A recent evaluation using chemokine receptor imaging in patients diagnosed with other solid tumor entities than PC did not reveal such an interdependence on an organ-tumor level [9]. For hematological neoplasms, a potential “lymphoma-sink” effect has been shown in patients with diffuse large B cell lymphoma (DLBCL) imaged with 2-[¹⁸F]FDG PET/CT [10, 11]. For CXCR4-targeted PET/CT, however, a lymphoma-sink effect has not been determined yet. In a theranostic setting, those information may be of relevance, as in patients with increasing lymphoma load, higher [¹⁷⁷Lu]Lu-/[⁹⁰Y]Y-PentixaTher activities could then be administered, thereby optimizing anti-lymphoma efficacy and minimizing side effects in organs at risk [6, 12]. As such, investigating the largest cohort of MZL patients imaged with [⁶⁸Ga]Ga-PentixaFor to date, we aimed to investigate whether such a potential lymphoma-sink effect is also present in individuals with MZL scheduled for chemokine receptor PET.

We retrospectively identified 73 patients with MZL who underwent [⁶⁸Ga]Ga-PentixaFor PET/CT from our institutional PET/CT database. The local institutional review board waived the need for further approval due to the retrospective nature of this study (waiver no° 20210726 02). Written informed consent of all patients was collected beforehand. Parts of this patient cohort have been investigated in previous studies [3, 4], however, without examining potential implications of lymphoma burden on normal organ radiotracer uptake.

Investigating a potential lymphoma-sink effect on CXCR4-targeted PET/CT for hematological malignancies, we evaluated a cohort of individuals diagnosed with MZL, which presented with a broad range of lymphoma load and in-vivo tracer uptake on PET. We did not observe relevant associations between normal organ uptake and lymphoma burden, thereby indicating that such a phenomenon may rather not be evident in MZL patients imaged with [⁶⁸Ga]Ga-PentixaFor PET. Those findings may be of relevance, as recent reports provided evidence that CXCR4-targeted theranostics is particularly useful in patients with advanced blood cancers, especially for MZL [3, 4]. In this regard, CXCR4-targeted radioligand therapy (RLT) based on pretherapeutic PET/CT has already achieved outcome benefits in end-stage lymphoma patients [5, 18, 19], thereby rendering this theranostic concept favorable for the referring hemato-oncologist [6]. Based on our findings, dose to unaffected organs may not decrease in patients with increasing CXCR4-positive lymphoma load or with elevated PET signal. Thus, other aspects, such as intra- or interpatient variability of uptake in normal organs may be of more importance to consider dosimetry for CXCR4-RLT planning than the lymphoma load [15, 20].

Recent reports investigating a tumor-sink effect in the context of theranostic radiotracers provided dissimilar results, including PC imaged with 18F- or 68Ga-labeled PET radiotracers or in patients scheduled for fibroblast activation protein-inhibitor- or somatostatin receptor (SSTR)-directed imaging [8, 13‐15, 21]. For instance, our group also evaluated this phenomenon in solid tumors after [⁶⁸Ga]Ga-PentixaFor administration and reported on no impact of tumor burden uptake on normal organ uptake [9]. Those studies are of importance, as all of those radiotracers can be used in a theranostic approach, i.e., after having determined the presence of the target, treatment with ß^-(minus)-emitting therapeutic equivalents can be conducted [22]. In this regard, higher activities could be administered for radiotracers harboring such a tumor-sink effect, which would then potentially result in higher doses to the tumor, but not to unaffected organs [21]. To date, however, investigations on a tumor-sink effect determined from baseline PET using theranostic tracers have been restricted to patients with solid tumors, including PC, neuroendocrine neoplasms, pancreatic cancer, lung or adrenocortical carcinoma [8, 9, 13‐15, 21]. Recent years, however, have witnessed an increasing evaluation of CXCR4-directed imaging and therapy in particular for patients with hematological malignancies, thereby expanding this theranostic concept towards hemato-oncology [6]. While a potential lymphoma-sink effect has been observed on 2-[¹⁸F]FDG PET/CT in patients with DLBCL [10, 11], dedicated studies investigating a potential lymphoma-sink effect using the theranostic PET probe [⁶⁸Ga]Ga-PentixaFor are still missing. To date, RLTs with the therapeutic equivalent [¹⁷⁷Lu]Lu- or [⁹⁰Y]Y-PentixaFor have been conducted based on pretherapeutic dosimetry to determine the appropriate amount of activity [5, 12, 19, 23, 24]. Based on our results, however, image findings on [⁶⁸Ga]Ga-PentixaFor PET may not justify exceptional high treatment activities. Thus, while CXCR4-directed PET is required to determine the presence of the target in-vivo [6], those scans can rather not replace dosimetry prior to RLT.

In hemato-oncology, recent efforts also turned towards “cold” CXCR4 inhibitory therapies, e.g., by investigating CXCR4 antagonist IgG1 antibodies, which achieved substantial anti-lymphoma effects by disrupting SDF1 pathways [25]. Preclinical models showed relevant benefit in multiple myeloma, acute myeloid leukemia or Hodgkin Lymphoma [25]. Of note, in all of those malignancies, [⁶⁸Ga]Ga-PentixaFor has provided evidence on visualizing chemokine receptor expression in sites of disease [7, 26, 27]. As such, given those recent developments of CXCR4-directed, non-radiolabeled drugs [25], our findings on a missing lymphoma-sink effect on PET may be of relevance not only for “hot,” but also for “cold” CXCR4 inhibitory therapies, including dosing studies.

This investigation has limitations, e.g., its retrospective design and small number of subjects. Also, no additional weighting was made for different volumes of segmented lymphoma lesions when calculating SUV values within the same patient. Additionally, a potential lymphoma sink effect may be underestimated because only a small number of patients in our study had very high LV or FLA. Moreover, due to the retrospective nature of this study, we were not able to provide data on an ex-vivo blood count analysis, which might have offered further insights on a potential lymphoma sink effect by measuring blood pool activity. Furthermore, while previous investigations focusing on other theranostic radiotracers have mainly applied relative thresholds for tumor delineation [13, 15], a recent investigation also used a fixed intra-individual threshold [8], e.g., based on the liver uptake. As this approach might allow for a more comparable tumor load delineation between scans, future studies may also conduct a respective re-analysis, preferably in a larger cohort with a broader range of LV. Last, we focused on MZL, as relative to others, this type of hematological malignancy has been well characterized by CXCR4-directed imaging including superiority to standard diagnostic work-up [3, 4], indicative for a more widespread use in patients with MZL in the near-term future. However, [⁶⁸Ga]Ga-PentixaFor has also provided reliable information on the current chemokine receptor status in other hemato-oncological entities [4]. As such, future studies may also evaluate a potential lymphoma-sink effect in other subtypes, in particular in those which have already benefitted from CXCR4-RLT, including T-cell lymphoma [5].

We observed no relevant associations between normal organ uptake and CXCR4-positive lymphoma burden in patients with MZL studied with [⁶⁸Ga]Ga-PentixaFor PET/CT. As such, relative to other theranostic radiotracers used for imaging and therapy of solid tumors, a lymphoma-sink effect may rather not be evident in MZL. Those findings may be of relevance in a theranostic setting, as recent reports provided evidence that CXCR4-targeted RLT is particularly useful in patients with advanced blood cancers. In addition, the herein described missing lymphoma-sink effect may also be of relevance for dosing studies using novel CXCR4-inhibitory “cold” drugs.