Littérature scientifique sur le sujet « 18F-Fludarabine »

Abstract Introduction: [18 F]-Fludarabine is a promising novel positron emission tomography (PET) radiotracer for lymphoid malignancies. The rationale for its development is the high selectivity of fludarabine uptake within lymphoid cells, irrespective of their cycle activity, and the fluorine atom within the molecule, which is replaced by [18 F] and leads to a positron emitting biomarker. Pre-clinical studies (Dhilly et al, Mol Imaging Biol 2014,16:118-26 ; Hovhannisyan et al, EJNMMI Res 2015,5:23) showed a marked tumor uptake in lymphoma-bearing mice. The aim of this study was to describe anatomical sites with abnormal [18F]-fludarabine uptake in DLBCL patients. This study was designed as a clinical proof of concept. Methods: [18F]-Fludarabine was produced according to a method already described (Guillouet et al, Mol Imaging Biol 2014,16:28-35). [18F]-Fludarabine PET/CT (Discovery RX VCT 64, GE Healthcare) was performed in 5 histologically confirmed and treatment naïve DLBCL patients (65 ± 8 years old). Successive partial body PET scans (skull vertex to mid-thigh) were acquired for 250 min after intravenous injection of [18F]-fludarabine with an activity of 4MBq/kg. PET images were analyzed drawing VOIs over the uptake sites on a late scan and projected onto all co-registered scans of the same subject. The intensity of tracer uptake was evaluated with standardized uptake value (SUVmax). The performance of [18F]fludarabine PET/CT was visually compared with conventional assessments (high-resolution CT) and [18F]-FDG PET. Results: CT and [18F]-FDG PET staging of the 5 patients was I to IV. No adverse event was recorded during and after the procedure. In all 5 patients, the uptake of [18F]-fludarabine coincides with sites expected to be involved following conventional staging. SUVmax were significantly higher in involved sites in comparison with non-lymphoma sites (Figure 1). As previously demonstrated in an animal model, we found no uptake in the cardiac muscle and brain in contrast to [18F]-FDG PET. Bone marrow was histologically normal in the 5 patients and [18F]-fludarabine PET displayed no hypermetabolism. A progressive splenic uptake (x4 to x8 at 250 min) was observed in every patient. The possibility of an unexpected splenic infiltration appears to be a better explanation than uptake by physiologically normal lymphoid tissue. Comparison of [18F]-FDG and [18F]-fludarabine PET showed discrepancies in 2 patients. The first had bilateral hilar [18F]-FDG uptakes (Figure 1C), not present in [18F]-fludarabine PET, which persisted on [18F]-FDG PET after completion of the treatment and disappearance of all suspected pathological sites. This pattern suggests a non-specific [18F]-FDG hypermetabolism. The second patient had a right testis positive [18F]-FDG PET, not evident with [18F]-fludarabine PET. Histology of the testis confirmed the presence of NHL. The interpretation of this would require further extensive data. Conclusion: [18F]-Fludarabine PET/CT appears to be a promising tool to diagnose discordance and follow-up NHL. These preliminary results showed a clear specificity of this novel radiotracer for lymphoma tissues and support the development of this innovative biomarker for lymphoproliferative diseases. Studies for a more detailed comparison with [18F]-FDG PET are in progress. Figure 2. Figure 2. Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 2674 Aim FDG positron emission tomography (PET) is the mainstay of response evaluation in some lymphoma subgroups such as DLBCL or HL according to Cheson criteria 2007. Due to its indolent behaviour, PET restaging has been poorly explored in Follicular Lymphoma (FL) Methods: The analysis was retrospectively conducted in pts with FL who underwent whole-body 18F-FDG-PET as part of response evaluation at the end of first line or savage treatment program at our institution from August 2001 to June 2010. Results: Seventy five patients were identified. Main clinical characteristics: median age 58 (range 26– 78); male 37 pts; B symptoms 6 pts; bulky disease 5 pts; stage IV 42 pts; bone marrow involvement 32 pts. Fifty-five pts were evaluated after first line treatment program, while 20 pts after salvage therapy program. Main chemotherapy regimen: CHOP or CHOP-like 38, CVP 11, polichemotherapy containing high-dose cytosine-arabinoside 11, fludarabine containing regimens 4. Furthermore, 19 pts underwent autologous peripheral stem-cell transplantation after either first line or salvage therapy. Eleven pts also received consolidation radiotherapy. Forty-two pts received Rituximab during chemotherapy. At the end of treatment, 54 pts reached complete remission as confirmed by PET. With a median follow-up of 53 months, a significantly lower actuarial 4yr PFS was observed in post-treatment PET+ versus. PET- patients: 35.1% vs. 74.8% (log rank p<0.01). Among all other prognostic factors analyzed (B-symptoms, bulky disease, chemotherapy regimens, chemotherapy vs chemoimmunotherapy, first line therapy vs salvage chemotherapy), only stage IV showed a correlation with PFS. In a multivariate Cox model including all patients, post-treatment PET+ (HR 2.20; C.I. 95%: 1.02–4.76 p<0.04) and Stage IV (HR 3.08; C.I. 95%: 1.23–7.73 p<0.01) were unfavorable predictors for PFS. Conclusion: This retrospective study demonstrates that post-treatment negative PET is a powerful predictor for PFS. Patients who are PET- can expect a prolonged PFS either in first line or successive lines of treatment. Future clinical trials are needed to evaluate a PET oriented approach focused on improving outcomes according to PET response. Disclosures: No relevant conflicts of interest to declare.

Abstract 18F-FDG PET (PET) imaging is now widely used in the management of patients with lymphoma, and has a recognised role in disease staging at diagnosis, determining response to treatment, and predicting response to autologous stem-cell transplantation (SCT). Reduced-intensity allogeneic SCT (RIT) has become an established therapy for patients with refractory or relapsed lymphoid malignancies, but the role of PET in RIT is unknown. We performed a prospective study to assess the role of PET in predicting outcome in RIT, and in directing intervention post-transplant. Sixty four patients with lymphoma were recruited from a single academic transplant centre. Transplant conditioning comprised fludarabine, melphalan and in-vivo alemtuzumab, and cyclosporine was given from day –1 to 3 months after RIT. PET and CT scans were performed pre-RIT and at 3, 6, 9, 15, 24 and 36-months post-RIT. In patients with chemotherapy-sensitive disease as assessed by CT scan, pre-transplant PET appearances did not influence the decision to proceed to transplant. Patients who progressed or relapsed (using clinical, CT or PET results), or who had mixed hematopoietic chimerism, received escalating dose donor lymphocyte infusions (DLI) in the absence of graft-versus-host disease. All 64 patients were at least 15 months (range 18–73 months) post RIT (25 follicular lymphoma, 16 Hodgkin lymphoma, 9 high-grade lymphoma, 9 mantle cell lymphoma, 5 other lymphomas), of whom 38 were PET-positive pre-transplant. With a median follow-up of 41 months, the pre-transplant PET status, (negative vs positive) had no effect on overall survival (65% vs 68%), diseasefree survival (32% vs 34%), relapse rate (56% vs 57%), and current DFS (55% vs 60%). Thirty four episodes of progression and relapse were observed in 29 patients: of these 15 (44%) were first detected by abnormal PET appearances in the presence of a normal or stable CT. No relapses were first apparent on CT and not on PET. DLI (either alone or in combination with chemotherapy or monoclonal antibody) were administered in 25 episodes of progression and relapse, and were directed by PET alone in 11 (44%). In 19 of the 25 episodes CR was achieved within 6 months of treatment. Additionally, 11 patients had PET negative residual masses on CT post-transplant. These patients were not given DLI and only 2 subsequently relapsed at the sites which were anatomically abnormal on the CT scan. Pre-transplant PET status did not influence survival or disease-free survival following allogeneic RIT. However post-transplant, PET detected progressive/recurrent lymphoma before the development of new abnormalities on CT, and thereby allowed earlier administration of immunotherapy, in 44% of episodes. The majority of patients with non-18F-FDG-avid residual abnormalities on CT post-transplant remained in durable remission, without receiving any treatment. Overall, PET changed the management in 18 out of 64 patients (28%). These findings would suggest that in contrast to autologous SCT, allogeneic transplantation using reduced intensity conditioning ± DLI may result in good outcomes for patients with chemotherapy-sensitive lymphoma, regardless of pretransplant PET appearances. Post-transplant surveillance by PET is useful for directing earlier use of immunotherapy for progressive/recurrent disease, and PET can also be used to characterise post-transplant metabolically inactive CT masses and allow appropriate withholding of DLI.

Bien que l’utilité de la TEP au [18F]FDG soit confirmée pour le diagnostic et le suivi thérapeutique chez les patients atteints de lymphome, la spécificité de la captation du [18F]FDG a été mise en doute en raison de sa dépendance au métabolisme du glucose, qui peut augmenter dans des conditions bégnines comme les processus inflammatoire ou infectieux. Compte tenu de ces limites, un nucléoside a été développé en tant que nouvel outil pour l'imagerie TEP ([18F]fludarabine). Une radiosynthèse entièrement automatisée a été mise en place et des études précliniques ont été menées sur des modèles murins de xénogreffes (lignées cellulaires folliculaires: RL7 et DOHH-2, myélome multiple (MM) : RPMI8226, lymphome du système nerveux central (LSNC) : MC116), parallèlement au [18F]FDG. Le profil de distribution de la radioactivité de la [18F]fludarabine dans des organes sélectionnés a confirmé le ciblage spécifique de la tumeur. Dans un modèle de lymphome folliculaire, nous avons évalué sa fiabilité pendant le traitement par rituximab et démontré - pas d’interférence entre le traitement et sa captation - une plus forte corrélation entre la fixation de ce radiopharmaceutique et les valeurs quantitatives extraites de l'histologie, comparée au [18F]FDG-TEP. En conséquence, cet outil TEP peut être considéré comme une approche prometteuse pour détecter la maladie résiduelle persistante pendant ou après un traitement par chimiothérapie. En outre, l’évaluation de la [18F]fludarabine lors d’un processus inflammatoire induit par la térébenthine a montré une accumulation significativement plus faible dans le tissu inflammé par comparaison à celle observée avec le [18F]FDG. Dans le MM, le rôle de la [18F]FDG-TEP reste limité en raison de son manque de sensibilité pour détecter une atteinte diffuse de la moelle osseuse et de petites lésions crâniennes dues à la fixation physiologique du [18F]FDG dans le cerveau. Nos données suggèrent que la TEP à la [18F]fludarabine pourrait représenter une modalité alternative et peut-être plus spécifique pour l'imagerie de MM. Dans notre dernière étude, sur les tumeurs cérébrales de xénogreffes, ce nouvel outil TEP a révélé des réponses significativement divergentes entre le LSNC et le glioblastome (GBM), tandis que le [18F]FDG a montré un chevauchement de fixation entre ces deux modèles. Une première étude chez l'homme a été entreprise pour un diagnostic initial, où 10 patients non traités ont été recrutés avec une leucémie lymphoïde chronique à cellules B (LLC) ou un lymphome B diffus à grandes cellules (LBDGC). Les scanners partiels successifs ont été acquis pendant 250 mn après l’injection i.v d’une activité de 4MBq/kg. Les résultats avec les modalités conventionnelles (TDM et/ou [18F]FDG-TEP) ont également été considérés. L'étude a également été conçue pour estimer la dosimétrie pour les principaux organes. Chez les patients atteints d’un LBDGC, une augmentation de la captation a été observée dans les sites considérés anormaux par TDM et [18F]FDG ; chez deux patients, des résultats contradictoires ont été observés avec ces deux radiopharmaceutiques. Chez les patients LLC, la fixation de la [18F]fludarabine a coïncidé avec les sites susceptibles d'être impliqués et a montré une captation significative dans la moelle osseuse hématopoïétique. Aucune fixation n'a été observée, quel que soit le groupe de maladies, dans le muscle cardiaque et le cerveau. De plus, la dose efficace moyenne a été révélée inférieure à la dose efficace rapportée pour le [18F]FDG. En conclusion, ces résultats précliniques et cliniques ont révélé une grande spécificité de ce radiopharmaceutique pour les tissus lymphoprolifératifs. De plus, cela pourrait être un outil robuste pour quantifier plus précisément la maladie, même avec des processus inflammatoires, évitant ainsi les résultats faussement positifs, et une approche innovante pour l'imagerie des maladies lymphoprolifératives caractérisées par une faible activité mitotique
Although PET using [18F]FDG has proved to be useful for diagnosis and therapy monitoring in patients with lymphoma, the specificity of [18F]FDG uptake has been critically questioned because of its dependence on glucose metabolism, which may indiscriminately increase in benign conditions such as inflammatory or infectious processes. Considering these drawbacks, an adenine nucleoside analogue was developed as a novel PET imaging probe ([18F]fludarabine). An efficient and fully automated radiosynthesis has been implemented and, subsequently preclinical studies in xenograft murine models (follicular cell lines: RL7 and DOHH-2, multiple myeloma (MM): RPMI8226, central nervous system (CNS) lymphoma: MC116) were conducted with this novel 18F-radiopharmaceutical in parallel with [18F]FDG. The pattern of the radioactivity distribution in selected organs confirmed the tumor-specific targeting. In a follicular lymphoma model, we evaluated its robustness during rituximab therapy and demonstrated - the treatment did not interfere with its uptake - a stronger correlation between quantitative values extracted from this 18F-radiopharmaceutical and histology when compared to [18F]FDG-PET. Accordingly, this PET tool may be considered as a promising approach for detecting the persistence of residual disease during or after rituximab-like treatment. Furthermore, its behaviour in turpentine-induced inflammatory process showed significantly weaker uptake in inflammation when compared to [18F]FDG. In MM, the role of [18F]FDG-PET remains limited because of its lack of sensitivity for detecting diffuse bone marrow involvement, small skull lesions due to the physiological [18F]FDG uptake in brain. Our data suggested that [18F]fludarabine-PET might represent an alternative and perhaps more specific modality for MM imaging. In our latest study, on xenograft brain tumors, this novel PET probe revealed significantly divergent responses between CNS lymphoma and glioblastoma (GBM), while [18F]FDG demonstrated overlap between the groups. A first in man study, was undertaken, for an initial diagnosis, where 10 untreated patients were enrolled with either B-cell chronic lymphocytic leukemia (CLL) or diffuse large B-cell lymphoma (DLBCL). Successive partial body scans were acquired for 250 min after i.v. injection with an activity of 4 MBq/kg. The results with conventional modalities (CT and/or [18F]FDG-PET) have also been investigated. The study was also designed to estimate its radiation dose for major organs. In DLBCL patients, increased uptake was observed in sites considered abnormal by CT and [18F]FDG; in two patients discrepancies were observed in comparison with [18F]FDG. In CLL patients, the uptake coincided with sites expected to be involved and displayed a significant uptake in hematopoietic bone marrow. No uptake was observed, whatever the disease group, in the cardiac muscle and brain. Moreover, its mean effective dose was below the effective dose reported for [18F]FDG. In conclusion, these preclinical and clinical findings revealed a great specificity of this 18F-radiopharmaeutical for lymphoma tissues. Furthermore, it might well be a robust tool for correctly quantifying the disease, even with inflammatory processes, thus avoiding the false-positive results, and an innovative approach for imaging lymphoid neoplasms with low mitotic activity

Le lymphome primitif du système nerveux central (LPSNC) est une pathologie au pronostic sombre, dont l'incidence est en hausse, notamment chez les patients âgés et immunocompétents. La démarche thérapeutique pour les patients atteints de LPSNC s'appuie sur l'évaluation de deux indicateurs pronostiques établis : l'âge et le performans status. Néanmoins, la nécessité d'améliorer les stratégies thérapeutiques actuelles, centrées sur une poly-chimiothérapie d'induction à base de méthotrexate à haute dose suivie potentiellement par un traitement d'entretien, a suscité un intérêt croissant dans l'identification de nouveaux biomarqueurs. Cette thèse se positionne dans ce contexte de recherche et d'innovation dans les LPSNC, promue par le réseau LOC (lymphome oculo-cérébral) en France, et visant à améliorer la stratification pronostique et le suivi thérapeutique chez ces patients.L'imagerie par résonance magnétique (IRM) cérébrale constitue aujourd'hui le gold standard dans le suivi des LPSNC. Cependant, plusieurs études récentes ont mis en évidence ses limites, en particulier devant le pourcentage élevé de patients récidivants rapidement malgré une réponse jugée complète sur l'évaluation de fin de traitement. Notre recherche explore le potentiel de la tomographie par émission de positon (TEP) au 18F-Fluorodeoxyglucose (FDG) combinée à l'IRM comme outil innovant dans la prise en charge des patients atteints de LPSNC. Cette recherche s'est articulée autour de trois axes principaux: d'une part la recherche de biomarqueurs TEP-IRM pronostiques de la réponse de fin de traitement d'induction, d'autre part l'évaluation de cette technique comme outil d'évaluation précoce de la réponse sous chimiothérapie et enfin l'exploitation de méthode d'intelligence artificielle pour affiner la compréhension physiopathologique via des analyses radiomiques poussées, et élaborer un modèle prédictif en deep-learning, généralisable à large échelle. Ce travail s'appuie sur les données prospectives longitudinales de la cohorte Localyse, une étude ancillaire de l'essai multicentrique de phase III BLOCAGE-01, qui étudie l'intérêt d'une chimiothérapie de maintenance chez les patients âgés, immunocompétents, atteints de LPSNC. Les résultats de ce travail doctoral ont permis l'identification de deux nouveaux biomarqueurs pronostiques en TEP FDG dans les LPSNC et ont démontré la supériorité potentielle de la TEP interim pour évaluer la réponse thérapeutique après deux cycles de chimiothérapie en comparaison avec l'IRM interim. Intégrant les avancées les plus récentes en matière d'analyse radiomique et d'apprentissage profond, cette thèse s'inscrit dans le développement d'outil robuste et novateur en IA appliquée à la neuro-oncologie. Enfin, elle examine le potentiel de la 18F-Fludarabine, un radiotraceur ciblant spécifiquement les lymphocytes B, qui pourrait offrir de nouvelles perspectives dans la prise en charge des patients atteints de LPSNC dans le futur. En conclusion, nos travaux contribuent au développement de nouveaux outils facilitant la gestion des patients atteints de LPSNC et ouvrent la voie au développement de stratégies thérapeutiques guidées par la TEP
Primary central nervous system lymphoma (PCNSL) is a malignancy with a dismal prognosis, increasingly prevalent, especially among elderly and immunocompetent patients. The therapeutic approach for PCNSL relies on evaluating established prognostic indicators: patient age and performance status. However, there is a growing need to enhance current therapeutic strategies, which are centered on high-dose methotrexate-based induction polychemotherapy, potentially followed by maintenance treatment. This has encouraged interest in identifying new biomarkers. This thesis positions itself within this research and innovation framework in PCNSL, supported by the LOC network (Lymphome Oculo-Cerebraux) in France, aiming to improve prognostic stratification and therapeutic monitoring for these patients. Currently, cerebral magnetic resonance imaging (MRI) is the gold standard for PCNSL follow-up. However, recent studies have highlighted its limitations, notably the high percentage of patients relapsing rapidly despite a complete response on end-of-treatment evaluation. Our research investigates the potential of positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) combined with MRI as an innovative tool in the management of PCNSL patients. The study is structured around three main axes: firstly, exploring PET-MRI FDG as a prognostic biomarker for end-of-induction treatment response; secondly, its utility as a tool for early evaluation of the chemotherapy response; and finally, exploiting artificial intelligence methods to refine the pathophysiological understanding through advanced radiomic analyses, and to develop a predictive deep-learning model scalable for broad application. This work relied on the the longitudinal prospective data from the Localyse cohort, an ancillary study of the phase III multicentric BLOCAGE-01 trial, investigating the utility of maintenance chemotherapy in aged, immunocompetent patients. The results of this doctoral research identified two novel prognostic biomarkers in FDG-PET for PCNSL and demonstrated the potential superiority of interim PET over interim MRI in assessing the therapeutic response post two chemotherapy cycles. Incorporating the latest advances in radiomic analysis and deep learning, this thesis contributes to the development of robust and innovative tools in AI applied to neuro-oncology. Lastly, it examines the potential of 18F-Fludarabine, a radiotracer specifically targeting B lymphocytes, which could offer new perspectives in the future management of PCNSL patients. In conclusion, our work facilitates the development of new tools for managing PCNSL patients, paving the way for treatment strategies guided by PET findings

Dans le but de développer un traceur spécifique des lymphomes non-Hodgkiniens pour l’imagerie TEP, nous nous sommes intéressés à la radiosynthèse de la Fludarabine, médicament destiné au traitement des maladies lymphoprolitératives. Nous avons mis au point le marquage au fluor-18 et réalisé son automatisation sur un appareil commercial. L’évaluation in vivo à partir d’études précliniques a montré que la [18F]Fludarabine présentait un meilleur contraste que le [18F]FDG et pourrait être utilisée pour le diagnostic et le suivi des lymphomes non-Hodgkiniens. Dans une seconde partie, nous nous sommes intéressés à la vectorisation cérébrale de la MIBG afin de développer un outil pour l’étude des terminaisons noradrénergiques, impliquées dans de nombreuses pathologies cérébrales. Nous avons développé un système basé sur l’utilisation d’un couple redox de type 1,4-dihydroquinoléine / sel de quinoléinium et réalisé son marquage au carbone-11. L’évaluation in vivo a permis de valider ce système de libération qui pourra ensuite être appliqué pour la vectorisation de la [125I]MIBG au niveau cérébral
We have investigated the radiosynthesis of Fludarabine, a drug used for the treatment of lymphoproliterative disorders, to develop a specific tracer of non-Hodgkin’s lymphoma for PET imaging. The radiolabelling with fluorine-18 and its automation on commercial apparatus were performed. The in vivo evaluation in preclinical studies showed that [18F]Fludarabine presents a better contrast than [18F]FDG and could be useful for diagnosis and monitoring of non-Hodgkin’s lymphoma. In a second part and in order to develop a tool for studying the norepinephrine system, involved in numerous cerebral pathologies, we have focused our research in the cerebral vectorization of MIBG. We developed a system based on 1,4-dihydroquinoline / quinolinium salt redox system and realized its labeling with carbon-11. The in vivo evaluation allowed to validate this chemical delivery system which would next used to vectorize the [125I]MIBG to the central nervous system