Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 133
Filtrar
1.
Leukemia ; 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32015491

RESUMO

Despite advances in chronic lymphocytic leukaemia (CLL) treatment, globally chemotherapy remains a central treatment modality, with chemotherapy trials representing an invaluable resource to explore disease-related/genetic features contributing to long-term outcomes. In 499 LRF CLL4 cases, a trial with >12 years follow-up, we employed targeted resequencing of 22 genes, identifying 623 mutations. After background mutation rate correction, 11/22 genes were recurrently mutated at frequencies between 3.6% (NFKBIE) and 24% (SF3B1). Mutations beyond Sanger resolution (<12% VAF) were observed in all genes, with KRAS mutations principally composed of these low VAF variants. Firstly, employing orthogonal approaches to confirm <12% VAF TP53 mutations, we assessed the clinical impact of TP53 clonal architecture. Whilst ≥ 12% VAF TP53mut cases were associated with reduced PFS and OS, we could not demonstrate a difference between <12% VAF TP53 mutations and either wild type or ≥12% VAF TP53mut cases. Secondly, we identified biallelic BIRC3 lesions (mutation and deletion) as an independent marker of inferior PFS and OS. Finally, we observed that mutated MAPK-ERK genes were independent markers of poor OS in multivariate survival analysis. In conclusion, our study supports using targeted resequencing of expanded gene panels to elucidate the prognostic impact of gene mutations.

2.
Nat Commun ; 10(1): 3615, 2019 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-31399598

RESUMO

Genome-wide association studies have provided evidence for inherited genetic predisposition to chronic lymphocytic leukemia (CLL). To gain insight into the mechanisms underlying CLL risk we analyze chromatin accessibility, active regulatory elements marked by H3K27ac, and DNA methylation at 42 risk loci in up to 486 primary CLLs. We identify that risk loci are significantly enriched for active chromatin in CLL with evidence of being CLL-specific or differentially regulated in normal B-cell development. We then use in situ promoter capture Hi-C, in conjunction with gene expression data to reveal likely target genes of the risk loci. Candidate target genes are enriched for pathways related to B-cell development such as MYC and BCL2 signalling. At 14 loci the analysis highlights 63 variants as the probable functional basis of CLL risk. By integrating genetic and epigenetic information our analysis reveals novel insights into the relationship between inherited predisposition and the regulatory chromatin landscape of CLL.


Assuntos
Epigênese Genética/genética , Epigênese Genética/fisiologia , Epigenômica , Predisposição Genética para Doença/genética , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Linfócitos B/metabolismo , Sequência de Bases , Cromatina/metabolismo , Metilação de DNA , Regulação Leucêmica da Expressão Gênica , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fatores de Transcrição
3.
Blood Adv ; 3(16): 2474-2481, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31434681

RESUMO

Chronic lymphocytic leukemia patients with mutated immunoglobulin heavy-chain genes (IGHV-M), particularly those lacking poor-risk genomic lesions, often respond well to chemoimmunotherapy (CIT). DNA methylation profiling can subdivide early-stage patients into naive B-cell-like CLL (n-CLL), memory B-cell-like CLL (m-CLL), and intermediate CLL (i-CLL), with differing times to first treatment and overall survival. However, whether DNA methylation can identify patients destined to respond favorably to CIT has not been ascertained. We classified treatment-naive patients (n = 605) from 3 UK chemo and CIT clinical trials into the 3 epigenetic subgroups, using pyrosequencing and microarray analysis, and performed expansive survival analysis. The n-CLL, i-CLL, and m-CLL signatures were found in 80% (n = 245/305), 17% (53/305), and 2% (7/305) of IGHV-unmutated (IGHV-U) cases, respectively, and in 9%, (19/216), 50% (108/216), and 41% (89/216) of IGHV-M cases, respectively. Multivariate Cox proportional analysis identified m-CLL as an independent prognostic factor for overall survival (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.24-0.87; P = .018) in CLL4, and for progression-free survival (HR, 0.25; 95% CI, 0.10-0.57; P = .002) in ARCTIC and ADMIRE patients. The analysis of epigenetic subgroups in patients entered into 3 first-line UK CLL trials identifies m-CLL as an independent marker of prolonged survival and may aid in the identification of patients destined to demonstrate prolonged survival after CIT.

4.
Blood ; 131(25): 2745-2760, 2018 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-29540348

RESUMO

The previous edition of the consensus guidelines of the International Workshop on Chronic Lymphocytic Leukemia (iwCLL), published in 2008, has found broad acceptance by physicians and investigators caring for patients with CLL. Recent advances including the discovery of the genomic landscape of the disease, the development of genetic tests with prognostic relevance, and the detection of minimal residual disease (MRD), coupled with the increased availability of novel targeted agents with impressive efficacy, prompted an international panel to provide updated evidence- and expert opinion-based recommendations. These recommendations include a revised version of the iwCLL response criteria, an update on the use of MRD status for clinical evaluation, and recommendations regarding the assessment and prophylaxis of viral diseases during management of CLL.


Assuntos
Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/terapia , Ensaios Clínicos como Assunto , Gerenciamento Clínico , Testes Genéticos/métodos , Humanos , Imunofenotipagem/métodos , Cariotipagem/métodos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Mutação , Estadiamento de Neoplasias/métodos , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Neoplasia Residual/patologia , Neoplasia Residual/terapia , Prognóstico
5.
Sci Rep ; 7: 41071, 2017 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-28112199

RESUMO

B-cell malignancies (BCM) originate from the same cell of origin, but at different maturation stages and have distinct clinical phenotypes. Although genetic risk variants for individual BCMs have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. We explored genome-wide association studies of chronic lymphocytic leukaemia (CLL, N = 1,842), Hodgkin lymphoma (HL, N = 1,465) and multiple myeloma (MM, N = 3,790). We identified a novel pleiotropic risk locus at 3q22.2 (NCK1, rs11715604, P = 1.60 × 10-9) with opposing effects between CLL (P = 1.97 × 10-8) and HL (P = 3.31 × 10-3). Eight established non-HLA risk loci showed pleiotropic associations. Within the HLA region, Ser37 + Phe37 in HLA-DRB1 (P = 1.84 × 10-12) was associated with increased CLL and HL risk (P = 4.68 × 10-12), and reduced MM risk (P = 1.12 × 10-2), and Gly70 in HLA-DQB1 (P = 3.15 × 10-10) showed opposing effects between CLL (P = 3.52 × 10-3) and HL (P = 3.41 × 10-9). By integrating eQTL, Hi-C and ChIP-seq data, we show that the pleiotropic risk loci are enriched for B-cell regulatory elements, as well as an over-representation of binding of key B-cell transcription factors. These data identify shared biological pathways influencing the development of CLL, HL and MM. The identification of these risk loci furthers our understanding of the aetiological basis of BCMs.


Assuntos
Pleiotropia Genética/genética , Estudo de Associação Genômica Ampla , Doença de Hodgkin/genética , Leucemia Linfocítica Crônica de Células B/genética , Mieloma Múltiplo/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Idoso , Feminino , Predisposição Genética para Doença , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Doença de Hodgkin/patologia , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Proteínas Oncogênicas/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
6.
Blood ; 129(5): 553-560, 2017 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-27903528

RESUMO

Hairy cell leukemia is an uncommon hematologic malignancy characterized by pancytopenia and marked susceptibility to infection. Tremendous progress in the management of patients with this disease has resulted in high response rates and improved survival, yet relapse and an appropriate approach to re-treatment present continuing areas for research. The disease and its effective treatment are associated with immunosuppression. Because more patients are being treated with alternative programs, comparison of results will require general agreement on definitions of response, relapse, and methods of determining minimal residual disease. The development of internationally accepted, reproducible criteria is of paramount importance in evaluating and comparing clinical trials to provide optimal care. Despite the success achieved in managing these patients, continued participation in available clinical trials in the first-line and particularly in the relapse setting is highly recommended. The Hairy Cell Leukemia Foundation convened an international conference to provide common definitions and structure to guide current management. There is substantial opportunity for continued research in this disease. In addition to the importance of optimizing the prevention and management of the serious risk of infection, organized evaluations of minimal residual disease and treatment at relapse offer ample opportunities for clinical research. Finally, a scholarly evaluation of quality of life in the increasing number of survivors of this now manageable chronic illness merits further study. The development of consensus guidelines for this disease offers a framework for continued enhancement of the outcome for patients.


Assuntos
Antineoplásicos/uso terapêutico , Cladribina/uso terapêutico , Leucemia de Células Pilosas/diagnóstico , Leucemia de Células Pilosas/tratamento farmacológico , Pentostatina/uso terapêutico , Gerenciamento Clínico , Humanos , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasia Residual/diagnóstico , Neoplasia Residual/tratamento farmacológico , Resultado do Tratamento
7.
Blood ; 128(19): 2319-2326, 2016 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-27528712

RESUMO

Chronic lymphocytic leukemia (CLL) can be familial; however, thus far no rare germ line disruptive alleles for CLL have been identified. We performed whole-exome sequencing of 66 CLL families, identifying 4 families where loss-of-function mutations in protection of telomeres 1 (POT1) co-segregated with CLL. The p.Tyr36Cys mutation is predicted to disrupt the interaction between POT1 and the telomeric overhang. The c.1164-1G>A splice-site, p.Gln358SerfsTer13 frameshift, and p.Gln376Arg missense mutations are likely to impact the interaction between POT1 and adrenocortical dysplasia homolog (ACD), which is a part of the telomere-capping shelterin complex. We also identified mutations in ACD (c.752-2A>C) and another shelterin component, telomeric repeat binding factor 2, interacting protein (p.Ala104Pro and p.Arg133Gln), in 3 CLL families. In a complementary analysis of 1083 cases and 5854 controls, the POT1 p.Gln376Arg variant, which has a global minor allele frequency of 0.0005, conferred a 3.61-fold increased risk of CLL (P = .009). This study further highlights telomere dysregulation as a key process in CLL development.


Assuntos
Mutação em Linhagem Germinativa/genética , Leucemia Linfocítica Crônica de Células B/genética , Proteínas de Ligação a Telômeros/genética , Sequência de Aminoácidos , Feminino , Humanos , Masculino , Linhagem , Sítios de Splice de RNA/genética , Homeostase do Telômero , Proteínas de Ligação a Telômeros/química
8.
Cell Rep ; 16(8): 2061-2067, 2016 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-27524613

RESUMO

Chronic lymphocytic leukemia (CLL) is an adult B cell malignancy. Genome-wide association studies show that variation at 15q15.1 influences CLL risk. We deciphered the causal variant at 15q15.1 and the mechanism by which it influences tumorigenesis. We imputed all possible genotypes across the locus and then mapped highly associated SNPs to areas of chromatin accessibility, evolutionary conservation, and transcription factor binding. SNP rs539846 C>A, the most highly associated variant (p = 1.42 × 10(-13), odds ratio = 1.35), localizes to a super-enhancer defined by extensive histone H3 lysine 27 acetylation in intron 3 of B cell lymphoma 2 (BCL2)-modifying factor (BMF). The rs539846-A risk allele alters a conserved RELA-binding motif, disrupts RELA binding, and is associated with decreased BMF expression in CLL. These findings are consistent with rs539846 influencing CLL susceptibility through differential RELA binding, with direct modulation of BMF expression impacting on anti-apoptotic BCL2, a hallmark of oncogenic dependency in CLL.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Elementos Facilitadores Genéticos , Predisposição Genética para Doença , Leucemia Linfocítica Crônica de Células B/genética , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-bcl-2/genética , Fator de Transcrição RelA/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Alelos , Linfócitos B/metabolismo , Linfócitos B/patologia , Sítios de Ligação , Linhagem Celular Tumoral , Cromatina/química , Cromatina/metabolismo , Mapeamento Cromossômico , Cromossomos Humanos Par 15 , Loci Gênicos , Estudo de Associação Genômica Ampla , Histonas/genética , Histonas/metabolismo , Humanos , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Razão de Chances , Ligação Proteica , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Risco , Fator de Transcrição RelA/metabolismo
9.
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
10.
Cancer Res ; 76(6): 1485-1493, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26964624

RESUMO

CYP3A enzymes metabolize endogenous hormones and chemotherapeutic agents used to treat cancer, thereby potentially affecting drug effectiveness. Here, we refined the genetic basis underlying the functional effects of a CYP3A haplotype on urinary estrone glucuronide (E1G) levels and tested for an association between CYP3A genotype and outcome in patients with chronic lymphocytic leukemia (CLL), breast, or lung cancers. The most significantly associated SNP was rs45446698, an SNP that tags the CYP3A7*1C allele; this SNP was associated with a 54% decrease in urinary E1G levels. Genotyping this SNP in 1,008 breast cancer, 1,128 lung cancer, and 347 CLL patients, we found that rs45446698 was associated with breast cancer mortality (HR, 1.74; P = 0.03), all-cause mortality in lung cancer patients (HR, 1.43; P = 0.009), and CLL progression (HR, 1.62; P = 0.03). We also found borderline evidence of a statistical interaction between the CYP3A7*1C allele, treatment of patients with a cytotoxic agent that is a CYP3A substrate, and clinical outcome (Pinteraction = 0.06). The CYP3A7*1C allele, which results in adult expression of the fetal CYP3A7 gene, is likely to be the functional allele influencing levels of circulating endogenous sex hormones and outcome in these various malignancies. Further studies confirming these associations and determining the mechanism by which CYP3A7*1C influences outcome are required. One possibility is that standard chemotherapy regimens that include CYP3A substrates may not be optimal for the approximately 8% of cancer patients who are CYP3A7*1C carriers.


Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Neoplasias da Mama/genética , Leucemia Linfocítica Crônica de Células B/genética , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Neoplasias da Mama/urina , Citocromo P-450 CYP3A , Estrona/urina , Feminino , Genótipo , Glucuronídeos/urina , Humanos , Leucemia Linfocítica Crônica de Células B/urina , Neoplasias Pulmonares/urina , Masculino , Pessoa de Meia-Idade , Adulto Jovem
11.
Br J Haematol ; 173(1): 127-36, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26846718

RESUMO

IGHV gene mutational status has prognostic significance in chronic lymphocytic leukaemia (CLL) but the percentage of mutations that correlates best with clinical outcome remains controversial. We initially studied 558 patients from diagnosis and found significant differences in median time to first treatment (TTFT) among Stage A patients and in overall survival (OS) for the whole cohort, between cases with <97% and 97-98·99% identity and between cases with 97-98·99% and ≥99% identity, when cases from the IGHV3-21 Stereotype Subset #2 were excluded. A significant difference in progression-free survival (PFS) and OS between those with <97% and 97-98·99% identity, but not between those with 97-98·99% and ≥99% identity was also observed in a validation cohort comprising 460 patients in the UK CLL4 trial. Cox Regression analyses in the Stage A cohort revealed that a model which incorporated <97%, 97-98·99% and ≥99% identity as subgroups, was a better predictor of TTFT in CLL than using the 98% cut-off. Multivariate analysis selected the three mutational subgroups as independent predictors of TTFT in Stage A patients, and of OS in the diagnostic cohort. This study highlights that cases with 97% identity should not be considered to have the same prognosis as other cases with mutated IGHV genes defined as <98% identity to germline.


Assuntos
Cadeias Pesadas de Imunoglobulinas/genética , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/mortalidade , Modelos Biológicos , Mutação , Adolescente , Adulto , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Taxa de Sobrevida
12.
Leuk Lymphoma ; 57(10): 2342-50, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-26732125

RESUMO

Chronic lymphocytic leukemia (CLL) is characterized by heterogeneous clinical behavior and there is a need for improved biomarkers. The current study evaluated the prognostic significance of serum free light chains (sFLC, kappa, and lambda) and other serum markers (bar, serum thymidine kinase (sTK), soluble CD23, and LDH) together with established biomarkers in 289 patients enrolled into the LRF CLL4 trial. In a multivariable analysis of serum markers alone, higher big and kappa light chains were statistically significant in predicting disease progression and higher blg, and sTK in predicting mortality. In multivariable analysis for overall survival the following were independently significant: ß2M levels, immunoglobulin gene (IGHV) mutational status (>98% homology), age, 17p13 deletions (>10%), and CD38 expression. ß2M is the only serum marker that retained clear independent value as a biomarker in the LRF CLL4 trial and remains powerfully prognostic requiring evaluation in any future method of risk stratifying patients.


Assuntos
Biomarcadores Tumorais , Cadeias Leves de Imunoglobulina/sangue , Leucemia Linfocítica Crônica de Células B/sangue , Leucemia Linfocítica Crônica de Células B/mortalidade , Microglobulina beta-2/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise de Sobrevida , Resultado do Tratamento
13.
Blood ; 128(19): 2319-2326, 2016 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-31654069

RESUMO

Chronic lymphocytic leukemia (CLL) can be familial; however, thus far no rare germ line disruptive alleles for CLL have been identified. We performed whole-exome sequencing of 66 CLL families, identifying 4 families where loss-of-function mutations in protection of telomeres 1 (POT1) co-segregated with CLL. The p.Tyr36Cys mutation is predicted to disrupt the interaction between POT1 and the telomeric overhang. The c.1164-1G>A splice-site, p.Gln358SerfsTer13 frameshift, and p.Gln376Arg missense mutations are likely to impact the interaction between POT1 and adrenocortical dysplasia homolog (ACD), which is a part of the telomere-capping shelterin complex. We also identified mutations in ACD (c.752-2A>C) and another shelterin component, telomeric repeat binding factor 2, interacting protein (p.Ala104Pro and p.Arg133Gln), in 3 CLL families. In a complementary analysis of 1083 cases and 5854 controls, the POT1 p.Gln376Arg variant, which has a global minor allele frequency of 0.0005, conferred a 3.61-fold increased risk of CLL (P = .009). This study further highlights telomere dysregulation as a key process in CLL development.

14.
Br J Haematol ; 172(2): 228-37, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26457986

RESUMO

With 10+ years follow-up in the Leukaemia Research Fund (LRF) CLL4 trial, we report the effect of salvage therapy, and the clinical/biological features of the 10-year survivors treated for chronic lymphocytic leukaemia (CLL). Overall survival (OS) was similar in the three randomized arms. With fludarabine-plus-cyclophosphamide (FC), progression-free survival (PFS) was significantly longer (P < 0.0001), but OS after progression significantly shorter, than in the chlorambucil or fludarabine arms (P < 0.0001). 614/777 patients progressed; 524 received second-line and 260 third-line therapy, with significantly better complete remission (CR) rates compared to first-line in the chlorambucil arm (7% vs. 13% after second-, 18% after third-line), but worse in the FC arm (38% vs. 15% after both second and third-line). OS 10 years after progression was better after a second-line CR versus a partial response (36% vs. 16%) and better with FC-based second-line therapy (including rituximab in 20%) or a stem cell transplant (28%) versus all other treatments (10%, P < 0.0001). The 176 (24%) 10-year survivors tended to be aged <70 years, with a "good risk" prognostic profile, stage A-progressive, achieving at least one CR, with a first-line PFS >3 years and receiving ≤2 lines of treatment. In conclusion, clinical/biological features and salvage treatments both influence the long-term outcome. Second-line therapies that induce a CR can improve OS in CLL patients.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/sangue , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Clorambucila/uso terapêutico , Ciclofosfamida/administração & dosagem , Progressão da Doença , Feminino , Seguimentos , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Masculino , Pessoa de Meia-Idade , Prognóstico , Indução de Remissão , Terapia de Salvação/métodos , Resultado do Tratamento , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico
15.
Best Pract Res Clin Haematol ; 28(4): 217-29, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26614900

RESUMO

Since 2006 when we last reviewed the literature concerning the use of purine analogues in hairy cell leukaemia (HCL), results from several new and updated series have been published. Here we examine these reports and consider their implications for patient management. The two purine analogues pentostatin and cladribine remain the first-line treatments of choice for all patients with HCL. Although they have not been compared in randomised trials, they appear to be equally effective. A complete response is important for the long-term outcome and we look at how best this can be achieved. Evidence is emerging which supports the use of either purine analogue plus an anti-CD20 monoclonal antibody after relapse, though questions remain concerning the scheduling of the monoclonal antibody. Patients refractory to the purine analogues may require alternative agents.


Assuntos
Antineoplásicos/uso terapêutico , Linfócitos B/efeitos dos fármacos , Cladribina/uso terapêutico , Leucemia de Células Pilosas/diagnóstico , Leucemia de Células Pilosas/tratamento farmacológico , Pentostatina/uso terapêutico , Linfócitos B/patologia , Seguimentos , Humanos , Indóis/uso terapêutico , Leucemia de Células Pilosas/mortalidade , Leucemia de Células Pilosas/patologia , Mutação , Prognóstico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/imunologia , Recidiva , Indução de Remissão , Rituximab/uso terapêutico , Sulfonamidas/uso terapêutico , Análise de Sobrevida , Vemurafenib
16.
Br J Haematol ; 171(5): 784-7, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26403440

RESUMO

We describe three cases of relapsed hairy cell leukaemia (HCL) treated with pentostatin plus rituximab. All three achieved bone marrow complete remission but had persistent splenomegaly and hypersplenism. Because of the clinical uncertainty of its significance, they were all splenectomized. The spleen histology showed no evidence of HCL, but a five-fold thickening of the splenic capsule and areas of fibrosis in the red pulp. This process may have contributed to the lack of elasticity and caused the persistent splenomegaly. We discuss the clinical implications for future patient management. The three patients remain in remission at 1 + , 5 + and 9 + years.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imunoterapia/efeitos adversos , Leucemia de Células Pilosas/terapia , Esplenectomia/métodos , Esplenomegalia/etiologia , Adulto , Doença Crônica , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pentostatina/administração & dosagem , Recidiva , Indução de Remissão , Rituximab/administração & dosagem , Baço/patologia , Esplenomegalia/patologia , Esplenomegalia/cirurgia
17.
Haematologica ; 99(4): 736-42, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24584352

RESUMO

ATM mutation and BIRC3 deletion and/or mutation have independently been shown to have prognostic significance in chronic lymphocytic leukemia. However, the relative clinical importance of these abnormalities in patients with a deletion of 11q encompassing the ATM gene has not been established. We screened a cohort of 166 patients enriched for 11q-deletions for ATM mutations and BIRC3 deletion and mutation and determined the overall and progression-free survival among the 133 of these cases treated within the UK LRF CLL4 trial. SNP6.0 profiling demonstrated that BIRC3 deletion occurred in 83% of 11q-deleted cases and always co-existed with ATM deletion. For the first time we have demonstrated that 40% of BIRC3-deleted cases have concomitant deletion and mutation of ATM. While BIRC3 mutations were rare, they exclusively occurred with BIRC3 deletion and a wild-type residual ATM allele. In 11q-deleted cases, we confirmed that ATM mutation was associated with a reduced overall and progression-free survival comparable to that seen with TP53 abnormalities, whereas BIRC3 deletion and/or mutation had no impact on overall and progression-free survival. In conclusion, in 11q-deleted patients treated with first-line chemotherapy, ATM mutation rather than BIRC3 deletion and/or mutation identifies a subgroup with a poorer outcome.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Cromossomos Humanos Par 11 , Proteínas Inibidoras de Apoptose/genética , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/mortalidade , Mutação , Deleção de Sequência , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteína 3 com Repetições IAP de Baculovírus , Aberrações Cromossômicas , Feminino , Deleção de Genes , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Avaliação de Resultados da Assistência ao Paciente , Polimorfismo de Nucleotídeo Único , Prognóstico , Ubiquitina-Proteína Ligases
18.
Haematologica ; 99(6): 1088-94, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24658818

RESUMO

We examined the prognostic influence of gender in chronic lymphocytic leukemia. Data from four randomized trials (involving 1821 patients) and three registration studies of stage-A disease (involving 1299 patients) were analyzed. Overall survival at 10 years was better for women than men in all trials (27% versus 15%; P=0.0001) and in the registration series (55% versus 43%; P<0.0001). More women than men in the trials were Binet stage A-progressive (26% versus 15%), but gender was an independent predictor of survival in multivariate analysis of clinical variables (P<0.0001). Women responded better to treatment (overall response 83%) than men (71%; P<0.0001), within each stage and age group, although fewer women than men received the full treatment dose (79% versus 85%; P=0.01). Women were more likely than men to experience toxicity (85% versus 78%, P=0.01), particularly gastro-intestinal toxicity (57% versus 42%, P<0.0001). Laboratory markers in the LRF CLL4 trial showed a significantly lower incidence in women than men of unmutated IGHV genes, raised beta-2 microglobulin, CD38 and Zap-70 positivity and TP53 deletions/mutations and/or 11q deletions. We also highlight the higher male:female ratios in randomized trials versus studies of early chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis. Chronic lymphocytic leukemia in women runs a more benign clinical course than in men. Gender was also an independent predictor of response, suggesting that pharmacokinetic differences between the sexes and a possible effect of estrogens may contribute to the better outcome. Understanding the reasons for the different outcome by gender may improve patients' management. (LRF CLL4 controlled-trials.com identifier: ISRCTN58585610).


Assuntos
Leucemia Linfocítica Crônica de Células B/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Incidência , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Sistema de Registros , Fatores Sexuais , Resultado do Tratamento
19.
Nat Genet ; 46(1): 56-60, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24292274

RESUMO

Genome-wide association studies (GWAS) of chronic lymphocytic leukemia (CLL) have shown that common genetic variation contributes to the heritable risk of CLL. To identify additional CLL susceptibility loci, we conducted a GWAS and performed a meta-analysis with a published GWAS totaling 1,739 individuals with CLL (cases) and 5,199 controls with validation in an additional 1,144 cases and 3,151 controls. A combined analysis identified new susceptibility loci mapping to 3q26.2 (rs10936599, P = 1.74 × 10(-9)), 4q26 (rs6858698, P = 3.07 × 10(-9)), 6q25.2 (IPCEF1, rs2236256, P = 1.50 × 10(-10)) and 7q31.33 (POT1, rs17246404, P = 3.40 × 10(-8)). Additionally, we identified a promising association at 5p15.33 (CLPTM1L, rs31490, P = 1.72 × 10(-7)) and validated recently reported putative associations at 5p15.33 (TERT, rs10069690, P = 1.12 × 10(-10)) and 8q22.3 (rs2511714, P = 2.90 × 10(-9)). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CLL.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Leucemia Linfocítica Crônica de Células B/genética , Polimorfismo de Nucleotídeo Único , Idoso , Estudos de Casos e Controles , Cromossomos Humanos Par 3 , Humanos , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Recombinação Genética , Proteínas de Ligação a Telômeros/genética
20.
Blood ; 122(26): 4253-8, 2013 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-24128861

RESUMO

Fludarabine plus cyclophosphamide (FC) is the chemotherapy backbone of modern chronic lymphocytic leukemia (CLL) treatment. CYP2B6 is a polymorphic cytochrome P450 isoform that converts cyclophosphamide to its active form. This study investigated the possible impact of genetic variation in CYP2B6 on response to FC chemotherapy in CLL. Available DNA samples from the LRF CLL4 trial, which compared chlorambucil, fludarabine, and FC, were screened by TaqMan real-time polymerase chain reaction assays for CYP2B6 SNPs c.516G>T and c.785A>G, which define the most common variant allele (*6). Among the 455 samples successfully genotyped, 265 (58.2%), 134 (29.5%), and 29 (6.4%) were classified as *1/*1, *1/*6, and *6/*6, respectively. Patients expressing at least one *6 allele were significantly less likely to achieve a complete response (CR) after FC (odds ratio 0.27; P = .004) but not chlorambucil or fludarabine. Analysis of individual response indicators confirmed that this inferior response resulted from impaired cytoreduction rather than delayed hemopoietic recovery. Multivariate analysis controlling for age, gender, stage, IGHV mutational status, 11q deletion, and TP53 deletion/mutation identified CYP2B6*6 and TP53 mutation/deletion as the only independent determinants of CR attainment after FC. Our study provides the first demonstration that host pharmacogenetics can influence therapeutic response in CLL. This trial is registered as an International Standard Randomised Control Trial, number NCT 58585610 at www.clinicaltrials.gov.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Hidrocarboneto de Aril Hidroxilases/genética , Ciclofosfamida/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/genética , Vidarabina/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/efeitos adversos , Citocromo P-450 CYP2B6 , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Farmacogenética , Prognóstico , Indução de Remissão , Vidarabina/administração & dosagem , Vidarabina/efeitos adversos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA