Radiotherapy for newly diagnosed primary central nervous system lymphoma: role and perspective

Whole brain radiotherapy (WBRT) has long been a key treatment of newly diagnosed primary central nervous system lymphoma (PCNSL). In the 1990s, the addition of high dose Methotrexate-based induction chemotherapy (HD MTX-based CT) has enabled a drastic improvement in PCNSL patients outcome. However, combined treatment has led to radiation-induced delayed neurotoxicity, especially in older patients. Alternative treatment strategies have been assessed to improve the efficacy and neurotoxicity ratio. Nowadays, in the elderly patients WBRT is widely omitted or deferred, and in younger patients WBRT is challenged by high dose chemotherapy with autologous stem cell transplant (HCT-ASCT) for consolidation treatment after HD MTX-based CT. In this setting, this review is addressed to clinicians with the aim to summarize the role of WBRT in the treatment of newly diagnosed PCNSL and its perspectives

Ibrutinib induces multiple functional defects in the neutrophil response against Aspergillus fumigatus

The Bruton tyrosine kinase inhibitor ibrutinib has become a leading therapy against chronic lymphoid leukemia. Recently, ibrutinib has been associated with the occurrence of invasive fungal infections, in particular invasive aspergillosis. The mechanisms underlying the increased susceptibility to fungal infections associated with exposure to ibrutinib are currently unknown. Innate immunity, in particular polymer-phonuclear neutrophils, represents the cornerstone of anti-Aspergillus immunity; however, the potential impact of ibrutinib on neutrophils has been little studied. Our study investigated the response to Aspergillus fumigatus and neutrophil function in patients with chronic lymphoid leukemia or lymphoma, who were undergoing ibrutinib therapy. We studied the consequences of ibrutinib exposure on the functions and anti-Aspergillus responses of neutrophils obtained from healthy donors and 63 blood samples collected at different time points from 32 patients receiving ibrutinib for lymphoid malignancies. We used both flow cytometry and video-microscopy approaches to analyze neutrophils’ cell surface molecule expression, cytokine production, oxidative burst, chemotaxis and killing activity against Aspergillus. Ibrutinib is associated, both in vitro and in patients under treatment, with multiple functional defects in neutrophils, including decreased production of reactive oxygen species, impairment of their capacity to engulf Aspergillus and inability to efficiently kill germinating conidia. Our results demonstrate that ibrutinib-exposed neutrophils develop significant functional defects that impair their response against Aspergillus fumigatus, providing a plausible explanation for the emergence of invasive aspergillosis in ibrutinib-treated patients

Primary central nervous system lymphomas:EHA–ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up

This EHA-ESMO Clinical Practice Guideline provides key recommendations for managing primary DLBCL of the CNS.The guideline covers clinical, imaging and pathological diagnosis, staging and risk assessment, treatment and follow-up.Algorithms for first-line and salvage treatments are provided.The author group encompasses a multidisciplinary group of experts from different institutions and countries in Europe.Recommendations are based on available scientific data and the authors' collective expert opinion

Role of Pericytes in the Development of the Radiotherapy-Induced Toxicity on the Central Nervous System. Development of an Animal Model of Cerebral Lymphoma Applied to Preclinical Therapeutic Trials

L’irradiation cérébrale thérapeutique comporte un risque de neurotoxicité tardive irréversible en partie lié à l’effet de l’irradiation sur le compartiment vasculaire cérébrale. Les péricytes et les communications entre les péricytes et les cellules endothéliales jouent un rôle majeur dans la stabilisation des vaisseaux, dans la formation et la régulation de la barrière hématoencéphalique et dans le contrôle du flux sanguin cérébral. Nous montrons, dans un modèle murin d’irradiation cérébrale, que les péricytes sont une cible précoce de l’irradiation cérébrale. Après irradiation, la morphologie des péricytes est modifiée et des marqueurs d’activations du péricytes sont surexprimés. En conséquence, la communication entre péricyte et cellule endothéliale est rompue, ce qui se traduit par une diminution de la capacité du péricyte à induire une constriction vasculaire après stimulation électrique. De façon concomitante, la perméabilité de la barrière hémato-encéphalique est anormalement augmentée après irradiation. Un traitement par thalidomide, administré dans la semaine précédant et suivant l’irradiation, prévient les conséquences de l’irradiation sur les péricytes. Les communications entre péricytes et cellules endothéliales sont maintenues ainsi que les fonctions contractiles des péricytes. L’imperméabilité de la barrière hématoencéphalique est également préservée. La voie de signalisation PDGF-β/PDGFR-β essentielle au recrutement des péricytes par les cellules endothéliales, est, au moins partiellement, impliquée dans l’effet protecteur de la thalidomide. Des études supplémentaires sont nécessaires pour définir les mécanismes sous tendant l’effet de l’irradiation sur les péricytes ainsi que l’effet protecteur de la thalidomide. Nous avons en parallèle mis au point un modèle murin de lymphome cérébral luciférase positif pour vérifier, dans un premier temps, l’innocuité de l’association de la radiothérapie et de la thalidomide et de ses dérivés de la classe des immunomodulateurs (iMids), le lénalidomide et le pomalidomide. Ces trois molécules ne diminuent pas l’effet antitumoral de la radiothérapie, mais l’association de radiothérapie et de pomalidomide est synergique sur la décroissance tumorale mesurée par l’évolution des courbes de bioluminescence. Le concept de normalisation de la vascularisation tumorale fait référence aux molécules capables, non pas de faire régresser les vaisseaux tumoraux anormaux, mais de les « normaliser » pour améliorer, d’une part, la disponibilité des chimiothérapies au sein de la tumeur, et d’autre part, l’oxygénation tumorale pour accroitre l’efficacité de la radiothérapie. Nos résultats sont en faveur d’un tel effet exercé par le pomalidomide dans notre modèle murin de lymphome cérébral, caractérisé par une infiltration tumorale périvasculaire, une fuite capillaire mais sans néo angiogenèse. Nos travaux fournissent un rationnel biologique à de futurs essais cliniques avec les iMids dans le traitement des lymphomes cérébraux primitifs voire des tumeurs malignes cérébrales.Therapeutic brain irradiation carries a risk of irreversible delayed neurotoxicity partly due to the effect of irradiation on the cerebral vascular compartment. Pericytes and communication between pericytes and endothelial cells play a major role in vessel stabilization in the formation and regulation of the blood-brain barrier and in the control of cerebral blood flow. We show in a murine model of brain irradiation, that pericytes are a target of early brain irradiation. After irradiation, the morphology of pericytes is altered and markers of activation of pericytes are overexpressed. Consequently, communication between the endothelial cell and pericyte is disrupted , which results in a decreased capacity of pericytes for inducing a vascular constriction after electrical stimulation. Concomitantly, the permeability of the blood - brain barrier is abnormally increased after irradiation. Treatment with thalidomide administered in the week before and after irradiation, prevents the effects of irradiation on pericytes . Communication between pericytes and endothelial cells are maintained as well as the contractile properties of pericytes. The impermeability of the blood brain barrier is also preserved. The PDGF-β/PDGFR-β signaling pathway, which is essential for the recruitment of pericytes by endothelial cells, is at least partially involved in the protective effect of thalidomide. Further studies are needed to define the mechanisms underlying the effect of irradiation on the pericytes and the protective effect of thalidomide. We have, in parallel, developed a model of murine luciferase positive CNS lymphoma to verify first, the safety of the combination of radiotherapy and thalidomide and its derivatives of the class of immunomodulators ( IMiDs ), lenalidomide and pomalidomide. These three molecules do not decrease the antitumor effect of radiotherapy, but the antitumoral effect of the association of radiotherapy and pomalidomide is synergistic. The concept of the normalization of the tumor vascularization refers to molecules capable not to induce regression of the abnormal tumor vessels but to "normalize" the tumoral vasculature in order to improve, on one hand , the availability of chemotherapy in the tumor , and on the other hand, the tumor oxygenation to increase the effectiveness of radiotherapy. Our results are in favor of such an effect exerted by pomalidomide in our murine model of cerebral lymphoma, characterized by perivascular tumor infiltration and capillary leak .Our work provide a biological rational for future clinical trials with IMiDs in the treatment of brain lymphomas or malignant brain tumors

Etude du rôle des péricytes dans le développement des lésions du système nerveux central induites par la radiothérapie. Développement d'un modèle animal de lymphome cérébral appliqué aux essais thérapeutiques précliniques.

L irradiation cérébrale thérapeutique comporte un risque de neurotoxicité tardive irréversible en partie lié à l effet de l irradiation sur le compartiment vasculaire cérébrale. Les péricytes et les communications entre les péricytes et les cellules endothéliales jouent un rôle majeur dans la stabilisation des vaisseaux, dans la formation et la régulation de la barrière hématoencéphalique et dans le contrôle du flux sanguin cérébral. Nous montrons, dans un modèle murin d irradiation cérébrale, que les péricytes sont une cible précoce de l irradiation cérébrale. Après irradiation, la morphologie des péricytes est modifiée et des marqueurs d activations du péricytes sont surexprimés. En conséquence, la communication entre péricyte et cellule endothéliale est rompue, ce qui se traduit par une diminution de la capacité du péricyte à induire une constriction vasculaire après stimulation électrique. De façon concomitante, la perméabilité de la barrière hémato-encéphalique est anormalement augmentée après irradiation. Un traitement par thalidomide, administré dans la semaine précédant et suivant l irradiation, prévient les conséquences de l irradiation sur les péricytes. Les communications entre péricytes et cellules endothéliales sont maintenues ainsi que les fonctions contractiles des péricytes. L imperméabilité de la barrière hématoencéphalique est également préservée. La voie de signalisation PDGF-b/PDGFR-b essentielle au recrutement des péricytes par les cellules endothéliales, est, au moins partiellement, impliquée dans l effet protecteur de la thalidomide. Des études supplémentaires sont nécessaires pour définir les mécanismes sous tendant l effet de l irradiation sur les péricytes ainsi que l effet protecteur de la thalidomide. Nous avons en parallèle mis au point un modèle murin de lymphome cérébral luciférase positif pour vérifier, dans un premier temps, l innocuité de l association de la radiothérapie et de la thalidomide et de ses dérivés de la classe des immunomodulateurs (iMids), le lénalidomide et le pomalidomide. Ces trois molécules ne diminuent pas l effet antitumoral de la radiothérapie, mais l association de radiothérapie et de pomalidomide est synergique sur la décroissance tumorale mesurée par l évolution des courbes de bioluminescence. Le concept de normalisation de la vascularisation tumorale fait référence aux molécules capables, non pas de faire régresser les vaisseaux tumoraux anormaux, mais de les normaliser pour améliorer, d une part, la disponibilité des chimiothérapies au sein de la tumeur, et d autre part, l oxygénation tumorale pour accroitre l efficacité de la radiothérapie. Nos résultats sont en faveur d un tel effet exercé par le pomalidomide dans notre modèle murin de lymphome cérébral, caractérisé par une infiltration tumorale périvasculaire, une fuite capillaire mais sans néo angiogenèse. Nos travaux fournissent un rationnel biologique à de futurs essais cliniques avec les iMids dans le traitement des lymphomes cérébraux primitifs voire des tumeurs malignes cérébrales.Therapeutic brain irradiation carries a risk of irreversible delayed neurotoxicity partly due to the effect of irradiation on the cerebral vascular compartment. Pericytes and communication between pericytes and endothelial cells play a major role in vessel stabilization in the formation and regulation of the blood-brain barrier and in the control of cerebral blood flow. We show in a murine model of brain irradiation, that pericytes are a target of early brain irradiation. After irradiation, the morphology of pericytes is altered and markers of activation of pericytes are overexpressed. Consequently, communication between the endothelial cell and pericyte is disrupted , which results in a decreased capacity of pericytes for inducing a vascular constriction after electrical stimulation. Concomitantly, the permeability of the blood - brain barrier is abnormally increased after irradiation. Treatment with thalidomide administered in the week before and after irradiation, prevents the effects of irradiation on pericytes . Communication between pericytes and endothelial cells are maintained as well as the contractile properties of pericytes. The impermeability of the blood brain barrier is also preserved. The PDGF-b/PDGFR-b signaling pathway, which is essential for the recruitment of pericytes by endothelial cells, is at least partially involved in the protective effect of thalidomide. Further studies are needed to define the mechanisms underlying the effect of irradiation on the pericytes and the protective effect of thalidomide. We have, in parallel, developed a model of murine luciferase positive CNS lymphoma to verify first, the safety of the combination of radiotherapy and thalidomide and its derivatives of the class of immunomodulators ( IMiDs ), lenalidomide and pomalidomide. These three molecules do not decrease the antitumor effect of radiotherapy, but the antitumoral effect of the association of radiotherapy and pomalidomide is synergistic. The concept of the normalization of the tumor vascularization refers to molecules capable not to induce regression of the abnormal tumor vessels but to "normalize" the tumoral vasculature in order to improve, on one hand , the availability of chemotherapy in the tumor , and on the other hand, the tumor oxygenation to increase the effectiveness of radiotherapy. Our results are in favor of such an effect exerted by pomalidomide in our murine model of cerebral lymphoma, characterized by perivascular tumor infiltration and capillary leak .Our work provide a biological rational for future clinical trials with IMiDs in the treatment of brain lymphomas or malignant brain tumors.PARIS11-SCD-Bib. électronique (914719901) / SudocSudocFranceF

Le méthotrexate à hautes doses dans le traitement des lymphomes malins non Hodgkiniens (prévalence et prise en charge des effets indésirables)

PARIS-BIUP (751062107) / SudocSudocFranceF

Le lymphome vitréo-rétinien : un challenge diagnostique et thérapeutique

International audiencePrimary vitreoretinal lymphoma (PVRL) is a rare form of primary central nervous system (CNS) lymphoma (PCNSL) arising in the intraocular compartment without brain involvement. Despite its apparent indolent clinical course, PVRL can cause permanent vision loss and CNS relapse, the major cause of death in patients with PVRL. The pathophysiology of PVRL is unknown. As in PCNSL, the transformation of the tumor cells likely originates outside the CNS, before the cells migrate to the eye and proliferate within an immune-permissive microenvironment. PVRL exhibits a biased immunoglobulin repertoire, suggesting underlying antigen selection. The diagnosis remains challenging, requiring close coordination between ophthalmologists and cytologists. Because of their rarity and fragility in the vitreous, lymphoma cells cannot always be identified. Interleukin levels, molecular biology, and imaging are used in combination with clinical ophthalmological examination to support the diagnosis of PVRL. Multi-institutional prospective studies are urgently needed to validate the equivocal conclusions regarding treatments drawn from heterogeneous retrospective or small cohort studies. Intravitreal injection of methotrexate or rituximab or local radiotherapy is effective at clearing tumor cells within the eyes but does not prevent CNS relapse. Systemic treatment based on high-dose methotrexate chemotherapy, with or without local treatment, might reduce this risk. At relapse, intensive consolidation chemotherapy followed by stem cell transplantation can be considered. Single-agent ibrutinib, lenalidomide, and temozolomide treatments are effective in patients with relapsed PVRL and should be tested as first-line treatments. Therapeutic response assessment based on clinical examination is improved by measuring cytokine levels but still needs to be refined

Low ADC in CNS Lymphoma

International audiencePatients with primary central nervous system lymphomas (PCNSLs) present with nonspecific clinical symptoms, which makes correct imaging evaluation essential for diagnostic and therapeutic management. In this work, we examined an 81-year-old man with recently discovered PCNSL using F-FDG PET/MRI, and we were able to differentiate between 2 lesions-PCNSL lymphoma extension and a recent ischemia. Our work shows that ischemia should be considered as a differential diagnosis for lymphoma progression. Although F-FDG PET or MRI alone cannot always give unambiguous solution, PET/MRI can greatly improve the diagnosis accuracy and help decide on the appropriate patient management