Comparative Evaluation of Response in Diffuse Large B-cell Lymphoma Using ⁶⁸Ga-Pentixafor PET/CT and ¹⁸F-FDG PET/CT

Introduction

Diffuse large B-cell lymphoma (DLBCL) is a highly aggressive non-Hodgkin lymphoma characterized by its distinct molecular and clinical features. Among these, the expression of the chemokine receptor CXCR4 plays a pivotal role in tumor dissemination and interaction with the tumor microenvironment.[123] The development of a new radiotracer called ⁶⁸Ga-Pentixafor has provided a means to detect and visualize CXCR4 expression in different types of malignancies, including lymphoma.[45]

¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET)/computed tomography (CT) is widely used for baseline staging and response assessment in DLBCL based on metabolic activity.[67] However, there is a growing interest in understanding the tumor microenvironment and its interaction with malignant cells. The CXCR4-directed imaging provides valuable insights into the tumor microenvironment and can complement the metabolic information provided by ¹⁸F-FDG PET/CT.[8]

CXCR4-directed imaging is more specific to tumors and shows less interference from normal physiological uptake. Unlike ¹⁸F-FDG tracer, which can cause significant interference in certain regions such as the head, neck, and intestinal area, CXCR4-directed PET/CT imaging can overcome these challenges and provide better staging and evaluation of treatment response.[89] Moreover, CXCR4-directed imaging has the potential for theranostics, allowing for targeted radionuclide therapy in refractory cases.[1011]

Here, we present a case study evaluating the use of CXCR4-directed PET/CT imaging with the novel radiotracer ⁶⁸Ga-Pentixafor for baseline staging and response assessment in diffuse large B-cell lymphoma and compare it with the standard ¹⁸F-FDG PET/CT.

Case Report

A 65-year-old male presented with a 1-month history of swelling on the right side of the neck. Fine-needle aspiration biopsy revealed high-grade B-cell non-Hodgkin lymphoma of the germinal center subtype, positive for CD79a. The patient exhibited no B symptoms but had an elevated serum lactate dehydrogenase level (630 IU/L). Blood counts and other clinical chemistry values were within normal limits.

Baseline imaging

¹⁸F-FDG PET/CT revealed metabolically active lesions in the right cervical, upper mediastinal, and abdominal para-aortic lymph nodes [Maximum intensity projection (MIP) image, Figures 1a and 2a, b], consistent with Lugano Stage III disease (SUVmax = 8.7 in the right cervical lymph nodes). Additionally, ⁶⁸Ga-Pentixafor PET/CT was conducted 3 days after the FDG scan as part of a prospective study approved by the ethical committee of the institute. The ⁶⁸Ga-Pentixafor PET/CT demonstrated concordant lesions [Figure 1b, MIP image] with relatively lower SUV values (SUVmax 3.2 right cervical). The para-aortic lymph nodes exhibited faint tracer uptake (SUVmax 2.4) but were still well-discernible on fused axial images [Figure 2c and d, fused axial images]. No discordant finding was found in baseline imaging. The bone marrow biopsy showed no evidence of malignant cell infiltration.

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Figure 1 (a) The baseline ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET) MIP image reveals metabolically active lesions in the right cervical, upper mediastinal, and abdominal para-aortic lymph nodes. (b) The baseline ⁶⁸Ga-Pentixafor PET scan shows comparable tracer uptake in disease-involved areas, with no additional findings. (c) The interim ¹⁸F-FDG PET indicates residual active disease in the right cervical and upper mediastinal regions, with a D score of 4. (d) Similar results are observed on the ⁶⁸Ga-Pentixafor PET. (e) The end-of-treatment ¹⁸F-FDG PET demonstrates intense metabolic activity in the right cervical and upper mediastinal lymph nodes, with a D score of 5. (f) The ⁶⁸Ga-Pentixafor PET reveals consistent imaging findings. PET: Positron emission tomography, ¹⁸F-FDG: ¹⁸F-fluorodeoxyglucose

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Figure 2 Fused axial images of (a and b) ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET)/computed tomography (CT) baseline staging reveal intense metabolically active lymph nodal mass in the right cervical and upper mediastinal regions (SUVmax 8.7). In (c and d), ⁶⁸Ga-Pentixafor PET/CT baseline staging demonstrates disease-involved sites with tracer uptake exhibiting relatively low intensity (SUVmax 3.2). The interim ¹⁸F-FDG PET/CT in (e and f) indicates residual disease in the right cervical and upper mediastinal regions and minimal residual disease in the abdominal para-aortic lymph nodes. Similarly, (g and h) ⁶⁸Ga-Pentixafor PET/CT presents comparable findings. In the end-of-treatment assessment shown in (i and j) with ¹⁸F-FDG PET/CT, metabolic activity persists in the right cervical and upper mediastinal lymph nodes (SUVmax 4.6) and low-grade activity in the abdominal para-aortic lymph node. Panels (k and l) of ⁶⁸Ga-Pentixafor PET/CT reflect similar imaging characteristics with those of ¹⁸F-FDG PET/CT, with minimal interference from physiological tracer distribution, allowing better delineation of the para-aortic lymph node. PET: Positron emission tomography, ¹⁸F-FDG: ¹⁸F-fluorodeoxyglucose, CT: Computed tomography

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Discussion

DLBCL, an aggressive lymphoproliferative disorder, requires accurate staging and response assessment to ensure optimal management. The preferred imaging modality for this purpose is ¹⁸F-FDG PET/CT, known for its high sensitivity and its capability to provide anatomical and metabolic insights.[16] However, limitations of ¹⁸F-FDG PET/CT, such as nonspecific tracer distribution and interference from physiological metabolic activity in areas such as the brain and intestines, can make it challenging to differentiate disease involvement from normal tissue activity.[711] Tumor heterogeneity often indicates varying metabolic activity across different sites of the disease. This diversity can be evaluated using CXCR imaging, which acts as an in vivo marker for tumor aggressiveness. Notably, increased tracer uptake has been observed in abdominal para-aortic lymph nodes with Pentixafor PET during end-of-treatment scans, suggesting a potentially aggressive disease state. This emphasizes the importance of understanding the metabolic variations within tumors.[12]

In this context, ⁶⁸Ga-Pentixafor PET/CT has emerged as a promising complementary imaging tool in various solid and hematological malignancies. By targeting the CXCR4 receptor, which is overexpressed in DLBCL, ⁶⁸Ga-Pentixafor PET/CT minimizes physiological tracer interference and provides comparable sensitivity to ¹⁸F-FDG PET/CT for staging and response assessment, even in anatomically challenging regions.[24] Its use may enhance diagnostic precision, particularly in nonspecific FDG or physiological uptake cases. It is also worth noting that no particular fasting preparation and glycemic control are required for Pentixafor imaging.[35]

Beyond diagnostic imaging, the role of ⁶⁸Ga-Pentixafor PET/CT extends to theranostic applications. The CXCR4-targeted radionuclide therapy, with radiolabeled molecules such as ⁹⁰Y- or ¹⁷⁷Lu-Pentixafor, can provide a promising option for refractory or relapsed disease.[111314] Selecting patients based on CXCR4 expression enhances targeted treatment, improving specificity and minimizing unnecessary interventions.[910] Although challenges persist, including variability in CXCR4 expression and SUVmax values, further studies are essential to refine and effectively incorporate these theranostic approaches into routine clinical practice.

This case demonstrates the feasibility of using CXCR4-targeted PET/CT for baseline staging and monitoring treatment response in DLBCL, complementing ¹⁸F-FDG PET/CT. Furthermore, it highlights the potential for personalized treatment strategies by utilizing CXCR4 expression to guide diagnostic and therapeutic decisions. Therefore, ⁶⁸Ga-Pentixafor serves as a crucial tool for determining eligibility for 177 Lu/90Y-Pentixather therapy in refractory DLBCL cases.[13151617] Future research is needed to establish standardized imaging protocols and validate the efficacy of CXCR4-directed radionuclide therapy, which could significantly enhance individualized care for DLBCL patients.