Keywords CXCR4 - chemokine receptor - theranostics - marginal zone lymphoma - T-cell lymphoma
- [68Ga]Ga-PentixaFor
Introduction
Theranostics combines molecular imaging and therapy through applying identical or
related radiolabelled molecules to specifically detect and damage cancerous tissues
[1 ]. While such radiopharmaceuticals are now routinely applied for solid tumours [2 ]
[3 ], recent years have witnessed an increasing use for hematopoietic malignancies, in
particular by targeting C-X-C motif chemokine receptor 4 (CXCR4) [4 ]. In the course of the annual meeting of the German Society for Haematology and Medical
Oncology held in October 2022, experts met to discuss recent developments in the field
of CXCR4-based theranostics and to devise some basic statements on potential clinical
applications and future perspectives of this concept.
In this manuscript, we present these statements in detail, along with a brief overview
on CXCR4-directed molecular imaging and therapy.
Expert panel statement I: CXCR4-directed molecular imaging may be useful for marginal
zone lymphoma patients
CXCR4-directed Molecular Imaging
CXCR4 upregulation in varying tumour entities render it as an attractive target to
identify cancerous tissue [5 ], which can be exploited using CXCR4-directed radiotracers, including the cyclic
68 Ga-labelled CXCR4-binding pentapeptide CPCR4.2 ([68 Ga]Ga-PentixaFor) [6 ]. Relative to the most widely used PET radiotracer 2-deoxy-2-[18 F]fuoro-D-glucose ([18 F]FDG), [68 Ga]Ga-PentixaFor often achieved equal, sometimes superior or at least complementary
diagnostic performance in nuclear oncology [7 ]
[8 ]
[9 ]
[10 ]. Accordingly, [68 Ga]Ga-PentixaFor has been extensively tested to identify sites of disease in patients
with solid tumours and haematological malignancies, providing promising results for
marginal zone (MZL, [Fig. 1 ]) and T-cell lymphoma (TCL) [9 ]
[11 ]. Beyond an improved read-out relative to the reference radiotracer [18 F]FDG, however, [68 Ga]Ga-PentixaFor also allows for quantification of CXCR4 expression in lymphoma manifestations
in vivo, thereby identifying patients that could therefore be eligible for CXCR4-directed
radioligand therapy (RLT) using the theranostic, β-emitting twin [177 Lu]Lu- or [90 Y]Y-PentixaTher [12 ].
Fig. 1 Maximum intensity projections of PET/CTs using [18F]FDG (leftmost panels) and [68Ga]Ga-PentixaFor
(rightmost panels) in a subject with orbital marginal zone lymphoma. The middle panels
show PET/CT images of axial sections of lymphoma manifestation using [18F]FDG (bottom)
and [68Ga]Ga-PentixaFor (top). On [18F]FDG, MZL manifestation is not visible due to
the physiological high uptake of the PET probe in brain tissue, whereas the [68Ga]Ga-PentixaFor-based
images enables detection of the manifestation in the periorbital area. Data from same
patient but different images as in Buck et al, J Nucl Med 2023 Jul;64(7):1009–1016
[4 ].
CXCR4-directed PET/CT for Marginal Zone Lymphoma
The most comprehensive approach investigating the use of [68 Ga]Ga-PentixaFor for imaging of solid and haematological neoplasms was conducted in
a multi-centric retrospective analysis from Vienna and Würzburg Universities [10 ]. [68 Ga]Ga-PentixaFor PET/CTs were conducted in 690 patients and almost 70% showed radiotracer
accumulation in sites of disease which were substantially higher than physiological
background activity. In this regard, the highest uptake was observed for multiple
myeloma (MM), mantle cell lymphoma (MCL) and MZL [10 ]. Duell et al. then imaged 22 newly diagnosed MZL patients with chemokine receptor
PET/CT and compared those findings with conventional, guideline-compatible diagnostic
work-up (including [18 F]FDG PET/CT, bone marrow biopsy, and endoscopy) [9 ]
[13 ]. In 16 of 18 PET-guided biopsy samples, imaging results could be confirmed upon
CXCR4 immunohistochemistry. [68 Ga]Ga-PentixaFor PET/CT had a significant impact on staging according to modified
Ann Arbor classification in nearly 50% (mostly upstaging) and, importantly, on treatment
decision in one third of the patients [9 ]. A more comprehensive investigation involving 100 MZL patients recently reported
comparable results [14 ]. [68 Ga]Ga-PentixaFor uptake was observed in 78% of the patients, and again, in almost
half of the subjects, this led to an upstaging using Ann Arbor classification. In
addition, an elevated CXCR4-PET signal showed a trend towards shorter progression-free
survival, suggesting that [68 Ga]Ga-PentixaFor may also represent a prognostic biomarker with regard to disease
progression and need for improved/intensified treatment [14 ].
As a sub-form of MZL, mucosa-associated lymphoid tissue (MALT) lymphomas are diagnostically
challenging as they often lack specific symptoms and are associated with multi-organ
involvement [15 ], but also known to overexpress CXCR4 [16 ]. Haug and colleagues examined MALT lymphoma patients with a wide range of organs
affected using [68 Ga]Ga-PentixaFor PET/magnetic resonance imaging (MRI) and found an intense uptake
in 33/36 patients, while three negative cases having undergone surgery for their orbital
MALT lymphomas prior to imaging [17 ]. Another prospective study used [68 Ga]Ga-PentixaFor PET/MRI to evaluate treatment responses after first-line Helicobacter pylori eradication in 26 gastric MALT lymphoma patients and compared CXCR4-based imaging
findings with a control group of 20 subjects without lymphoma [18 ]. [68 Ga]Ga-PentixaFor PET/MRI yielded a 100% detection rate, as confirmed in time-matched
gastric biopsies. Furthermore, neither false-positive nor false-negative results were
obtained, and overall, between 93% and 100% accuracy, sensitivity, specificity, positive
and negative predictive values for the detection of residual gastric disease were
determined.
At present, diagnostics of MZL and MALT lymphoma are rather complex due to the heterogeneity
of the disease and often cumbersome for the patients when multiple biopsies and possibly
endoscopies are required [13 ]. This, together with the provided benefit of CXCR4-targeted PET/CT as summarized
above, led the experts to suggest that [68 Ga]PentixaFor PET might serve as a valuable diagnostic tool for MZL including MALT
lymphoma, and should be further developed in prospective clinical trials.
Expert panel statement II: CXCR4-based theranostics may be useful in advanced, treatment-refractory
T-cell lymphoma
CXCR4-directed Radioligand Therapy
After having identified CXCR4 expression using [68 Ga]Ga-PentixaFor PET, the positron emitter can be exchanged with an α- or β-emitting
radionuclide that exerts direct cell damaging effects, e.g., [177 Lu]Lu-/[90 Y]Y-PentixaTher [19 ]. Of note, this theranostic counterpart exhibits not only anti-lymphoma, but also
myeloablative effects due to targeting the hematopoietic stem/progenitor/cell (HSPC)
compartment, which may be desired for selected patients affected with hematopoietic
neoplasms to prepare for hematopoietic stem cell transplantation (HSCT) [12 ]. As a biological rationale, expression of CXCR4 is not only pronounced in lymphoma
sites, but also in cells of the bone marrow [20 ]. Thus, CXCR4-mediated RLT then also allows targeting of the HSPC niche beyond targeting
manifestations of the underlying CXCR4-positive disease [12 ].
CXCR4-directed treatment for T-Cell Lymphoma
In peripheral TCL, a wide range of first-line treatment regimens exists, which are
frequently not able to provide long-term disease control or cure. Targeted and more
effective therapeutic regimens are available for patients with CD30 expressing TCLs
[21 ]. However, CD30 is expressed only in approximately half of the patients [22 ]. In selected patients, which are refractory to standard therapeutic regimen (chemotherapy
± CD30 antibody ± high-dose therapy and autologous HSCT), allogeneic HSCT involving
cytotoxic bone marrow ablation (myeloablation) may be indicated [23 ]. In this regard, CXCR4-directed RLT using [90 Y]Y-PentixaTher may also provide relevant myeloablative efficacy [11 ]. For instance, in four TCL patients with advanced disease having exhausted all previous
treatment options, a retrospective examination with CXCR4-PET/CT was followed by CXCR4-targeted
RLT combined with conditioning regimen and HSCT. One of these patients developed tumour
lysis syndrome and transient grade 3 kidney failure, while one patient died more than
two weeks after RLT after developing septicaemia. Partial metabolic response was observed
in one and complete metabolic response in the two other patients (with one subject
also treated with additional radioimmunotherapy; [Fig. 2 ]) [11 ]. As such, CXCR4-mediated RLT may serve as an effective conditioning therapy for
HSCT with concurrent anti-lymphoma activity in treatment-refractory TCL in advanced
disease setting.
Fig. 2 Complete metabolic response after CXCR4-directed radioligand therapy (RLT) in a patient
affected with advanced, treatment-refractory T-cell lymphoma. After RLT, conditioning
therapy and allogeneic haematopoietic stem cell transplantation were conducted, leading
to successful engraftment. (A ) Maximum intensity projections of CXCR4-targeted [68Ga]PentixaFor PET/CTs before
(leftmost panel) and 4 months after (rightmost panel) RLT with [90Y]PentixaTher. Prior
to therapy, multiple CXCR4-positive foci on transaxial PET/CTs were visible, including
lymphonodal, peritoneal and bone manifestations (middle panels, left), whereas imaging
four months after RLT showed a complete response (middle panels, right). (B ) Time course of lactate dehydrogenase (LDH, in U/l) serving as a surrogate marker
of induced lymphoma damage. An initial peak of LDH was followed by a rapid decrease,
indicating an immediate response to CXCR4-directed RLT independent of conditioning
therapy. Data from same patient but different images as in Buck et al, J Nucl Med,
2023 Jan;64(1):34–39 [11 ].
Expert panel statement III: Prospective trials are required to provide additional
data and guidelines on CXCR4-directed imaging and therapy in malignancies of the hematopoietic
origin
Considering the wide range of highly promising but often preliminary or only retrospectively
assessed data, the experts concluded that there is a need for prospective studies
investigating the use of CXCR4-directed radiopharmaceuticals for both imaging and
therapy. At present, prospective trials for CXCR4-directed RLT are in preparation,
aimed at investigating the activity, tolerable dose and side effects of [90 Y]Y-PentixaTher in patients with recurrent or refractory primary or isolated secondary
central nervous system lymphoma, (PTT101, EudraCT No. 2021–002364–43), multiple myeloma
(MM) and other lymphoma subtpes (COLPRIT trial, EudraCT No. 2022–002989–33) [24 ]
[25 ]. Another registered study investigates [68 Ga]Ga-PentixaFor PET/CT for initial staging and therapeutic monitoring for MM (NCT04561492)
[26 ]. In addition, a basket trial enrolling approximately 20 patients will also broaden
the diagnostic experience on [68 Ga]Ga-PentixaFor in patients with varying hematopoietic (pre)neoplasms, including
monoclonal gammopathy of undetermined significance, smoldering MM and Non-Hodgkin
lymphoma (NCT05093335) [27 ]. Moreover, a phase III study in MZL patients will compare [68 Ga]Ga-PentixaFor with [18 F]FDG PET/CT in 148 patients examined in 28 participating European centres [28 ]. [Table 1 ] provides an overview of planned and currently recruiting studies on CXCR4-directed
imaging and therapy in patients affected with malignancies of the hematopoietic system.
Table 1 Overview of selected prospective clinical trials on CXCR4-directed Theranostics focusing
on Haematological Malignancies.
Purpose
Study Abbreviation*
Registration No.
Brief Description
Status
*if available.
Diagnosis
PentiMyelo
NCT04561492
Phase I/II study using [68 Ga]Ga-PentixaFor PET/CT for staging and therapeutic monitoring of multiple myeloma
(MM) patients scheduled for first line treatment [26 ]
Recruiting
NCT05093335
Phase I/II study using [68 Ga]Ga-PentixaFor PET/CT in treatment-naïve, therapy-refractory or relapsed patients
with proven monoclonal gammopathy of undetermined significance, smoldering MM, or
Non-Hodgkin lymphoma [27 ]
Recruiting
PTF301 (LYMFOR)
EU CT No 2022–500918–25
Phase III study using [68 Ga]Ga-PentixaFor PET/CT relative to [18 F]FDG PET/CT for staging of patients with marginal zone lymphoma [28 ]
Planned
PENTI-MIDAS
NCT05321862
Phase I/II study using [68 Ga]Ga-PentixaFor for staging and assessment of minimal residual disease in MM patients
eligible for hematopoietic stem cell transplantation [29]
Not yet Recruiting
Therapy
COLPRIT
EudraCT No. 2022–002989–33
Phase I/II study evaluating CXCR4-directed radioligand therapy (RLT) in advanced lymphoproliferative
disease [24 ]
Planned
PENTILULA
Phase I/II study evaluating RLT with [177 Lu]Lu-PentixaTher in patients with relapsed or refractory CXCR4+ acute leukemia
Planned
PENTALLO
Phase I study testing RLT with [177 Lu]Lu-PentixaTher prior to allograft transplantation in acute myeloid leukemia/acute
lymphocytic leukemia patients
Planned
PTT101
EudraCT No. 2021–002364–43
Phase I/II dose escalation study to evaluate safety, tolerability, biodistribution
and efficacy of [90 Y]Y-PentixaTher for recurrent or refractory primary or isolated secondary central
nervous system lymphoma [25 ]
Planned
As agreed by the expert panel, these studies and others yet to be conceived should
ultimately allow for assessing the most appropriate applications of the theranostic
concept.
Conclusions
CXCR4-directed theranostics using the PET agent [68 Ga]Ga-PentixaFor and its therapeutic twin [177 Lu]Lu-/[90 Y]Y-PentixaTher has been extensively investigated in recent years. Based on these
results, its diagnostic use appears to be promising in patients with MZL including
MALT lymphoma. For therapeutic applications, anti-lymphoma efficacy exerted by CXCR4
RLT may be useful in advanced and treatment-refractory TCL. Nonetheless, data from
prospective studies are required to allow for incorporation of this theranostic strategy
into clinical practice.
