Pentixather: paving the way for radioligand therapy in oncohematology

KEYWORDS:

• pentixather
• pentixafor
• positron emission computed tomography
• chemokine receptor
• CXCR4
• theranostics

1. Introduction

An increasing volume of scientific data highlights the crucial significance of chemokines, a group of cytokines known for their capacity to prompt gradient-dependent directional chemotaxis, in the advancement and proliferation of tumors [1,2]. These communication molecules are released by a wide variety of epithelial and stromal cells and execute their biological roles through interactions with chemokine receptors [3].

Among the chemokine receptors, the C-X-C motif chemokine receptor 4 (CXCR4) has garnered significant attention from the scientific community due to its established role as a coreceptor for human immunodeficiency virus (HIV) entry [4]. Stromal cell-derived factor-1, a chemokine now referred to as C-X-C Motif Chemokine Ligand 12 (CXCL12), has been identified as the specific ligand for CXCR4. The interplay within the network involving the CXCR4-CXCL12 axis plays an intricate role in regulating cell survival and migration [5]. In the context of hematopoiesis, the CXCL12-CXCR4 axis regulates the homing of hematopoietic stem/progenitor cells to the bone marrow [1].

However, beyond its association with HIV, recent research has revealed an upregulation of this receptor in various malignancies [6]. In particular, pre-clinical studies have provided evidence that the metastatic process in pancreatic, thyroid, prostate, melanoma, and colon cancers is mediated by CXCR4, facilitating the migration of cancer cells toward organs expressing CXCL12. Furthermore, the significance of the CXCR4-CXCL12 axis in cancer has been bolstered by findings that inhibitors targeting CXCR4 demonstrate anti-tumor effects [7].

Concerning hematological malignancies, CXCR4 overexpression has been identified in diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and Hodgkin lymphoma (HL). Furthermore, CXCR4 overexpression, which is heterogeneous in nature, is observed in mantle cell lymphoma (MCL) and mucosa-associated lymphoid tissue lymphoma (MALT) [8]. Additionally, the CXCR4-CXCL12 axis plays a crucial role in the pathogenesis of multiple myeloma (MM), facilitating the mobilization and egression of MM cells [9].

In light of these considerations, CXCR4 has emerged as an appealing biomarker for a targeted approach to molecular imaging and radioligand therapy (RLT), aligning with the so-called theranostic paradigm. Along this path, a CXCL12-analogue, namely Pentixafor, a cyclic pentapeptide, has been successfully labeled with the positron-emitter gallium-68 (⁶⁸Ga) using the metal chelating agent 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) [10]. The resulting radiopharmaceutical, [⁶⁸Ga]Ga-Pentixafor, was successfully employed for the imaging of a wide range of hematological conditions (lymphomas, MM, chronic lymphocytic leukemias, and myeloproliferative tumors), as well as nonhematological malignancies, yielding promising results [11]. Complementing its use in imaging, Pentixather, labeled with the beta-emitters [¹⁷⁷Lu] or [⁹⁰Y], has been developed as a therapeutic agent. [¹⁷⁷Lu]Lu/[⁹⁰Y]Y-Pentixather demonstrated high-affinity binding with CXCR4-expressing tumors, exhibiting specificity and selectivity both in vitro and in vivo [12]. In addition to its anti-tumoral properties, Pentixather also demonstrated myeloablative effects by targeting the hematopoietic stem/progenitor cell (HSPC) compartment. This could benefit certain patients with hematopoietic neoplasms who require preparation for hematopoietic stem cell transplantation (HSCT) [13,14]. Despite these promising findings, the availability of clinical evidence regarding Pentixather RLT in hematological disorders remains limited, particularly in terms of large-scale clinical trials and long-term studies. In the present editorial, we summarize the primary applications of Pentixather RLT in oncohematology (Table 1). Additionally, we will address the necessary steps for its potential implementation in clinical practice.

Table 1. First clinical applications of Pentixather in multiple myeloma and lymphomas.

Author	Year/Country	Study	Tumor	n. of patients	Radionuclide per treatment	Safety	Results	Comment
Herrmann et al. [15]	2016/USA +Germany	First-in-human	MM	3	177Lu, (n = 2) 90Y. (n = 1)	No relevant adverse effects within 1 week	PR (n = 1) CR (n = 1) Deceased (n = 1), 177Lu	Pentixather RLT resulted effective and tolerable also in heavily pretreated patients
Lapa et al. [16]	2017/Germany	Pilot study	MM	8	177Lu, (n = 6) 90Y, (n = 4)	Sepsis, (n = 1) Tumor lysis syndrome. (n = 1)	PR (n = 5) CR (n = 1) Deceased (n = 2)	Pentixather showed anti-tumor effectiveness and tolerable toxicity
Maurer et al. [17]	2019/Germany	Retrospective study	MM, (n = 10) DLBCL, (n = 6) AL (n = 4) MCL (n = 1) TCL (n = 1)	22	177Lu, (n = 6) 90Y, (n 19)	Neutropenia and thrombocytopenia, (n = 20), Infections, (n = 9)	NA	Pentixather presented a tolerable toxicity profile
Lapa et al. [18]	2019/Germany	NA	NHL (n = 6)	6	90Y	Deceased for infectious complications in aplasia (n = 2)	PR (n = 2) mixed response (n = 2) Deceased (n = 2)	Apart from hematotoxicity, no further acute adverse events were recorded.
Dreher et al. [19]	2024/Germany	Retrospective study	AL (n = 4) NHL (n = 17)	21	90Y	GFR decrease grade ≥ 3 (n = 1), GOT elevation grade ≥ 3(n = 1)	NA	Pentixather exerts a direct anti-lymphoma activity and presents a tolerable toxicity profile
Buck et al. [20]	2023/Germany	Feasibility Study	T-cell lymphoma	4	90Y	Tumor lysis syndrome	CR (n = 2) and PR (n = 1)	Pentixather resulted as an effective conditioning regimen

AL: acute leukemia; DLBCL: diffuse large B cell lymphoma; GFR: glomerular filtration rate; GOT: glutamic oxaloacetic transaminase; MCL: mantle cell lymphoma; MM: multiple myeloma; NA: not available; NHL: Non-Hodgkin Lymphoma; TCL: T-cell prolymphocytic leukemia; 177Lu: lutetium-177; 90Y: yttrium-90; RLT: radioligand therapy.

2. Multiple myeloma

Herrmann and colleagues conducted a pilot study involving three heavily pre-treated, relapsed MM patients who underwent Pentixather RLT [15]. All participants had prior autologous stem cell transplantation (SCT) and active, extensive disease. Before therapy, [⁶⁸Ga]Ga-Pentixafor and [¹⁸F]F-Fluorodeoxyglucose (FDG) Positron Emission Tomography/Computed Tomography (PET/CT) was employed to identify FDG-avid lesions with low CXCR4 expression. Dosimetry with [¹⁷⁷Lu]Lu-Pentixather was performed to assess organ radiation doses, considering a threshold of 23 Gy for the kidneys, the limiting-dose organs. Patients 1 and 2 received 15.2 and 23.5 GBq of [¹⁷⁷Lu]Lu-Pentixather, respectively, while patient 3 received 6.3 GBq of [⁹⁰Y]Y-Pentixather. Nephrotoxicity mitigation included pre-treatment with arginine and lysine. Patient responses were evaluated using biochemical and [¹⁸F]FDG criteria. Patient 1 showed a partial response, patient 3 achieved a complete metabolic response, and patient 2 developed sepsis post-SCT. No acute adverse events occurred during or within 1 week after Pentixather administration. Patients 1 and 3 succumbed to MM progression at 6 and 3 months post-RLT, respectively, while patient 2 died from sepsis 3 weeks after therapy completion.

Lapa and colleagues investigated Pentixather RLT in therapy-refractory MM patients, enrolling eight patients, six of whom had extensive extramedullary disease [16]. Patient selection involved using the dual tracer [⁶⁸Ga]Ga-Pentixafor/[¹⁸F]FDG, adhering to the procedures outlined by Herrmann et al. [15]. Of the eight patients, seven received one cycle of RLT, while one patient underwent three cycles, in conjunction with chemotherapy and stem cell support. RLT involved the use of [¹⁷⁷Lu]Lu- (n = 6) or [⁹⁰Y]Y- (n = 4) Pentixather, with activities ranging from 7.6 to 23.5 GBq and 2.6–6.3 GBq, respectively. Tumor doses ranging from 30 to 70 Gy led to significant anti-myeloma activity, yielding one complete remission and five out of eight partial remissions. One sepsis-related fatality and a lethal tumor lysis syndrome occurred during the subsequent follow-up. The median overall survival was 223 days. However, it is important to note that in both the studies conducted by Herrmann’s and Lapa’s groups [15,16], RLT was administered alongside high-dose conventional chemotherapy followed by consecutive SCT. Consequently, it is challenging to isolate and evaluate the therapeutic efficacy of each treatment in the reported settings. Figure 1 provides an illustrative example of an MM patient treated with Pentixather.

Figure 1. An illustrative example of Pentixather RLT in a MM patient. (a) Baseline dual tracer [¹⁸F]FDG/[⁶⁸Ga]Ga-Pentixafor PET/CT showed multiple lesions, strongly CXCR4-positive. (b) [¹⁷⁷Lu]Lu-Pentixather planar images demonstrated tracer incorporation within skeletal lesions. (c) Follow-up [⁶⁸Ga]Ga-Pentixafor PET/CT depicted partial response to the RLT. Reprinted from Lapa et al. [16], under a Creative Commons Attribution 4.0 International License (http://creativecommons.Org/licenses/by/4.0/). No changes were made.

Evidence of the use of Pentixather in MM can also be obtained from the study by Maurer et al. [17], which primarily focused on the safety profile of Pentixather RLT during 25 treatments in 22 patients with lymphoproliferative disorders (DLBCL, MCL), leukemia, or MM. Patient selection and dosimetry align with previous protocols [15,16]. Two patients received repeated Pentixather doses due to extensive disease. Administered doses ranged 7.6–23.5 GBq for [¹⁷⁷Lu]Lu-Pentixather (6 therapies), and 2.4–8.4 GBq for [⁹⁰Y]Y-Pentixather (19 therapies). In specific instances, tailored to individual patients and the characteristics of their disease, the administration of a second radiopharmaceutical succeeded RLT: [¹⁸⁸Re]Re-CD66 (in 6 cases), [⁹⁰Y]Y-Ibritumomab Tiuxetan (in one case), and [¹⁵³Sa]Sa-Ethylenediamine (in one case). In these scenarios, adjustments to the Pentixather dosage were made based on the renal doses resulting from the supplementary radionuclide therapies. Issues with the hematopoietic system were common, including anemia, neutropenia, and thrombocytopenia. These were grade ≥3 in 80% of cases, irrespective of the radionuclides used. In 36% of cases, neutropenia led to infections of grade ≥3. Kidney failure and hepatotoxicity were rare. Notably, in certain cases, the supplementary administration of the second radiopharmaceutical may have influenced the emergence of the observed toxicities. Importantly, Pentixather RLT did not adversely impact subsequent hematopoietic stem cell engraftment.

3. Lymphomas

The research group from the studies above also assessed the feasibility of [⁹⁰Y]Y-Pentixather RLT as part of the conditioning regimen before allogeneic stem cell transplantation in a cohort of six patients with heavily pretreated relapsed DLBCL [18]. CXCR4-directed RLT led to a partial response in treating lymphoma in two cases (both treated with radioimmunotherapy targeting CD20 or CD66 to enhance anti-lymphoma activity) and a mixed response in two cases. By contrast, one patient died of central nervous system aspergillosis 29 days after RLT and another of sepsis in aplasia 34 days after RLT. However, it should be noted that transplantation-related mortality was within the reported ranges for allogeneic SCT, as stated by the same authors, and was not further increased by the addition of RLT. The occurrence of partial response in two out of six cases from the previously mentioned study [18], where CXCR4-directed RLT was combined with radioimmunotherapy, raised questions regarding the anti-lymphoma activity of [⁹⁰Y]Y-Pentixather RLT. However, Dreher et al. [19] enrolled 21 heavily pretreated NHL patients submitted to [⁹⁰Y]Y-Pentixather RLT to gain further insights. They found that serum lactate-dehydrogenase (LDH), a surrogate marker of lymphoma cell kill, peaked two days post-RLT and decreased afterward. This suggests that CXCR4-targeted RLT exhibits direct antilymphoma activity. In addition, the authors observed significant myeloablative effects, even before applying the conditioning regimen, consistent with data from previously cited papers on MM [15–17]. Grade 3 events, primarily associated with organ toxicity parameters such as liver and kidneys, were recorded in 8% of cases [19]. A comprehensive investigation into the potential of CXCR4-targeted RLT was conducted by Buck and colleagues involving four patients with advanced T-cell lymphoma (TCL), who underwent [⁹⁰Y]Y-Pentixather as a conditioning regimen before HSCT [20]. CXCR-4 expression in all patients was evaluated using [⁶⁸Ga]Ga-Pentixafor PET/CT, while pretreatment dosimetry was performed with [¹⁷⁷Lu]Lu-Pentixather. One patient received CD66-directed radioimmunotherapy following [⁹⁰Y]Y-Pentixather to augment therapeutic efficacy. Lymphoma-absorbed doses of up to 33.2 Gy were achieved with RLT, demonstrating minimal acute toxicity, except for one patient who developed tumor lysis syndrome. Follow-up assessments revealed two cases of complete response and one case of partial response, with a median progression-free survival of 7 months, affirming the potential of CXCR-4 RLT as a conditioning regimen in this clinical context.

4. Final considerations and conclusions

Upon reviewing the existing scientific data, some considerations regarding the role of Pentixather RLT in oncohematologic disorders emerge. Firstly, an essential step in patient selection involves evaluating CXCR4 expression via [⁶⁸Ga]Ga-Pentixafor PET/CT. In this regard, while it is not likely that [⁶⁸Ga]Ga-Pentixafor PET/CT might replace [¹⁸F]FDG for the staging and monitoring of lymphomas or MM, a complementary role of the two traces might be hypothesized in well-selected clinical settings [21]. Employing dual-tracer PET/CT with both [¹⁸F]FDG and [⁶⁸Ga]Ga-Pentixafor is beneficial in identifying metabolically active lesions lacking CXCR4 expression. In such cases, using long axial field-of-view (LAFOV) PET/CT scanners, known for their high sensitivity, could allow implementing low-dose protocols, thus reducing radiation exposure [22].

Secondly, choosing between [¹⁷⁷Lu] and [⁹⁰Y] labeling for Pentixather RLT remains unresolved. While both isotopes have been extensively studied, particularly in neuroendocrine and hepatic tumors [23,24], the former, with its lower energy emission and shorter range in the matter, might offer a safer toxicity profile for treating smaller lesions. On the other hand, the different half-lives of the two radionuclides (i.e. 2.7 days for [⁹⁰Y] and 6.647 days for [¹⁷⁷Lu], respectively) should be considered, as suggested by Maurer et al. [17], when deciding the most appropriate interval for additional conditioning and possibly SCT, to minimize the risk of infectious complications during the neutropenic phase. This issue should be the object of further investigation. Notably, Pentixather RLT’s complexity, often used alongside treatments like chemotherapy and radiotherapy, presents challenges in isolating its specific impact on hematological toxicity. While hematologic toxicity is a primary concern and requires careful consideration for treatment viability, Pentixather’s unique ability to act as a conditioning regimen before stem cell transplantation distinguishes it in the current theranostic landscape. Indeed, there are currently no available data on patients who have received SCT after RLT with Pentixather without undergoing conditioning chemotherapy regimens. One of the most challenging aspects in evaluating the role of CXCR4-targeted RLT lies in the need to disentangle the impact of RLT alone as a conditioning regimen before HSCT in patients with lymphoma and MM, especially in light of the complexity of algorithms adopted in various studies. In this regard, Dreher’s study identified a conditioning activity from RLT before administering chemotherapeutic conditioning regimens [19]. Following this line of inquiry, further investigations should be pursued, including those concerning the sequential use of RLT and radioimmunotherapy in this specific clinical setting.

Thirdly, further exploration is needed to integrate Pentixather into MM and lymphoma treatment regimens, especially those documented in heavily pre-treated patients under compassionate use. Lastly, most of the scientific evidence for this approach comes from a single research group, highlighting the need for validation through multicenter studies. In this regard, it is noteworthy that there is a burgeoning interest in scientific inquiries into CXCR4-targeted RLT across various hematologic contexts, focusing on advancing ligand radiochemistry and exploring the potential of alpha particles. On one front, an active clinical trial (NCT06132737) is investigating the potential efficacy of [⁹⁰Y]Y-Pentixather in managing patients with lymphomatous central nervous system involvement. Concurrently, another clinical trial aims to evaluate [⁶⁸Ga]Ga-Pentixather as an alternative to [⁶⁸Ga]Ga-Pentifaxor, aligning [⁶⁸Ga]Ga-Pentixather with [¹⁷⁷Lu/⁹⁰Y]-Pentixather in MM theranostics. Additionally, the ongoing study NCT05557708 is poised to yield significant insights into the potential of CXCR4-targeting utilizing alpha particles, renowned for their high linear energy transfer and limited range in biological matter.

In conclusion, Pentixather RLT emerges as a promising option for treating hematological malignancies, but its full potential and scope are not yet fully understood. The current limited evidence emphasizes the need for more comprehensive research. Prospective, well-designed clinical trials are essential to accurately define this theranostic approach’s role in clinical practice.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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Funding

The paper was not funded.