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2.
J Clin Pathol ; 72(11): 778-782, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31473630

RESUMO

SF3B1 is the largest subunit of the Spliceosome Factor 3b (SF3B) complex and part of the U2 small nuclear ribosomal protein. It functions as an important part of spliceosomal assembly, converting precursor messenger RNA (mRNA) to mRNA ready for ribosomal translation. Mutations of SF3B1 are commonly seen in myelodysplastic syndromes with ring sideroblasts (MDS-RS)and MDS/myeloproliferative neoplasm (MPN-RS-T). These mutations are typically heterozygous missense substitutions, of which, 55% involve K700E. MDS-RS and MDS/MPN-RS-T usually carry a more favourable prognosis than other subtypes of MDS. SF3B1 itself does not influence survival in these conditions, but does correlate with increased thrombotic risk. Mutated SF3B1 is present in 9%-15% of chronic lymphocytic leukaemia cases and on its own correlates with improved responsiveness to ibrutinib, but is associated with additional adverse genetic abnormalities including TP53 and ATM mutations, which traditionally confer adverse outcomes.


Assuntos
Biomarcadores Tumorais/genética , Eritroblastos/patologia , Leucemia Linfocítica Crônica de Células B/genética , Mutação , Síndromes Mielodisplásicas/genética , Fosfoproteínas/genética , Fatores de Processamento de RNA/genética , Predisposição Genética para Doença , Humanos , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Leucemia Linfocítica Crônica de Células B/terapia , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/patologia , Síndromes Mielodisplásicas/terapia , Fenótipo , Fosfoproteínas/química , Fosfoproteínas/metabolismo , Prognóstico , Conformação Proteica , Fatores de Processamento de RNA/química , Fatores de Processamento de RNA/metabolismo , Spliceossomos/genética , Spliceossomos/metabolismo , Relação Estrutura-Atividade
3.
BMC Cancer ; 19(1): 809, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31412798

RESUMO

BACKGROUND: Eradication of minimal residual disease (MRD), at the end of Fludarabine-Cyclophosphamide-Rituximab (FCR) treatment, is a validated surrogate marker for progression-free and overall survival in chronic lymphocytic leukaemia. But such deep responses are also associated with severe immuno-depletion, leading to infections and the development of secondary cancers. METHODS: We assessed, blood MRD and normal immune cell levels at the end of treatment, in 162 first-line FCR patients, and analysed survival and adverse event. RESULTS: Multivariate Landmark analysis 3 months after FCR completion identified unmutated IGHV status (HR, 2.03, p = 0.043), the level of MRD reached (intermediate versus low, HR, 2.43, p = 0.002; high versus low, HR, 4.56, p = 0.002) and CD4 > 200/mm3 (HR, 3.30, p <  0.001) as factors independently associated with progression-free survival (PFS); neither CD8 nor NK counts were associated with PFS. The CD4 count was associated with PFS irrespective of IGHV mutational status, but only in patients with detectable MRD (HR, 3.51, p = 0.0004, whereas it had no prognostic impact in MRD < 10- 4 patients: p = 0.6998). We next used a competitive risk model to investigate whether immune cell subsets could be associated with the risk of infection and found no association between CD4, CD8 and NK cells and infection. CONCLUSIONS: Consolidation/maintenance trials based on detectable MRD after FCR should investigate CD4 T-cell numbers both as a selection and a response criterion, and consolidation treatments should target B-cell/T-cell interactions.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfócitos T CD4-Positivos/patologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Feminino , Seguimentos , Humanos , Região Variável de Imunoglobulina/genética , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/patologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasia Residual , Prognóstico , Rituximab/efeitos adversos , Rituximab/uso terapêutico , Análise de Sobrevida , Resultado do Tratamento , Vidarabina/efeitos adversos , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico
4.
Presse Med ; 48(7-8 Pt 1): 807-815, 2019.
Artigo em Francês | MEDLINE | ID: mdl-31447332

RESUMO

Chronic lymphocytic leukemia is the most frequent adult leukemia. Eighty per cent of the patients are asymptomatic at diagnosis and 30% of the patients will be never treated. The diagnosis is based on the blood smear examination and immunophenotyping by flow cytometry of blood lymphocytes. The first line option is immunochemotherapy in 90% of the patients without genetic abnormalities associated with chemo resistance. The use of new compounds targeting different pathways is more frequent especially in relapsing patients and could be an alternative to the chemotherapy in the future. Asymptomatic patients with a stable disease assessed by the specialist can be followed by the general practitioner with a blood count and clinical examination every six months or once a year.


Assuntos
Leucemia Linfocítica Crônica de Células B , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Diagnóstico Diferencial , Humanos , Imunofenotipagem/métodos , Imunoterapia , Leucemia Linfocítica Crônica de Células B/classificação , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/patologia , Leucemia Linfocítica Crônica de Células B/terapia , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Terapias em Estudo/métodos , Terapias em Estudo/tendências
5.
Presse Med ; 48(7-8 Pt 1): 792-806, 2019.
Artigo em Francês | MEDLINE | ID: mdl-31447335

RESUMO

Chronic lymphoproliferative disorders should be classified according to the revised 2016 WHO classification. Biopsies are not mandatory for all chronic lymphoproliferative disorders as blood or bone marrow cytologroachical approach can be sufficient for some lymphoma entities. Diagnostic is based on a multidiscplinary approach taking into account clinical presentation, histopathological, cytological, immunophenotypical features (immunohistochemistry and Flow cytometry) and molecular pattern (translocation by FISH, Mutations landscape by NGS, and genomic abnormalities by CGH array). An important heterogeneity of clinical presentation and prognosis arises within the same lymphoma subtype. Clinical evolution is characterized by relapses, cytological progression and transformation into diffuse large B cell lymphoma, aggressive lymphoma or high-grade lymphomas.


Assuntos
Linfócitos B/patologia , Leucemia Linfocítica Crônica de Células B/classificação , Leucemia Linfocítica Crônica de Células B/patologia , Transtornos Linfoproliferativos/classificação , Transtornos Linfoproliferativos/patologia , Doença Crônica , Diagnóstico Diferencial , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Transtornos Linfoproliferativos/diagnóstico , Síndrome
7.
BMC Neurol ; 19(1): 200, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31426757

RESUMO

BACKGROUND: Primary central nervous system (CNS) small lymphocytic lymphoma (SLL), as a type of low-grade lymphoma, is extremely rare. The diagnosis of CNS SLL is challenging due to its variable clinical and radiological features, which may overlap with those of diffuse large B-cell lymphoma (DLBCL). Primary CNS SLL differs from DLBCL in that it has an indolent clinical course and a good prognosis. Thus, it is important to distinguish SLL from DLBCL. By reviewing the literature, only two cases of low-grade SLL, primarily located in the CNS and involving the brain parenchyma and dura, have been reported. To our knowledge, primary CNS SLL in the bilateral ventricles has never been reported. Interestingly, the two cases in our report are identical in terms of the clinical presentations, magnetic resonance imaging (MRI) features, pathological results and prognoses. CASE PRESENTATION: Both patients presented with headaches. MRI suggested solid lesions located in the bilateral ventricles that were isointense on T1-weighted images and hypointense on T2-weighted images. After the injection of contrast agent (gadolinium, Gd), the intraventricular lesions were homogeneously enhanced and hyperperfused. CSF cytology revealed malignant cells. Brain biopsy revealed diffuse proliferation of small lymphocytes with positive labelling of B-cell immunomarkers. The primary origin in the CNS was confirmed with no evidence of systemic lymphoma. Two patients were given high doses of methotrexate-based chemotherapy and were free from symptoms and progression for more than 1-year of follow-up. CONCLUSIONS: The presence of homogeneously enhanced intraventricular MRI lesions should raise the suspicion of primary CNS SLL.


Assuntos
Neoplasias Encefálicas/patologia , Ventrículos Cerebrais/patologia , Leucemia Linfocítica Crônica de Células B/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
10.
J Cancer Res Clin Oncol ; 145(11): 2823-2834, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31468122

RESUMO

PURPOSE: The optimal dose intensity for conditioning prior to allogeneic hematopoietic stem cell transplantation (alloHSCT) for chronic lymphocytic leukemia (CLL) is unknown. METHODS: We retrospectively compared outcomes of patients who received a first alloHCST after non-myeloablative (NMA) and reduced intensity conditioning (RIC). Data of 432 patients with a median age of 55 years were included, of which 86 patients underwent NMA and 346 RIC. RESULTS: The median follow-up after alloHSCT was 4.3 years. Compared to the RIC group, more NMA patients had purine-analog-sensitive disease, were in complete remission and received matched related donor transplantation. After RIC, the probabilities for 5-year OS, EFS, CIR, and NRM were 46%, 38%, 28%, and 35% and after NMA the respective probabilities were 52%, 43%, 25%, and 32%. In multivariate analysis, remission status prior to conditioning but not RIC versus NMA conditioning had a significant impact on CIR, EFS, and OS. CONCLUSION: Presumed higher anti-leukemic activity of RIC versus NMA conditioning did not translate into better outcomes after alloHSCT, but better remission status prior to conditioning did. Effective pathway inhibitor-based salvage therapies combined with NMA conditioning might thus represent the most attractive contemporary approach for alloHSCT for patients with CLL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doença Enxerto-Hospedeiro/mortalidade , Transplante de Células-Tronco Hematopoéticas/mortalidade , Leucemia Linfocítica Crônica de Células B/mortalidade , Condicionamento Pré-Transplante/mortalidade , Adulto , Idoso , Bussulfano/administração & dosagem , Terapia Combinada , Ciclofosfamida/administração & dosagem , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/epidemiologia , Humanos , Incidência , Leucemia Linfocítica Crônica de Células B/patologia , Leucemia Linfocítica Crônica de Células B/terapia , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Prognóstico , Indução de Remissão , Estudos Retrospectivos , Taxa de Sobrevida , Transplante Homólogo , Adulto Jovem
11.
Hematol Oncol ; 37(4): 392-400, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31420873

RESUMO

Ibrutinib, a first-generation Bruton's tyrosine kinase (BTK) inhibitor, could improve immunity of relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) patients. Whether zanubrutinib, a second-generation selective BTK inhibitor, has similar effects as ibrutinib remains to be determined. Dynamics of number and immunophenotype of immune cells during zanubrutinib treatment in 25 R/R CLL/SLL patients were examined by flow cytometry and blood routine tests. The expression intensity of programmed death-1 (PD-1) on total CD4+ (P < .01), total CD8+ (P < .01), and T helper cells (P < .05) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) on total CD4+ (P = .010) and regulatory T cells (P < .05) reduced after treatment. There were significant differences in expression intensity of CD19 (P < .01), C-X-C chemokine receptor type 5 (CXCR5) (P < .01), and CD49d (P < .05) on B cells before and after treatment. Downregulation of PD-1 on T cells and CXCR5 and CD19 on B cells were observed in nearly all patients after zanubrutinib treatment. Programmed death-ligand 1 expression downregulated, especially in the female, CLL, normal spleen, normal ß2-macroglobulin (ß2-MG) and abnormal lactate dehydrogenase (LDH) subgroups, and CTLA-4 expression on CD4+ T cells tended to decrease in the male, old, CLL, splenomegaly, abnormal ß2-MG, normal LDH, IGHV-mutated and wild-type tumor protein 53 subgroups after zanubrutinib treatment. These findings suggest that zanubrutinib can regulate immunity primarily by improving T cell exhaustion, inhibiting suppressor cells and disrupting CLL cells migration through downregulation of adhesion/homing receptors. Furthermore, favorable changes in cell number and immunophenotype were preferably observed in patients without adverse prognostic factors.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Proteínas de Neoplasias/antagonistas & inibidores , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Idoso , Antineoplásicos/farmacologia , Subpopulações de Linfócitos B/efeitos dos fármacos , Feminino , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Imunofenotipagem , Células Matadoras Naturais/efeitos dos fármacos , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Receptores de Antígenos de Linfócitos B/imunologia , Subpopulações de Linfócitos T/efeitos dos fármacos
13.
Med Oncol ; 36(9): 79, 2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31375939

RESUMO

Chronic lymphocytic leukemia (CLL) is one of the most frequent lymphoproliferative diseases. CLL is characterized by unusual heterogeneity, which probably reflects its biological and genetic lack of homogeneity. Clonal chromosome aberrations belong to the most important prognostic and predictive factors in CLL. This research was aimed at observing clonal evolution in CLL at the chromosomal level, and assessing its clinical significance in relation to selected prognostic factors. The study involved 72 untreated patients with CLL. The preliminary investigations using cytogenetic banding analysis (CBA) and FISH were performed at the time of diagnosis, and again after about 24 months to observe clonal changes (clonal evolution). In addition, other parameters were evaluated, i.e., the expression of ZAP-70 kinase, CD38 antigen, and the mutation statuses of IGVH and NOTCH1 genes. Classic prognostic factors, i.e., categorized ZAP70 and CD38 expressions as well as mutations in IGVH and NOTCH1 genes did not influence the course of clonal evolution in the examined group of patients. Clonal evolution was detected in 45.8% of patients by means of CBA, and in 19.4% patients with FISH. Analysis of chromosomal aberrations in the examined group of patients showed that the incidence of 17p deletions and translocations in karyotypes has a negative impact on overall survival. CE was found to be a risk factor for the occurrence of disease progression (OR = 2.22). Our observations indicate that combined CBA and FISH are the most optimal techniques for monitoring clonal evolution in the course of CLL.


Assuntos
Evolução Clonal/genética , Leucemia Linfocítica Crônica de Células B/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Aberrações Cromossômicas , Bandeamento Cromossômico , Progressão da Doença , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariótipo , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Taxa de Sobrevida
14.
Surg Pathol Clin ; 12(3): 719-731, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31352984

RESUMO

Technical advances in diagnostic modalities have led to the characterization of indolent lymphoid disorders similar to the in situ lesions described in epithelial malignancies. These early and indolent lymphoid lesions share clinicopathologic characteristics with well-characterized lymphoid malignancies such as chronic lymphocytic leukemia and follicular lymphoma. The in situ lesions have an indolent clinical course with only a minor subset shown to progress to frank malignancies. In addition to the in situ lesions, new indolent lymphoproliferative disorders have been recently characterized. Diagnosis and characterization of these indolent lesions is necessary to prevent overtreatment with aggressive therapeutic regimens.


Assuntos
Linfoma Folicular/patologia , Transtornos Linfoproliferativos/patologia , Linfócitos B/patologia , Diagnóstico Diferencial , Humanos , Imunofenotipagem/métodos , Leucemia Linfocítica Crônica de Células B/patologia , Linfocitose/patologia , Linfoma de Célula do Manto/patologia , Prognóstico
15.
Lancet Haematol ; 6(9): e470-e479, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31324600

RESUMO

BACKGROUND: In patients with chronic lymphocytic leukaemia, achievement of a complete response with minimal residual disease of less than 0·01% (ie, <1 chronic lymphocytic leukaemia cell per 10 000 leukocytes) in bone marrow has been associated with improved progression-free survival. We aimed to explore the activity of induction therapy for 9 months with obinutuzumab and ibrutinib, followed up with a minimal residual disease-driven therapeutic strategy for 6 additional months, in previously untreated patients. METHODS: We did a single-arm, phase 2 trial in 27 university hospitals, general hospitals, and specialist cancer centres in France. Eligible patients were at least 18 years old and previously untreated, and had immunophenotypically confirmed B-cell chronic lymphocytic leukaemia; an Eastern Cooperative Oncology Group (ECOG) performance status score of less than 2; a Binet stage C according to IWCLL 2008 criteria or Binet stage A and B with active disease; no 17p deletion or absence of p53 mutation; and were considered medically fit. In the first part of the study (induction phase), all participants received eight intravenous infusions of obinutuzumab 1000 mg over six 4-weekly cycles and oral ibrutinib 420 mg once per day for 9 months. In part 2, after assessment on day 1 of month 9, patients with a complete response and bone marrow minimal residual disease of less than 0·01% received only oral ibrutinib 420 mg once per day for 6 additional months. Patients with a partial response, or with a complete response and bone marrow minimal residual disease of 0·01% or more, received 6 months of four 4-weekly cycles of intravenous fludarabine, cyclophosphamide, and obinutuzumab 1000 mg, alongside continuing ibrutinib 420 mg once per day. The primary endpoint was the proportion of patients achieving a complete response with bone marrow minimal residual disease less than 0·01% on day 1 of month 16 assessed by intention to treat (ITT). This trial is registered with ClinicalTrials.gov (number NCT02666898) and is still open for follow-up. FINDINGS: Between Oct 27, 2015, and May 16, 2017, 135 patients were enrolled. After induction treatment (day 1 of month 9), 130 patients were evaluable, of which ten (8%) achieved a complete response with bone marrow minimal residual disease of less than 0·01% and were assigned to ibrutinib, and 120 (92%) were assigned to ibrutinib plus fludarabine, cyclophosphamide, and obinutuzumab. After minimal residual disease-guided treatment (day 1 of month 16), 84 (62%, 90% CI 55-69) of 135 patients (ITT population) achieved a complete response with bone marrow minimal residual disease of less than 0·01%. The most common haematological adverse event was thrombocytopenia (in 45 [34%] of 133 patients at grade 1-2 in months 1-9 and in 43 [33%] of 130 patients at grade 1-2 in months 9-15). The most common non-haematological adverse events were infusion-related reactions (in 83 [62%] patients at grade 1-2 in months 1-9) and gastrointestinal disorders (in 62 [48%] patients at grades 1 and 2 in months 9-15). 49 serious adverse events occurred, most frequently infections (ten), cardiac events (eight), and haematological events (eight). No treatment-related deaths occurred. INTERPRETATION: Obinutuzumab and ibrutinib induction therapy followed by a minimal residual disease driven strategy is safe and active in patients with previously untreated chronic lymphocytic leukaemia. With longer follow-up, including assessing the evolution of minimal residual disease, if response is maintained, this strategy could be an option in the first-line setting in patients with chronic lymphocytic leukaemia, although randomised evidence is needed. FUNDING: Roche, Janssen.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Esquema de Medicação , Feminino , Gastroenteropatias/etiologia , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasia Residual , Pirazóis/efeitos adversos , Pirimidinas/efeitos adversos , Taxa de Sobrevida , Trombocitopenia/etiologia , Resultado do Tratamento , Proteína Supressora de Tumor p53/genética
16.
Blood ; 134(11): 851-859, 2019 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-31340982

RESUMO

Zanubrutinib is a potent and highly selective inhibitor of Bruton tyrosine kinase (BTK). In this first-in-human, open-label, multicenter, phase 1 study, patients in part 1 (3 + 3 dose escalation) had relapsed/refractory B-cell malignancies and received zanubrutinib 40, 80, 160, or 320 mg once daily or 160 mg twice daily. Part 2 (expansion) consisted of disease-specific cohorts, including treatment-naive or relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The primary end points were safety and tolerability, and definition of the maximum tolerated dose (part 1). Additional end points included pharmacokinetics/pharmacodynamics and preliminary efficacy. Reported herein are results from 144 patients enrolled in the dose-finding and CLL/SLL cohorts. No dose-limiting toxicities occurred in dose escalation. Median BTK occupancy in peripheral blood mononuclear cells was >95% at all doses. Sustained complete (>95%) BTK occupancy in lymph node biopsy specimens was more frequent with 160 mg twice daily than 320 mg once daily (89% vs 50%; P = .0342). Consequently, 160 mg twice daily was selected for further investigation. With median follow-up of 13.7 months (range, 0.4-30.5 months), 89 CLL/SLL patients (94.7%) remain on study. Most toxicities were grade 1/2; neutropenia was the only grade 3/4 toxicity observed in >2 patients. One patient experienced a grade 3 subcutaneous hemorrhage. Among 78 efficacy-evaluable CLL/SLL patients, the overall response rate was 96.2% (95% confidence interval, 89.2-99.2). Estimated progression-free survival at 12 months was 100%. Zanubrutinib demonstrated encouraging activity in CLL/SLL patients, with a low incidence of major toxicities. This trial was registered at www.clinicaltrials.gov as #NCT02343120.


Assuntos
Leucemia de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma de Células B/tratamento farmacológico , Piperidinas/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Leucemia de Células B/metabolismo , Leucemia de Células B/patologia , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Piperidinas/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/farmacocinética , Pirimidinas/farmacocinética , Resultado do Tratamento , Adulto Jovem
17.
Virchows Arch ; 475(6): 795-798, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31317311

RESUMO

The traditional concept of unidirectional maturation of hematopoietic cells has been called into question due to the recognition of lineage plasticity, which is increasingly found also in the clonal evolution of hematopoietic and lymphoid malignancies. Here we present an unusual case of a patient with TP53-mutated chronic lymphocytic leukemia (CLL) treated with a PI3Kδ inhibitor evolving to clonally related Langerhans cell histiocytosis (LCH) with acquired BRAF V600E and STK11 mutations and loss of expression of PAX-5 and other examined B cell markers. In indolent B cell lymphoma, transformation to a more aggressive high-grade lymphoma occurs frequently during the course of disease and is thought to be caused by clonal evolution. Our case further supports the concept of significant lineage plasticity in lymphomas and raises the question of a potential role of novel pharmacologic agents in clonal evolution.


Assuntos
Evolução Clonal , Histiocitose de Células de Langerhans/patologia , Ilhotas Pancreáticas/patologia , Leucemia Linfocítica Crônica de Células B/patologia , Neoplasias Pancreáticas/patologia , Feminino , Histiocitose de Células de Langerhans/genética , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/patologia , Pessoa de Meia-Idade
18.
Expert Opin Ther Pat ; 29(7): 487-496, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31154862

RESUMO

INTRODUCTION: Studies presented in patents show that a novel chemotherapeutic agent, venetoclax, might be useful in additional therapeutic indications. Venetoclax is approved in America for the treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Venetoclax selectively inhibits the B-cell lymphoma-2 (Bcl-2) protein, an anti-apoptotic protein that can be overexpressed in most B-cell lymphoid malignancies. AREAS COVERED: This is a review of all the patents granted until November 2018, with venetoclax in the examples or claim section of the patent document. The patents include the synthesis, polymorphism, formulations, in vitro and in vivo efficacy as well as the therapeutic application of venetoclax. EXPERT OPINION: The approved indications for treatment with venetoclax are limited but expanding rapidly. Studies suggest that venetoclax might be useful in several other therapeutic indications, mostly other hematological malignancies. Numerous studies use venetoclax in combinations with other therapeutic agents. Such combinational treatment shows promising results in additional indications as well as drug-resistant cancers. Venetoclax is an interesting new therapeutic involved in a variety of clinical research. Patent applications in recent years even include venetoclax in somewhat exotic fields such as type 1 diabetes, asthma, and Zika virus treatment.


Assuntos
Antineoplásicos/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Sulfonamidas/administração & dosagem , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Resistencia a Medicamentos Antineoplásicos , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Patentes como Assunto , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Sulfonamidas/farmacologia
19.
Blood ; 134(5): 432-444, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31151986

RESUMO

Chronic lymphocytic leukemia (CLL) occurs in 2 major forms: aggressive and indolent. Low miR-29b expression in aggressive CLL is associated with poor prognosis. Indiscriminate miR-29b overexpression in the B-lineage of mice causes aberrance, thus warranting the need for selective introduction of miR-29b into B-CLL cells for therapeutic benefit. The oncofetal antigen receptor tyrosine kinase orphan receptor 1 (ROR1) is expressed on malignant B-CLL cells, but not normal B cells, encouraging us with ROR1-targeted delivery for therapeutic miRs. Here, we describe targeted delivery of miR-29b to ROR1+ CLL cells leading to downregulation of DNMT1 and DNMT3A, modulation of global DNA methylation, decreased SP1, and increased p21 expression in cell lines and primary CLL cells in vitro. Furthermore, using an Eµ-TCL1 mouse model expressing human ROR1, we report the therapeutic benefit of enhanced survival via cellular reprograming by downregulation of DNMT1 and DNMT3A in vivo. Gene expression profiling of engrafted murine leukemia identified reprogramming of cell cycle regulators with decreased SP1 and increased p21 expression after targeted miR-29b treatment. This finding was confirmed by protein modulation, leading to cell cycle arrest and survival benefit in vivo. Importantly, SP1 knockdown results in p21-dependent compensation of the miR-29b effect on cell cycle arrest. These studies form a basis for leukemic cell-targeted delivery of miR-29b as a promising therapeutic approach for CLL and other ROR1+ B-cell malignancies.


Assuntos
Pontos de Checagem do Ciclo Celular/genética , Leucemia Linfocítica Crônica de Células B/genética , MicroRNAs/genética , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/antagonistas & inibidores , Animais , Biomarcadores Tumorais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Metilação de DNA , Modelos Animais de Doenças , Epigênese Genética , Humanos , Imunoconjugados/administração & dosagem , Imunoconjugados/química , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/patologia , Camundongos , MicroRNAs/administração & dosagem , MicroRNAs/química , Nanopartículas/administração & dosagem , Nanopartículas/química , Taxa de Sobrevida , Nanomedicina Teranóstica , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Blood ; 134(7): 641-644, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31243043

RESUMO

Mutational analyses performed following acquired ibrutinib resistance have suggested that chronic lymphocytic leukemia (CLL) progression on ibrutinib is linked to mutations in Bruton tyrosine kinase (BTK) and/or phospholipase Cγ2 (PLCG2) genes. Mutational information for patients still on ibrutinib is limited. We report a study aimed to provide a "snapshot" of the prevalence of mutations in a real-life CLL cohort still on ibrutinib after at least 3 years of treatment. Of 204 patients who initiated ibrutinib via an early-access program at 29 French Innovative Leukemia Organization (FILO) centers, 63 (31%) were still on ibrutinib after 3 years and 57 provided a fresh blood sample. Thirty patients had a CLL clone ≥0.5 × 109/L, enabling next-generation sequencing (NGS); BTK and PLCG2 mutations were detected in 57% and 13% of the NGS samples, respectively. After median follow-up of 8.5 months from sample collection, the presence of a BTK mutation was significantly associated with subsequent CLL progression (P = .0005 vs no BTK mutation). Our findings support that mutational analysis should be considered in patients receiving ibrutinib who have residual clonal lymphocytosis, and that clinical trials are needed to evaluate whether patients with a BTK mutation may benefit from an early switch to another treatment.


Assuntos
Tirosina Quinase da Agamaglobulinemia/genética , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Fosfolipase C gama/genética , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Seguimentos , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Mutação
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