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2.
Hematol Oncol ; 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31732977

RESUMO

A major revolution in the treatment of chronic lymphocytic leukemia (CLL) began with the approval of ibrutinib, a first-in-class oral inhibitor of Bruton tyrosine kinase (BTK), for the treatment of relapsed/refractory (R/R) and/or TP53 mutated patients with CLL. However, 5 years later, some issues relating to this disorder still remain including the fact that with ibrutinib only a relatively small proportion of patients achieve complete remission and that ibrutinib-resistant CLL clones can develop in about 20% of patients. In addition, therapy must still be given continuously, and toxicities leading to drug discontinuation occur in about 30% of patients. In the meantime second-generation BTK inhibitors have already aroused considerable interest and gathered momentum. A possible strategy to overcome some of these obstacles is to combine ibrutinib with other targeted agents especially in high-risk disease, such as previously treated refractory patients or those with TP53 aberrations or complex karyotypes, in whom rapid eradication of disease is most desirable. Therapy with single agent ibrutinib should be part of a sequential approach for patients with low risk disease, especially in older patients (aged >70 years) with a higher burden of comorbidities. Long-term results of ongoing studies combining Ibrutinib with (chemo)-immunotherapy or other targeted agents are eagerly awaited. Future clinical trials are indeed still needed to provide answers to these open questions.

3.
Leuk Lymphoma ; 60(6): 1352-1353, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30678518
5.
Blood ; 133(9): 940-951, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30538135

RESUMO

Mantle cell lymphoma (MCL) is characterized by the t(11;14)(q13;q32) translocation resulting in overexpression of cyclin D1. However, a small subset of cyclin D1- MCL has been recognized, and approximately one-half of them harbor CCND2 translocations while the primary event in cyclin D1-/D2- MCL remains elusive. To identify other potential mechanisms driving MCL pathogenesis, we investigated 56 cyclin D1-/SOX11+ MCL by fluorescence in situ hybridization (FISH), whole-genome/exome sequencing, and gene-expression and copy-number arrays. FISH with break-apart probes identified CCND2 rearrangements in 39 cases (70%) but not CCND3 rearrangements. We analyzed 3 of these negative cases by whole-genome/exome sequencing and identified IGK (n = 2) and IGL (n = 1) enhancer hijackings near CCND3 that were associated with cyclin D3 overexpression. By specific FISH probes, including the IGK enhancer region, we detected 10 additional cryptic IGK juxtapositions to CCND3 (6 cases) and CCND2 (4 cases) in MCL that overexpressed, respectively, these cyclins. A minor subset of 4 cyclin D1- MCL cases lacked cyclin D rearrangements and showed upregulation of CCNE1 and CCNE2. These cases had blastoid morphology, high genomic complexity, and CDKN2A and RB1 deletions. Both genomic and gene-expression profiles of cyclin D1- MCL cases were indistinguishable from cyclin D1+ MCL. In conclusion, virtually all cyclin D1- MCLs carry CCND2/CCND3 rearrangements with immunoglobulin genes, including a novel IGK/L enhancer hijacking mechanism. A subset of cyclin D1-/D2-/D3- MCL with aggressive features has cyclin E dysregulation. Specific FISH probes may allow the molecular identification and diagnosis of cyclin D1- MCL.


Assuntos
Ciclina D2/genética , Ciclina D3/genética , Elementos Facilitadores Genéticos , Rearranjo Gênico , Cadeias Leves de Imunoglobulina/genética , Linfoma de Célula do Manto/genética , Idoso , Ciclina D1/genética , Ciclina D1/metabolismo , Feminino , Humanos , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Transcrição SOXC/genética , Translocação Genética
6.
Acta Haematol ; 141(1): 1-6, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30428459

RESUMO

Multiparameter flow cytometry (MFC)-based clonality assessment is a powerful method of diagnosis and follow-up in monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). However, the relevance of intraclonal heterogeneity in immunophenotypic studies remains poorly understood. The main objective of this work was to characterize the different immunophenotypic subclones in MGUS and MM patients and to investigate their correlation with disease stages. An 8-color MFC protocol with 17 markers was used to identify the subclones within the neoplastic compartment of 56 MGUS subjects, 151 newly diagnosed MM patients, 30 MM subjects in complete remission with detectable minimal residual disease, and 36 relapsed/refractory MM patients. Two or more clusters were observed in > 85% of MGUS subjects, 75% of stage I MM patients, and < 15% in stage III. Likewise, a significant correlation between the dominant subclone size, secondary cytogenetic features, and changes in the expression of CD27, CD44, and CD81 was detected. The loss of intraclonal equilibrium may be an important factor related with kinetics and risk of progression not well considered to date in MFC studies. The MFC strategy used in this work can provide useful biomarkers in MGUS and MM.


Assuntos
Biomarcadores/metabolismo , Citometria de Fluxo/métodos , Mieloma Múltiplo/diagnóstico , Paraproteinemias/diagnóstico , Aberrações Cromossômicas , Humanos , Receptores de Hialuronatos/metabolismo , Imunofenotipagem , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Estadiamento de Neoplasias , Paraproteinemias/metabolismo , Paraproteinemias/patologia , Tetraspanina 28/metabolismo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
7.
Haematologica ; 104(3): 576-586, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30262568

RESUMO

Mutations in genes of the RAS-BRAF-MAPK-ERK pathway have not been fully explored in patients with chronic lymphocytic leukemia. We, therefore, analyzed the clinical and biological characteristics of chronic lymphocytic leukemia patients with mutations in this pathway and investigated the in vitro response of primary cells to BRAF and ERK inhibitors. Putative damaging mutations were found in 25 of 452 patients (5.5%). Among these, BRAF was mutated in nine patients (2.0%), genes upstream of BRAF (KITLG, KIT, PTPN11, GNB1, KRAS and NRAS) were mutated in 12 patients (2.6%), and genes downstream of BRAF (MAPK2K1, MAPK2K2, and MAPK1) were mutated in five patients (1.1%). The most frequent mutations were missense, subclonal and mutually exclusive. Patients with these mutations more frequently had increased lactate dehydrogenase levels, high expression of ZAP-70, CD49d, CD38, trisomy 12 and unmutated immunoglobulin heavy-chain variable region genes and had a worse 5-year time to first treatment (hazard ratio 1.8, P=0.025). Gene expression analysis showed upregulation of genes of the MAPK pathway in the group carrying RAS-BRAF-MAPK-ERK pathway mutations. The BRAF inhibitors vemurafenib and dabrafenib were not able to inhibit phosphorylation of ERK, the downstream effector of the pathway, in primary cells. In contrast, ulixertinib, a pan-ERK inhibitor, decreased phospho-ERK levels. In conclusion, although larger series of patients are needed to corroborate these findings, our results suggest that the RAS-BRAF-MAPK-ERK pathway is one of the core cellular processes affected by novel mutations in chronic lymphocytic leukemia, is associated with adverse clinical features and could be pharmacologically inhibited.

9.
Br J Haematol ; 182(3): 429-433, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-28643365
11.
Best Pract Res Clin Haematol ; 30(1-2): 99-108, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28288723

RESUMO

Extranodal mucosa associated lymphoid tissue (ENMALT) marginal zone lymphomas may arise at any site of the body. The most frequent localizations other than gastrointestinal and eye are salivary gland, skin, lung and thyroid. These lymphomas usually arise in a setting of inflammation due to a persistent infection or autoimmune diseases such as Sjogren syndrome in salivary MALT lymphomas and Hashimoto's thryroiditis in thyroid lymphomas. They affect middle-aged patients with a female predominance when lymphoma arises in certain locations. Patients often present with localised stage I or II although disseminated disease may be present at diagnosis or relapse in a third of the cases. Biopsy of the affected site is mandatory to establish the diagnosis and a full work-up staging is recommended. The clinical course is indolent and prognosis is good despite that recurrences following response to therapy are frequent. Surgery, radiotherapy and/or Rituximab based regimens are effective in these lymphomas.


Assuntos
Linfoma de Zona Marginal Tipo Células B , Doença de Hashimoto/diagnóstico , Doença de Hashimoto/imunologia , Doença de Hashimoto/patologia , Doença de Hashimoto/terapia , Humanos , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Linfoma de Zona Marginal Tipo Células B/imunologia , Linfoma de Zona Marginal Tipo Células B/patologia , Linfoma de Zona Marginal Tipo Células B/terapia , Pessoa de Meia-Idade , Estadiamento de Neoplasias
13.
Expert Rev Hematol ; 10(3): 251-258, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28128670

RESUMO

INTRODUCTION: Large granular lymphocytic leukemia (LGLL) is a low grade lymphoproliferative disorder characterized by the clonal proliferation of large granular lymphocytes (LGL) and recognised by the WHO. The diagnosis and management of these patients is challenging due to the limited information from prospective studies. Guidelines for front-line therapy have not been established. The prognosis is favourable with median overall survivals greater than 10 years. Areas covered: This manuscript is a review of the clinical features, diagnosis, pathogenesis and, in particular, the various available therapeutic options for this rare lymphoid leukemia. A systematic literature search using electronic PubMed database has been carried out. Expert commentary: A watch and wait strategy without therapeutic intervention is recommended in asymptomatic patients. The immunomodulators methotrexate, cyclophosphamide and cyclosporin are the most commonly used drugs in the routine practice with responses ranging from 50 to 65% and without evidence of cross-resistance among them. Purine analogs such as 2´deoxycoformycin and fludarabine alone or in combination may be indicated in patients with bulky and/or widespread disease. Trials using monoclonal antibodies such as Alemtuzumab and agents targeting the disrupted JAK/STAT pathway in LGLL such as JAK-3 inhibitors are promising particularly in a relapse setting.


Assuntos
Leucemia Linfocítica Granular Grande/diagnóstico , Leucemia Linfocítica Granular Grande/terapia , Algoritmos , Evolução Clonal/genética , Terapia Combinada , Gerenciamento Clínico , Predisposição Genética para Doença , Humanos , Leucemia Linfocítica Granular Grande/etiologia , Leucemia Linfocítica Granular Grande/mortalidade , Fenótipo , Prognóstico , Resultado do Tratamento
14.
Br J Haematol ; 174(5): 767-75, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27151266

RESUMO

Historically, an increase in the percentage and number of circulating prolymphocytes in chronic lymphocytic leukaemia (CLL) has been associated with strong expression of surface immunoglobulin, trisomy 12 and a poor outcome. This study re-examines the biological and clinical significance of increased peripheral blood prolymphocytes in 508 patients at entry into the randomized UK Leukaemia Research Fund CLL4 trial. It also investigates the associations between increased prolymphocytes and a comprehensive array of biomarkers. 270 patients (53%) had <5% prolymphocytes, 167 (33%) had 5-9%, 60 (12%) had 10-14% and 11 (2%) had ≥15% prolymphocytes. We show that a higher proportion of prolymphocytes (≥10%) was independently associated with NOTCH1 mutations (P = 0·006), absence of 13q deletion (P = 0·001), high CD38 expression (P = 0·02) and unmutated IGHV genes (P = 0·01). Deaths due to Richter syndrome were significantly more common amongst patients who had ≥10% vs <10% prolymphocytes (13% vs 2%) respectively (P < 0·0001). ≥10% prolymphocytes was also associated with a shorter progression-free survival (Hazard ratio [HR] 1·50 [95% confidence interval [CI]: 1·16-1·93], P = 0·002) and overall survival (HR 1·99 [95% CI: 1·53-2·59], P < 0·0001). Our data support the routine examination of blood films in CLL and suggest that a finding of an increased proportion of prolymphocytes may be a trigger for further evaluation of clinical and laboratory features of progressive disease.


Assuntos
Biomarcadores Tumorais/análise , Leucemia Linfocítica Crônica de Células B/patologia , Subpopulações de Linfócitos/patologia , ADP-Ribosil Ciclase 1/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Deleção Cromossômica , Transtornos Cromossômicos/diagnóstico , Cromossomos Humanos Par 13 , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/mortalidade , Linfócitos/patologia , Masculino , Glicoproteínas de Membrana/análise , Pessoa de Meia-Idade , Mutação , Prognóstico , Receptor Notch1/genética , Taxa de Sobrevida
17.
Am J Surg Pathol ; 40(2): 192-201, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26426381

RESUMO

Splenic diffuse red pulp small B-cell lymphoma (SDRPL) is considered an indolent neoplasm and its pathogenesis is not well known. We investigated the molecular characteristics of 19 SDRPL patients, 5 of them with progressive disease. IGHV genes were mutated in 9/13 (69%). Cytogenetic and molecular studies identified complex karyotypes in 2 cases, and IGH rearrangements in 3, with PAX5 and potentially TCL1 as partners in each one of them. Copy number arrays showed aberrations in 69% of the tumors, including recurrent losses of 10q23, 14q31-q32, and 17p13 in 3, and 9p21 in 2 cases. Deletion of 7q31.3-q32.3 was present in only 1 case and no trisomies 3 or 18 were detected. NOTCH1 and MAP2K1 were mutated in 2 cases each, whereas BRAF, TP53, and SF3B1 were mutated each in single cases. No mutations were found in NOTCH2 or MYD88. Four of the 5 patients with aggressive disease had mutations in NOTCH1 (2 cases), TP53 (1 case), and MAP2K1 (1 case). The progression-free survival of patients with mutated genes was significantly shorter than in the unmutated (P=0.011). These findings show that SDRPL share some mutated genes but not chromosomal alterations, with other splenic lymphomas, that may confer a more aggressive behavior.


Assuntos
Biomarcadores Tumorais/genética , Linfoma de Células B/genética , MAP Quinase Quinase 1/genética , Mutação , Receptor Notch1/genética , Neoplasias Esplênicas/genética , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Biomarcadores Tumorais/análise , Biópsia , Chile , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Progressão da Doença , Intervalo Livre de Doença , Europa (Continente) , Feminino , Deleção de Genes , Dosagem de Genes , Rearranjo Gênico , Genes de Cadeia Pesada de Imunoglobulina , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Linfoma de Células B/química , Linfoma de Células B/patologia , Linfoma de Células B/terapia , Masculino , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular , Fenótipo , Valor Preditivo dos Testes , Fatores de Risco , Neoplasias Esplênicas/química , Neoplasias Esplênicas/patologia , Neoplasias Esplênicas/terapia , Fatores de Tempo
19.
Clin Cancer Res ; 22(8): 2032-40, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-26647217

RESUMO

PURPOSE: Prompted by the extensive biases in the immunoglobulin (IG) gene repertoire of splenic marginal-zone lymphoma (SMZL), supporting antigen selection in SMZL ontogeny, we sought to investigate whether antigen involvement is also relevant post-transformation. EXPERIMENTAL DESIGN: We conducted a large-scale subcloning study of the IG rearrangements of 40 SMZL cases aimed at assessing intraclonal diversification (ID) due to ongoing somatic hypermutation (SHM). RESULTS: ID was identified in 17 of 21 (81%) rearrangements using the immunoglobulin heavy variable (IGHV)1-2*04 gene versus 8 of 19 (40%) rearrangements utilizing other IGHV genes (P= 0.001). ID was also evident in most analyzed IG light chain gene rearrangements, albeit was more limited compared with IG heavy chains. Identical sequence changes were shared by subclones from different patients utilizing the IGHV1-2*04 gene, confirming restricted ongoing SHM profiles. Non-IGHV1-2*04 cases displayed both a lower number of ongoing SHMs and a lack of shared mutations (per group of cases utilizing the same IGHV gene). CONCLUSIONS: These findings support ongoing antigen involvement in a sizable portion of SMZL and further argue that IGHV1-2*04 SMZL may represent a distinct molecular subtype of the disease.


Assuntos
Alelos , Antígenos/imunologia , Linfoma de Zona Marginal Tipo Células B/genética , Linfoma de Zona Marginal Tipo Células B/imunologia , Receptores de Antígenos de Linfócitos B/genética , Neoplasias Esplênicas/genética , Neoplasias Esplênicas/imunologia , Motivos de Aminoácidos , Sequência de Aminoácidos , Substituição de Aminoácidos , Regiões Determinantes de Complementaridade/química , Regiões Determinantes de Complementaridade/genética , Perfilação da Expressão Gênica , Rearranjo Gênico de Cadeia Pesada de Linfócito B , Humanos , Cadeias Pesadas de Imunoglobulinas/química , Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/química , Região Variável de Imunoglobulina/genética , Linfoma de Zona Marginal Tipo Células B/patologia , Modelos Biológicos , Mutação , Neoplasias Esplênicas/patologia , Transcriptoma
20.
Best Pract Res Clin Haematol ; 28(4): 253-63, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26614904

RESUMO

Hairy cell leukaemia-variant (HCL-V) is a rare B-cell malignancy that affects elderly males and manifests with splenomegaly, lymphocytosis and cytopenias without monocytopenia. The neoplastic cells have morphological features of prolymphocytes and hairy cells. The immunophenotype is that of a clonal B-cell CD11c and CD103 positive but, unlike classical HCL, CD25, CD123 and CD200 negative. The spleen histology is similar to classical HCL and the pattern of bone marrow infiltration is interstitial and/or intrasinusoidal. Mutations of the immunoglobulin heavy chain (IGVH) are seen in two thirds of cases with a preferential VH4-34 family usage. There is no distinct chromosomal abnormality but del17p13 and mutations of the TP53 gene are frequent. Mutations in the MAP2K1 gene have been documented in half of the cases. The course is chronic with median survivals of 7-9 years. Patients are refractory to purine analogues and the most effective therapy is the combination of 2-chlorodeoxyadenosine and Rituximab.


Assuntos
Antineoplásicos/uso terapêutico , Cladribina/uso terapêutico , Leucemia de Células Pilosas/tratamento farmacológico , Linfocitose/tratamento farmacológico , Rituximab/uso terapêutico , Esplenomegalia/tratamento farmacológico , Idoso , Antígenos CD/genética , Antígenos CD/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/patologia , Medula Óssea/efeitos dos fármacos , Medula Óssea/imunologia , Medula Óssea/patologia , Deleção Cromossômica , Cromossomos Humanos Par 17 , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Cadeias Pesadas de Imunoglobulinas/imunologia , Leucemia de Células Pilosas/genética , Leucemia de Células Pilosas/mortalidade , Leucemia de Células Pilosas/patologia , Linfocitose/genética , Linfocitose/mortalidade , Linfocitose/patologia , MAP Quinase Quinase 1/genética , MAP Quinase Quinase 1/imunologia , Masculino , Mutação , Baço/efeitos dos fármacos , Baço/imunologia , Baço/patologia , Esplenomegalia/genética , Esplenomegalia/mortalidade , Esplenomegalia/patologia , Análise de Sobrevida , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/imunologia
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