Long-term analysis of the RiBVD phase II trial reveals the unfavorable impact of <i>TP53</i> mutations and hypoalbuminemia in older adults with mantle cell lymphoma; for the LYSA group

Between 2011 and 2012, a phase II trial evaluated the use of the RiBVD (rituximab, bendamustine, velcade and dexamethasone) combination as first-line treatment for mantle cell lymphoma (MCL) patients over the age of 65. We have now re-examined the classic prognostic factors, adding an assessment of TP53 mutation status. Patients (N=74; median age 73 years) were treated with the RiBVD combination. Median progression-free survival (mPFS) was 79 months and median overall survival (mOS) was 111 months. TP53 mutation status was available for 54/74 (73%) patients. TP53 mutations (TP53mt) were found in 12 patients (22.2%). In multivariate analysis, among the prognostic factors (PF) evaluated, only TP53mt and an albumin level (Alb) 3.6 g/dL were independently associated with a shorter mPFS. A hazard ratio (HR) of 3.16 (1.3-9.9, P=0.014) was obtained for TP53mt versus TP53 wild-type (wt), and 3.6 (1.39-9.5, P=0.009) for Alb <3.6 g/dL versus Alb ≥3.6 g/dL. In terms of mOS, multivariate analysis identified three PF: TP53mt (HR: 5.9 [1.77-19.5, P=0.004]), Alb <3.6 g/dL (HR: 5.2 [1.46- 18.5, P=0.011]), and ECOG=2 (HR: 3.7 [1.31-10.6, P=0.014]). Finally, a score combining TP53 status and Alb distinguished three populations based on the presence of 0, 1, or 2 PF. For these populations, mPFS was 7.8 years, 28 months, and 2.5 months, respectively. Our prolonged follow-up confirmed the efficacy of the RiBVD regimen, comparing it favorably to other regimens. TP53mt and hypoalbuminemia emerge as strong PF that can be easily integrated into prognostic scores for older adult patients with MCL

Méningite à listeria monocytogènes et leucémie lymphoïde chronique (à propos de deux observations et revue de la littérature)

AMIENS-BU Santé (800212102) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Thalidomide et Myélome multiple

Qui pourrait oublier le drame sans précédent des années 1950-60, causé par le Thalidomide ? Ce médicament était alors largement prescrit aux femmes enceintes en tant qu'hypnotique. Il fut la cause de plusieurs milliers de cas de malformations chez les nouveaux-nés. Le médicament fut donc retiré du marché en 1962. Pourtant, le Thalidomide connaît aujourd'hui un regain d'intérêt. Réservé à l'usage hospitalier, il permet actuellement de traiter certaines pathologies rares et graves (lupus érythémateux, rejet du greffon contre l'hôte...) et notamment le myélome multiple réfractaire et/ou en rechute dans lequel il présente une Autorisation Temporaire d'Utilisation. Largement connu pour ses effets teratogènes, une vigilance est alors indispensable. Les effets indésirables engendrés par la prise du Thalidomide doivent toujours être présents à l'esprit, en particulier ses effets tératogènes et neurotoxiques souvent irréversibles. Ils limitent son utilisation au long cours et impliquent des règles très strictes de prescription et de surveillance.AMIENS-BU Santé (800212102) / SudocSudocFranceF

Place du médecin généraliste dans la prise en charge des patients atteints de cancer en Picardie (enquête auprès de 500 généralistes et de 134 patients cancéreux en Picardie)

L organisation des soins en cancérologie a été repensée par les politiques de Santé Publique sur la base de la pluridisciplinarité dont le pivot serait le médecin traitant. Cette étude régionale avait l objectif de décrire la place actuelle du généraliste dans la prise en charge cancérologique en Picardie, sa relation avec les cancérologues, et le rôle du réseau oncologique picard. Secondairement, l avis des patients cancéreux a été recueilli. L étude réalisée du 23 janvier au 7 mars 2013 a comporté deux enquêtes-questionnaires prospectives d opinions. La première de 25 questions a été adressée à 500 généralistes libéraux de Picardie (tirage aléatoire informatique), la seconde de 15 questions aux patients cancéreux de six centres cancérologiques. Le taux de réponses a été de 22,8 %. Les généralistes ont confirmé leur implication dans tous les stades de la prise en charge hormis les décisions thérapeutiques face à une insuffisance de compétences et d informations. La mauvaise communication des cancérologues, la faiblesse des structures de proximité et la méconnaissance de l organisation en réseau ont été relevées par plus de la moitié des généralistes. Malgré leur prise en charge globale du patient, les décisions importantes restant gérées par le cancérologue, les généralistes se sentent mis à part. Pourtant, une information adaptée et rapide leur suffirait pour améliorer la continuité des soins. Les outils de communication, le Dossier Médical Personnalisé (DMP) ou le mail sécurisé et l action du réseau devraient aider cette collaboration. Au terme du plan cancer 2009-2013, les volontés d amélioration de la prise en charge sont toujours réelles mais il faudra accomplir des efforts considérables pour parvenir aux objectifs prévus pour réintégrer le rôle du médecin traitant.Cancer treatment has been evaluated by the French Public Health policies, which advocate a cooperative work in with the general practitioner as a coordinator. This survey had three aims: first, to describe the role of general practitioners in the management of patients suffering from cancer, then to describe their relationship with the oncologists and finally, to evaluate the role of the oncological network in Picardy. Some patients suffering from cancer were also surveyed. The survey, carried out from January 23rd to March 7th , 2013 in Picardy, was composed of two questionnaires. The first one was sent to 500 randomly chosen general practitioners. The second one was filled in by patients from six cancer treatment centers. 22,8% of the general practitioners answered the survey. They confirmed their involvement except for the therapy choice. More than half of the general practitioners also pointed out a lack of communication from cancerologists, a lack of local cancer centers and said they were not aware of the network organization. Despite the global care of the patient, the general practitioners feel put aside because the cancerologist still remains in charge of the cancer treatment. However, a fast and appropriate piece of information would be enough to improve following up the care. The means of communication, the Personal Medical Records, the use of the secured email or the network should allow to help this coordination. By the end of the action against cancer (2009-2013), there is still a wish to improve the care of patients, but significant efforts must be made to emphasize the role of the attending physician.AMIENS-BU Santé (800212102) / SudocSudocFranceF

Apport de l'éculizumab dans le traitement de l'hémoglobinurie paroxystique nocturne

L hémoglobinurie paroxystique nocturne (HPN) ou maladie de Marchiafava-Micheli est une maladie rare de la cellule souche hématopoïétique, due à une mutation somatique acquise du gène PIG-A. La mutation de ce gène empêche ou limite la synthèse normale des molécules d ancrage de glycophophatidylinositol (GPI), responsables de la fixation de nombreuses protéines à la surface cellulaire. Parmi celles-ci, on retrouve le CD59 et le CD55, protéines inhibitrices du complément, qui empêchent normalement l assemblage final du complexe d attaque membranaire (CAM). L HPN est la conséquence d un déficit d ancrage membranaire de ces deux protéines, se manifestant sur le plan clinique par une hémolyse intravasculaire. On note aussi souvent dans cette maladie une insuffisance médullaire ainsi que des épisodes thromboemboliques. Les progrès de la cytométrie en flux en font l outil diagnostique de référence mettant en évidence le déficit des molécules ancrées par le GPI. Sur le plan nosographique, on oppose l HPN classique, très hémolytique, à la forme aplasique (syndrome aplasie-HPN), où le clone peut être retrouvé au diagnostic ou durant l évolution de la maladie. Le facteur pronostique majeur de l HPN reste la survenue de complications thromboemboliques, de localisations souvent atypiques. Les événements thrombotiques constituent la plus importante cause de morbidité et de mortalité. Sur le plan thérapeutique, la forme classique de la maladie a bénéficié de l avènement de l éculizumab, anticorps dirigé contre la fraction C5 du complément. La forme aplasique est une indication d allogreffe en cas de donneur géno-identique ou de traitement immunosuppresseur en l absence de donneur. Les complications thrombotiques répétées restent, même à l heure actuelle, des facteurs affectant la survie des patients.Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired disorder of hematopoietic stem cells. PNH is related to a somatic mutation in the phosphatidylinositol glycan class A (PIG-A), X-linked gene, responsible for a deficiency in glycosylphosphatidylinositol-anchored proteins (GPI-AP). The lack of one of the GPI-AP complement regulatory proteins (CD59) leads to haemolysis. The disease is diagnosed with haemolytic anemia, marrow failure or episodes of venous thrombosis. The diagnosis is based on flow cytometry, which allowed direct quantification of the GPI-AP-deficient cells. From earlier descriptions, the clinical polymorphism of PNH has been recognized by two presentations; one form, predominantly haemolytic without overt marrow failure, referred to classic PNH and the other one, with marrow failure, was often described as the aplastic anemia PNH syndrome (AA-PNH). Thromboses remain a major life threatening complication affecting outcomes in both disease subcategories. Thrombotic events are characterized by involvement of unusual sites (hepatic, mesenteric, cerebral, dermal veins). In classic PNH, recent studies have focused on inhibiting the complement cascade with encouraging clinical results using eculizumab, a C5-inhibitor humanized monoclonal antibody. Concerning the AA-PNH syndrome, bone marrow transplantation (BMT) is the reference treatment in young patients with a sibling donor. Immunosuppressive therapy remains an important treatment modality in this subcategory for patients without a donor or ineligible for BMT. Recurrent thrombotic events remains even now associated with bad prognosis, whatever the form of the disease.AMIENS-BU Santé (800212102) / SudocSudocFranceF

Lymphome de Hodgkin et tuberculose ganglionnaire (à propos de deux cas et revue de la littérature)

Le lymphome de Hodgkin et la tuberculose ganglionnaire sont deux pathologies d actualité, avec de nombreuses recherches fondamentales en cours pour le lymphome de Hodgkin. Ces deux pathologies peuvent être associées chez un même patient. La tuberculose ganglionnaire est plus fréquemment associée au lymphome de Hodgkin qu aux autres néoplasies. Si cette association est connue depuis longtemps, elle n est que peu rapportée. Nous avons choisi de décrire deux observations d association de lymphome de Hodgkin et de tuberculose ganglionnaire. Dans la première observation, le diagnostic de lymphome de Hodgkin de type scléronodulaire, stade III Bb est obtenu au cours d une coelioscopie avec biopsie d adénopathie abdominale (péri-splénique). Le traitement combiné par chimiothérapie de type LISK et radiothérapie permet d obtenir une rémission complète à un an. Après 4 années de rémission complète, sont découvertes fortuitement des adénopathies cervicales, qui resteront stables pendant 9 ans. La biopsie ganglionnaire réalisée devant l augmentation de volume brutale révèlera une tuberculose ganglionnaire sans rechute du lymphome de Hodgkin associée. A ce jour, le traitement antituberculeux permet l amélioration clinique, avec une bonne tolérance. Dans la deuxième observation, la biopsie d une adénopathie sus-claviculaire droite révèle un lymphome de Hodgkin de type scléronodulaire, CD30+, CD15+ et CD20-, dans une variante granulomateuse de diagnostic difficile, stade III Bb, associé à la présence de BAAR en rapport avec une tuberculose ganglionnaire. Malgré deux lignes de chimiothérapie par ABVD puis BEACOPP associé de façon concomitante à un traitement antituberculeux classique, la modification brutale d une adénopathie sus-claviculaire droite et l insuffisance de réponse au traitement, motivent la réalisation de nouvelles biopsies qui confirment la persistance de BAAR, sans identification en culture, ni en PCR, et sans arguments histologiques pour une rechute du lymphome de Hodgkin. L instauration d un traitement antituberculeux comportant la clarithromycine permet à ce jour la régression spectaculaire de l adénopathie. La comparaison de ces deux observations avec celles de la littérature illustre l importance des effets délétères du lymphome de Hodgkin sur la réponse immunitaire à médiation cellulaire comme facteur prédisposant à la tuberculose. Ceci est vrai dans les diagnostics concomitants, ou lorsque le lymphome précède la tuberculose, mais que penser des cas où c est la tuberculose qui précède le lymphome ? Celle-ci peut-elle avoir un rôle dans la lymphomonogénèse ? Le praticien doit savoir que ces deux pathologies peuvent coexister et y penser en cas de mauvaise réponse au traitement, ou lorsqu une rechute de la maladie initiale est suspectée, tant le risque est important si de mauvais choix thérapeutiques sont faits.Hodgkin's lymphoma and lymph node tuberculosis are two actual diseases, with many research in progress for Hodgkin's lymphoma generation. These two diseases may be associated in the same patient. The lymph node tuberculosis is more frequently associated with Hodgkin s lymphoma than other cancer. If this association has long been known, it is little reported. We chose to describe two cases of association of Hodgkin's lymphoma and lymph node tuberculosis. In the first case, the diagnosis of Hodgkin's lymphoma nodular sclerosis type, stage III Bb is obtained during a coelioscopy with biopsy of abdominal lymph nodes (peri-splenic). The combined treatment with chemotherapy LISK type and radiotherapy enables a complete remission at one year. After 4 years of complete remission, were discovered fortuitously cervical lymph nodes, which remain stable for 9 years. The lymph node biopsy performed for improvement of their volume reveal lymph node tuberculosis without relapse of Hodgkin's lymphoma associated. To date, TB treatment allows clinical improvement, with good tolerance. In the second case, biopsy of a right supraclavicular lymph node revealed a Hodgkin's lymphoma nodular sclerosis type, CD30 +, CD15 + and CD20-, in a granulomatous variant with difficult diagnosis, stage III Bb, associated with the presence of BAAR related with lymph node tuberculosis. Despite two lines of chemotherapy with ABVD and BEACOPP combined concomitantly with standard TB treatment, the abrupt change of right supraclavicular lymphadenopathy and inadequate response to treatment, motivate new biopsies confirming the persistence of BAAR, without identification in culture, or PCR, for mycobacterium tuberculosis, and no histological arguments for a relapse of Hodgkin lymphoma. The introduction of TB treatment with clarithromycin allows to date, the regression of lymphadenopathy. Comparing these observations with those of the literature illustrates the importance of the deleterious effects of Hodgkin's lymphoma on the cell mediated immune response as a factor predisposing to tuberculosis. This is true in concomitant diagnosis, or when the lymphoma precedes tuberculosis, but what about the case of tuberculosis precedes the lymphoma? Could she have a role in lymphomonogenesis? The physician must know that these two pathologies may coexist and think for when poor response to treatment appears, or when a relapse of the initial disease is suspected, so the risk is important if ill-treatment choices are made.AMIENS-BU Santé (800212102) / SudocSudocFranceF

Multi-drug resistance mediated by P-glycoprotein overexpression is not correlated with ZAP-70/CD38 expression in B-cell chronic lymphocytic leukemia

International audienceZAP-70 and CD38 expression can identify B-cell chronic lymphocytic leukemia with an inferior clinical outcome. Many groups have investigated the meaning of the expression of these two proteins and the correlation with the bad prognosis in B-CLL. But nobody has investigated the relation between the multidrug resistance mediated by Pgp overexpression (MDR1) and ZAP-70/CD38 coexpression. Forty-one untreated and stage A patients, either ZAP-70(+)CD38(+) or ZAP-70(-)CD38(-), were tested to determine the MDR1 status. MDR1 was observed in 41% of CLL ZAP-70(+)CD38(+) and in 37% of CLL ZAP-70(-)CD38(-). The difference was not significant (p = 0.745). Patients with ZAP-70 and CD38 positive CLL can not be candidates for MDR1 antagonists

Concomitant systemic and central nervous system non-Hodgkin lymphoma: the role of consolidation in terms of high dose therapy and autologous stem cell transplantation. A 60-case retrospective study from LYSA and the LOC network

The purpose of our study is to determine the outcome of patients with systemic non-Hodgkin lymphoma presenting with neurologic localization at diagnosis, as well as the impact of consolidation in terms of high-dose therapy followed by autologous stem cell transplantation. Newly diagnosed non-Hodgkin lymphoma patients with concomitant systemic and neurological involvement at diagnosis were included in this study. Sixty patients (37 males; 25 females) were included. Median age was 61 years (23–85 years). Histological subtype was mainly diffuse large B-cell lymphoma (n=54; 90%). The International prognostic index was over 2 in 41 (72%) patients. Median number of extranodal sites was 2 (range: 1–5). Central nervous system involvement alone was documented in 48 patients. Paravertebral involvement with epidural mass and cord compression and positive cerebrospinal fluid were present in 7 patients. Five patients had both central nervous system and epidural involvement. First-line chemotherapy was mainly anthracycline-based (88%) plus high-dose methotrexate (74%) with or without cytarabine. Consolidation with high-dose therapy followed by autologous stem cell transplantation was performed in 19 patients. For the whole population, overall response rate after induction chemotherapy was 76%. Three-year progression-free survival and overall survival were 42±7% and 44±7%, respectively. For patients under 66 years of age, consolidation strategy using high-dose therapy followed by autologous stem cell transplantation positively impacted 3-year overall survival and progression free survival (P=0.008) and (P=0.003), respectively. In multivariate analysis, high-dose therapy had a positive impact on 3-year overall survival and progression-free survival for the whole population as well as for patients under 66 years old in CR after induction therapy (OS [HR=0.22 (0.07–0.67)] and progression-free survival [HR=0.17 (0.05–0.54)]). In conclusion, non-Hodgkin lymphoma prognosis with concomitant systemic and neurological involvement at diagnosis is poor with a high risk of relapse when treated with conventional chemotherapies alone. This retrospective study supports the feasibility and the potential benefit of a consolidative strategy with high-dose therapy followed by autologous stem cell transplantation in this subset of patients. This strategy and the best intensive chemotherapy regimen remain to be validated in prospective trials

ASXL1 but not TET2 mutations adversely impact overall survival of patients suffering systemic mastocytosis with associated clonal hematologic non-mast-cell diseases.

Systemic mastocytosis with associated hematologic clonal non-mast cell disease (SM-AHNMD) is a rare and heterogeneous subtype of SM and few studies on this specific entity have been reported. Sixty two patients with Systemic mastocytosis with associated hematologic clonal non-mast cell disease (SM-AHNMD) were presented. Myeloid AHNMD was the most frequent (82%) cases. This subset of patients were older, had more cutaneous lesions, splenomegaly, liver enlargement, ascites; lower bone mineral density and hemoglobin levels and higher tryptase level than lymphoid AHNMD. Defects in KIT, TET2, ASXL1 and CBL were positive in 87%, 27%, 14%, and 11% of cases respectively. The overall survival of patients with SM-AHNMD was 85.2 months. Within the myeloid group, SM-MPN fared better than SM-MDS or SM-AML (p = 0.044,). In univariate analysis, the presence of C-findings, the AHNMD subtypes (SM-MDS/CMML/AML versus SM-MPN/hypereosinophilia) (p = 0.044), Neutropenia (p = 0.015), high monocyte level (p = 0.015) and the presence of ASXL1 mutation had detrimental effects on OS (p = 0.007). In multivariate analysis and penalized Cox model, only the presence of ASXL1 mutation remained an independent prognostic factor that negatively affected OS (p = 0.035). SM-AHNMD is heterogeneous with variable prognosis according to the type of the AHNMD. ASXL1 is mutated in a subset of myeloid AHNMD and adversely impact on OS