Sujet(s)
2',5'-Oligoadenylate synthetase/génétique , Chromosomes humains de la paire 12/composition chimique , Introns , Leucémie chronique lymphocytaire à cellules B/génétique , Polymorphisme de nucléotide simple , Allèles , Études cas-témoins , Cartographie chromosomique , Fréquence d'allèle , Locus génétiques , Prédisposition génétique à une maladie , Étude d'association pangénomique , Humains , Leucémie chronique lymphocytaire à cellules B/anatomopathologie , Odds ratio , RisqueSujet(s)
Antinéoplasiques/pharmacologie , Surveillance des médicaments , Résistance aux médicaments antinéoplasiques , Leucémie chronique lymphocytaire à cellules B/traitement médicamenteux , Sélection de patients , Essais contrôlés randomisés comme sujet , Vidarabine/analogues et dérivés , Dosage biologique , Études de suivi , Humains , Leucémie chronique lymphocytaire à cellules B/sang , Leucémie chronique lymphocytaire à cellules B/mortalité , Études multicentriques comme sujet , Récidive tumorale locale/sang , Récidive tumorale locale/traitement médicamenteux , Récidive tumorale locale/mortalité , Valeur prédictive des tests , Pronostic , Répartition aléatoire , Taux de survie , Vidarabine/pharmacologieSujet(s)
Gènes MHC de classe I/génétique , Antigène HLA-A2/génétique , Leucémie chronique lymphocytaire à cellules B/étiologie , Polymorphisme de nucléotide simple/génétique , Études cas-témoins , ADN tumoral/génétique , Femelle , Études de suivi , Analyse de profil d'expression de gènes , Étude d'association pangénomique , Humains , Mâle , Séquençage par oligonucléotides en batterie , Réaction de polymérisation en chaîne , Pronostic , Facteurs de risqueSujet(s)
Analyse de profil d'expression de gènes , Leucémie à tricholeucocytes/génétique , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Antimétabolites antinéoplasiques/administration et posologie , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Aberrations des chromosomes , Association thérapeutique , ADN tumoral/génétique , Femelle , Dosage génique , Gènes tumoraux , Gènes suppresseurs de tumeur , Humains , Leucémie à tricholeucocytes/classification , Leucémie à tricholeucocytes/traitement médicamenteux , Leucémie à tricholeucocytes/chirurgie , Mâle , Adulte d'âge moyen , Polymorphisme de nucléotide simple , SplénectomieSujet(s)
Cytidine deaminase/génétique , Variation génétique , Leucémie à tricholeucocytes/génétique , Lymphome B de la zone marginale/génétique , Tumeurs spléniques/génétique , Technique de Western , Différenciation cellulaire , Cytidine deaminase/métabolisme , Humains , Chaines lourdes des immunoglobulines/génétique , Région variable d'immunoglobuline/génétique , Immunophénotypage , Leucémie à tricholeucocytes/métabolisme , Leucémie à tricholeucocytes/anatomopathologie , Lymphome B de la zone marginale/métabolisme , Lymphome B de la zone marginale/anatomopathologie , Mutation/génétique , ARN messager/génétique , ARN messager/métabolisme , RT-PCR , Tumeurs spléniques/métabolisme , Tumeurs spléniques/anatomopathologieRÉSUMÉ
In a series of 48 patients with splenic marginal zone lymphoma (SMZL) with circulating villous lymphocytes, we describe the clinical and laboratory features of nine cases that transformed to high-grade B-cell lymphoma. These patients had a significantly greater incidence of peripheral lymph node involvement at diagnosis when compared to SMZL patients who did not transform (P < 0.03). While transformation in the bone marrow is frequently refractory to therapy and associated with poor outcome in SMZL, lymph node transformation responds well to chemotherapy with durable progression-free and overall survival.
Sujet(s)
Transformation cellulaire néoplasique/anatomopathologie , Noeuds lymphatiques/anatomopathologie , Lymphocytes/anatomopathologie , Lymphome B de la zone marginale/anatomopathologie , Tumeurs spléniques/anatomopathologie , Sujet âgé , Loi du khi-deux , Survie sans rechute , Femelle , Humains , Lymphome B de la zone marginale/traitement médicamenteux , Lymphome B de la zone marginale/mortalité , Mâle , Adulte d'âge moyen , Pronostic , Tumeurs spléniques/traitement médicamenteux , Tumeurs spléniques/mortalité , Taux de survieSujet(s)
Chromosomes humains de la paire 8 , Prédisposition génétique à une maladie , Leucémie chronique lymphocytaire à cellules B/étiologie , Polymorphisme de nucléotide simple , Analyse de mutations d'ADN , Femelle , Génotype , Humains , Leucémie chronique lymphocytaire à cellules B/génétique , Mâle , Adulte d'âge moyen , Facteurs de risqueRÉSUMÉ
BACKGROUND: Previous studies of patients with chronic lymphocytic leukaemia reported high response rates to fludarabine combined with cyclophosphamide. We aimed to establish whether this treatment combination provided greater survival benefit than did chlorambucil or fludarabine. METHODS: 777 patients with chronic lymphocytic leukaemia requiring treatment were randomly assigned to fludarabine (n=194) or fludarabine plus cyclophosphamide (196) for six courses, or chlorambucil (387) for 12 courses. The primary endpoint was overall survival, with secondary endpoints of response rates, progression-free survival, toxic effects, and quality of life. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number NCT 58585610. FINDINGS: There was no significant difference in overall survival between patients given fludarabine plus cyclophosphamide, fludarabine, or chlorambucil. Complete and overall response rates were better with fludarabine plus cyclophosphamide than with fludarabine (complete response rate 38%vs 15%, respectively; overall response rate 94%vs 80%, respectively; p<0.0001 for both comparisons), which were in turn better than with chlorambucil (complete response rate 7%, overall response rate 72%; p=0.006 and 0.04, respectively). Progression-free survival at 5 years was significantly better with fludarabine plus cyclophosphamide (36%) than with fludarabine (10%) or chlorambucil (10%; p<0.00005). Fludarabine plus cyclophosphamide was the best combination for all ages, including patients older than 70 years, and in prognostic groups defined by immunoglobulin heavy chain gene (V(H)) mutation status and cytogenetics, which were tested in 533 and 579 cases, respectively. Patients had more neutropenia and days in hospital with fludarabine plus cyclophosphamide, or fludarabine, than with chlorambucil. There was less haemolytic anaemia with fludarabine plus cyclophosphamide (5%) than with fludarabine (11%) or chlorambucil (12%). Quality of life was better for responders, but preliminary analyses showed no significant difference between treatments. A meta-analysis of these data and those of two published phase III trials showed a consistent benefit for the fludarabine plus cyclophosphamide regimen in terms of progression-free survival. INTERPRETATION: Fludarabine plus cyclophosphamide should now become the standard treatment for chronic lymphocytic leukaemia and the basis for new protocols that incorporate monoclonal antibodies.
Sujet(s)
Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Leucémie chronique lymphocytaire à cellules B/traitement médicamenteux , Sujet âgé , Chlorambucil/administration et posologie , Chlorambucil/effets indésirables , Cyclophosphamide/administration et posologie , Cyclophosphamide/effets indésirables , Survie sans rechute , Femelle , Humains , Leucémie chronique lymphocytaire à cellules B/mortalité , Leucémie chronique lymphocytaire à cellules B/anatomopathologie , Mâle , Adulte d'âge moyen , Analyse de survie , Vidarabine/administration et posologie , Vidarabine/effets indésirables , Vidarabine/analogues et dérivésRÉSUMÉ
A possible role for DNA mismatch repair defects and microsatellite instability (MSI) in the pathogenesis of a number of B-cell lymphoproliferative disorders has recently been debated. To gain further insight into the impact of MSI on B-CLL, we evaluated samples from a series of 982 patients using the mono-satellite markers BAT25 and BAT26, which are highly sensitive in demonstrating classical mismatch repair (MMR) deficiency. Only 1% of cases displayed MSI and this was not correlated with stage of disease or family history of B-CLL. A sub-polymorphic germline variant of BAT25 was identified in one familial case, which was also detected in the patient's affected brother. In conclusion, our study demonstrates that MSI does not have a prominent role in the pathogenesis of B-CLL.
Sujet(s)
Réparation de mésappariement de l'ADN , Réparation de l'ADN/génétique , Leucémie chronique lymphocytaire à cellules B/génétique , Instabilité des microsatellites , Sujet âgé , Marqueurs biologiques tumoraux/génétique , Santé de la famille , Femelle , Marqueurs génétiques , Humains , Leucémie chronique lymphocytaire à cellules B/étiologie , Mâle , Répétitions microsatellites , Adulte d'âge moyenSujet(s)
Facteurs d'échange de nucléotides guanyliques/génétique , Leucémie chronique lymphocytaire à cellules B/étiologie , Protéines proto-oncogènes/génétique , Transactivateurs/génétique , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Protéines adaptatrices de signalisation des récepteurs à domaine de mort , Santé de la famille , Femelle , Mutation germinale , Humains , Leucémie chronique lymphocytaire à cellules B/génétique , Mâle , Adulte d'âge moyenRÉSUMÉ
AIMS: To augment the limited literature on bone marrow (BM) appearances in T-cell large granular lymphocyte (LGL) leukaemia and to identify a histological signature to aid in diagnosis of this condition. METHODS AND RESULTS: A descriptive analysis of the histology of the BM in T-cell LGL leukaemia was performed (n = 38). Antibodies against CD3, CD4, CD5, CD8, CD16, CD56, CD57 and CD20 or CD79a were employed. Antibodies against CD68 (macrophages) and CD34 (sinusoids) were also included. BM was normocellular or hypercellular in the majority of cases, with interstitial lymphoid infiltration in 97%. Lymphoid nodules were present in 55% and intrasinusoidal permeation in 58%. Apoptotic figures and haemosiderin deposition were common. All cases showed trilinear haematopoiesis with normal or increased megakaryopoiesis and erythropoiesis, but normal/reduced myelopoiesis. Reticulin was increased (Grade II-III). Immunohistochemistry revealed interstitial infiltration in all cases and helped to identify lymphoid nodules in two-thirds of cases. Preferential localization of CD8+ T lymphocytes to the interstitium and CD4+ T lymphocytes to the periphery of CD20+ B-cell nodules was seen in almost 90% of cases. CONCLUSIONS: Nodules with non-clonal B-cell centres surrounded by CD4+ cells, with interstitial CD8+ cells, are a characteristic finding in T-cell LGL leukaemia and may represent a histological signature for this condition.
Sujet(s)
Cellules de la moelle osseuse/anatomopathologie , Moelle osseuse/anatomopathologie , Leucémie à cellules T/anatomopathologie , Lymphocytes T/anatomopathologie , Adulte , Sujet âgé , Antigènes CD/métabolisme , Apoptose , Marqueurs biologiques tumoraux/métabolisme , Moelle osseuse/métabolisme , Cellules de la moelle osseuse/métabolisme , Femelle , Hématopoïèse/physiologie , Hémosidérine/métabolisme , Humains , Immunohistochimie , Leucémie à cellules T/métabolisme , Tissu lymphoïde/métabolisme , Tissu lymphoïde/anatomopathologie , Mâle , Adulte d'âge moyen , Lymphocytes T/métabolismeRÉSUMÉ
Mantle cell lymphoma (MCL), characterised by t(11;14)(q13;q32), has a poor prognosis. Many cases have additional cytogenetic abnormalities, and often have a complex karyotype. Fluorescence in situ hybridisation (FISH) was used to study 60 cases with leukaemic presentation of MCL, to determine the frequency, clinical correlations and prognostic impact of a panel of molecular cytogenetic abnormalities: 17p13 (TP53 locus), 13q14, 12 p11.1-q11 (centromere), 6q21 and 11q23. CD38 expression, of prognostic value in chronic lymphocytic leukaemia (CLL), was also studied, and correlations with clinical and cytogenetic abnormalities sought. Eighty per cent of cases had at least one abnormality in addition to t(11;14). Deletions at 17p13 (TP53) and 13q14 were most frequent and involved the majority of the leukaemic clone. Cases with TP53 deletion were more likely to have splenomegaly and marked leucocytosis (>30 x 10(9)/l), and less likely to have lymphadenopathy than those without deletion. Deletions at 11q23 and 6q21 were associated with extranodal disease. 13q14 and 11q23 deletions showed a trend towards worse prognosis by univariate analysis. In multivariate analysis, deletions at 13q14 and 6q21 were independent predictors of poor outcome. Deletion at 17p13 did not show prognostic impact in this series. CD38, positive in two-thirds of cases, was associated with male gender and nodal disease but not with any cytogenetic abnormality, or with survival.
Sujet(s)
Aberrations des chromosomes , Chromosomes humains de la paire 11/génétique , Chromosomes humains de la paire 14/génétique , Leucémies/génétique , Lymphome à cellules du manteau/génétique , Antigènes CD38/sang , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Marqueurs biologiques tumoraux/sang , Délétion de segment de chromosome , Méthodes épidémiologiques , Femelle , Humains , Hybridation fluorescente in situ , Mâle , Adulte d'âge moyen , Pronostic , Translocation génétiqueRÉSUMÉ
B-prolymphocytic leukemia (B-PLL) is a rare disease with poor prognosis. To further characterize the biological features of this disease, we analyzed immunoglobulin heavy chain (IgVH) mutations, ZAP-70 and CD38 in 19 cases with de novo B-PLL. Immunoglobulin heavy chain genes analysis showed an unmutated pattern (>98% homology to germ line) in 9/17 cases (53%), with 100% homology in eight. In the remaining, it ranged from 90 to 97.4%, with three cases slightly mutated (98-95%) and five heavily mutated (<95%). All B-PLL utilized members of VH3 (11/17) and VH4 (6/17) families, with V3-23, V4-59 and V4-34 gene accounting for more than half of them, regardless of mutational status. ZAP-70, assessed by flow cytometry, ranged from 1 to 91% cells, being > or =20% in 57% of cases. CD38 ranged from 1 to 99% (median 21%). There was no correlation between IgVH status and ZAP-70 or CD38 expression, but male gender and del(17p) were more common in the unmutated group. Neither IgVH mutations, CD38 expression nor del(17p) influenced patients' outcome. Unexpectedly, ZAP-70+ B-PLL patients survived longer (40 months) than ZAP-70- B-PLL (8 months). B-PLL appears biologically heterogeneous regarding IgVH mutations, ZAP-70 and CD38 expression, showing a pattern distinct from that of other lymphoproliferative disorders.
Sujet(s)
Antigènes CD38/génétique , Chaines lourdes des immunoglobulines/génétique , Région variable d'immunoglobuline/génétique , Leucémie chronique lymphocytaire à cellules B/génétique , Leucémie prolymphocytaire/génétique , Glycoprotéines membranaires/génétique , ZAP-70 Protein-tyrosine kinase/génétique , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Aberrations des chromosomes , Analyse de mutations d'ADN , Femelle , Cytométrie en flux , Humains , Hybridation fluorescente in situ , Mâle , Adulte d'âge moyen , PronosticSujet(s)
Protéines du cycle cellulaire/génétique , Protéines de liaison à l'ADN/génétique , Délétion de gène , Gènes p53/génétique , Leucémie chronique lymphocytaire à cellules B/génétique , Protein-Serine-Threonine Kinases/génétique , Protéine p53 suppresseur de tumeur/physiologie , Protéines suppresseurs de tumeurs/génétique , Protéines mutées dans l'ataxie-télangiectasie , Aberrations des chromosomes , Humains , Hybridation fluorescente in situ , Caryotypage , Protéine p53 suppresseur de tumeur/génétiqueSujet(s)
Lymphocytes B/anatomopathologie , Leucémie chronique lymphocytaire à cellules B/génétique , Hyperlymphocytose/diagnostic , Hyperlymphocytose/génétique , Adolescent , Adulte , Répartition par âge , Sujet âgé , Causalité , Clones cellulaires , Prédisposition génétique à une maladie , Dépistage génétique , Humains , Leucémie chronique lymphocytaire à cellules B/épidémiologie , Hyperlymphocytose/épidémiologie , Adulte d'âge moyen , Prévalence , Appréciation des risques , Facteurs de risqueRÉSUMÉ
We describe a case of natural killer (NK) cell leukemia with acute presentation, systemic symptoms and hepatosplenomegaly. The uniform and aberrant phenotype of NK cells with infiltration of bone marrow and spleen was in keeping with a malignant diagnosis. Aggressive presentation was demonstrated by marked constitutional symptoms and significant tumor burden (liver, spleen, blood, bone marrow). The subsequent clinical course has been indolent, but this may have been influenced by treatment. Treatment consisted sequentially of splenectomy, intravenous pentostatin and the combination of cyclosporine A and recombinant human erythropoietin and has resulted in survival of over 48 months. We discuss the difficulties in the diagnosis of this condition, explore possible causes of cytopenia(s), and highlight the role of immunosuppression in controlling disease manifestations in large granular lymphocyte proliferative disorders.