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1.
Ann Hematol ; 99(4): 765-772, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32062741

RESUMO

Bone marrow WT1 mRNA levels assessed by the ELN method are useful to establish prognostic correlations in myeloid malignancies treated with chemotherapy or hematopoietic stem cell transplantation (HCT). Those patients with WT1 levels below ten copies have a good outcome. However, some of these patients relapse. To further characterize this group of cases, we applied a new and sensitive digital (ddPCR) WT1 method. A consecutive series of 49 patients with treated myeloid malignancies and with an ELN WT1 quantitation of < 10 copies were included in the study. All cases (47 AML and 2 MDS) have received intensive chemotherapy or HCT. One to four micrograms of total RNA were retrotranscribed to obtain ≥ 10,000 ABL1 copies using the ELN protocol. Only those cases with a good quality cDNA were used in the ddPCR WT1 test. The ddPCR Gene Expression WT1 Assay of Bio-Rad© was used to perform the PCR amplification, and the microdroplets were quantified in the Bio-Rad's QX200 droplet reader. Eighteen patients showed a negative WT1 ddPCR assay (0 copies/µl), whereas 31 cases were positive (results ranged from 1 to 15.2 copies/µl). Survival analysis showed statistically significant differences in terms of OS between both groups, 83 ± 8% vs. 46 ± 9% (p = 0.024). A statistically significant correlation was also found between ddPCRWT1 results and CD123+ cell number detected by flow cytometry (p = 0.024). Larger series of patients tested with the current ddPCRWT1 method will solve whether it could be used to stratify patients with myeloid malignancies achieving deep WT1 molecular response (< 10 copies).


Assuntos
Genes do Tumor de Wilms , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/genética , Reação em Cadeia da Polimerase/métodos , Adulto , Idoso , DNA Complementar/genética , Feminino , Citometria de Fluxo , Dosagem de Genes , Humanos , Imunofenotipagem , Lactente , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , RNA Neoplásico/genética , Reação em Cadeia da Polimerase em Tempo Real , Adulto Jovem
2.
J Hematol Oncol ; 11(1): 96, 2018 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-30041662

RESUMO

Recurrent deletions of the CDKN2A/ARF/CDKN2B genes encoded at chromosome 9p21 have been described in both pediatric and adult acute lymphoblastic leukemia (ALL), but their prognostic value remains controversial, with limited data on adult T-ALL. Here, we investigated the presence of homozygous and heterozygous deletions of the CDKN2A/ARF and CDKN2B genes in 64 adult T-ALL patients enrolled in two consecutive trials from the Spanish PETHEMA group. Alterations in CDKN2A/ARF/CDKN2B were detected in 35/64 patients (55%). Most of them consisted of 9p21 losses involving homozygous deletions of the CDKNA/ARF gene (26/64), as confirmed by single nucleotide polymorphism (SNP) arrays and interphase fluorescence in situ hybridization (iFISH). Deletions involving the CDKN2A/ARF/CDKN2B locus correlated with a higher frequency of cortical T cell phenotype and a better clearance of minimal residual disease (MRD) after induction therapy. Moreover, the combination of an altered copy-number-value (CNV) involving the CDKN2A/ARF/CDKN2B gene locus and undetectable MRD (≤ 0.01%) values allowed the identification of a subset of T-ALL with better overall survival in the absence of hematopoietic stem cell transplantation.


Assuntos
Inibidor de Quinase Dependente de Ciclina p15/genética , Deleção de Genes , Genes p16 , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Proteína Supressora de Tumor p14ARF/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Humanos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Prognóstico
4.
Leukemia ; 30(4): 929-36, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26639181

RESUMO

In chronic lymphocytic leukemia (CLL) the level of minimal residual disease (MRD) after therapy is an independent predictor of outcome. Given the increasing number of new agents being explored for CLL therapy, using MRD as a surrogate could greatly reduce the time necessary to assess their efficacy. In this European Research Initiative on CLL (ERIC) project we have identified and validated a flow-cytometric approach to reliably quantitate CLL cells to the level of 0.0010% (10(-5)). The assay comprises a core panel of six markers (i.e. CD19, CD20, CD5, CD43, CD79b and CD81) with a component specification independent of instrument and reagents, which can be locally re-validated using normal peripheral blood. This method is directly comparable to previous ERIC-designed assays and also provides a backbone for investigation of new markers. A parallel analysis of high-throughput sequencing using the ClonoSEQ assay showed good concordance with flow cytometry results at the 0.010% (10(-4)) level, the MRD threshold defined in the 2008 International Workshop on CLL guidelines, but it also provides good linearity to a detection limit of 1 in a million (10(-6)). The combination of both technologies would permit a highly sensitive approach to MRD detection while providing a reproducible and broadly accessible method to quantify residual disease and optimize treatment in CLL.


Assuntos
Antígenos CD/metabolismo , Citometria de Fluxo/normas , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Leucemia Linfocítica Crônica de Células B/terapia , Neoplasia Residual/diagnóstico , Adolescente , Adulto , Terapia Combinada , Europa (Continente) , Feminino , Seguimentos , Humanos , Imunofenotipagem , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Estadiamento de Neoplasias , Neoplasia Residual/genética , Neoplasia Residual/metabolismo , Prognóstico , Adulto Jovem
5.
Blood Cancer J ; 5: e352, 2015 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-26430723

RESUMO

Acute myeloid leukemia (AML) is a heterogeneous disease whose prognosis is mainly related to the biological risk conferred by cytogenetics and molecular profiling. In elderly patients (⩾60 years) with normal karyotype AML miR-3151 have been identified as a prognostic factor. However, miR-3151 prognostic value has not been examined in younger AML patients. In the present work, we have studied miR-3151 alone and in combination with BAALC, its host gene, in a cohort of 181 younger intermediate-risk AML (IR-AML) patients. Patients with higher expression of miR-3151 had shorter overall survival (P=0.0025), shorter leukemia-free survival (P=0.026) and higher cumulative incidence of relapse (P=0.082). Moreover, in the multivariate analysis miR-3151 emerged as independent prognostic marker in both the overall series and within the unfavorable molecular prognostic category. Interestingly, the combined determination of both miR-3151 and BAALC improved this prognostic stratification, with patients with low levels of both parameters showing a better outcome compared with those patients harboring increased levels of one or both markers (P=0.003). In addition, we studied the microRNA expression profile associated with miR-3151 identifying a six-microRNA signature. In conclusion, the analysis of miR-3151 and BAALC expression may well contribute to an improved prognostic stratification of younger patients with IR-AML.


Assuntos
Biomarcadores Tumorais/genética , Leucemia Mieloide Aguda/genética , MicroRNAs/genética , Proteínas de Neoplasias/genética , Adolescente , Adulto , Idoso , Análise Citogenética , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Fatores de Risco , Transcriptoma , Adulto Jovem
6.
Leukemia ; 29(2): 369-76, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25036192

RESUMO

Serial quantification of BCR-ABL1 mRNA is an important therapeutic indicator in chronic myeloid leukaemia, but there is a substantial variation in results reported by different laboratories. To improve comparability, an internationally accepted plasmid certified reference material (CRM) was developed according to ISO Guide 34:2009. Fragments of BCR-ABL1 (e14a2 mRNA fusion), BCR and GUSB transcripts were amplified and cloned into pUC18 to yield plasmid pIRMM0099. Six different linearised plasmid solutions were produced with the following copy number concentrations, assigned by digital PCR, and expanded uncertainties: 1.08±0.13 × 10(6), 1.08±0.11 × 10(5), 1.03±0.10 × 10(4), 1.02±0.09 × 10(3), 1.04±0.10 × 10(2) and 10.0±1.5 copies/µl. The certification of the material for the number of specific DNA fragments per plasmid, copy number concentration of the plasmid solutions and the assessment of inter-unit heterogeneity and stability were performed according to ISO Guide 35:2006. Two suitability studies performed by 63 BCR-ABL1 testing laboratories demonstrated that this set of 6 plasmid CRMs can help to standardise a number of measured transcripts of e14a2 BCR-ABL1 and three control genes (ABL1, BCR and GUSB). The set of six plasmid CRMs is distributed worldwide by the Institute for Reference Materials and Measurements (Belgium) and its authorised distributors (https://ec.europa.eu/jrc/en/reference-materials/catalogue/; CRM code ERM-AD623a-f).


Assuntos
Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Plasmídeos/genética , Reação em Cadeia da Polimerase em Tempo Real/normas , Calibragem , Clonagem Molecular , DNA , Proteínas de Escherichia coli/genética , Dosagem de Genes , Humanos , Proteínas de Membrana Transportadoras/genética , Proteínas Proto-Oncogênicas c-bcr/genética , RNA Mensageiro/metabolismo , Padrões de Referência
7.
Leukemia ; 28(4): 804-12, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24072101

RESUMO

Acute myeloid leukemia (AML) is a heterogeneous disease, and optimal treatment varies according to cytogenetic risk factors and molecular markers. Several studies have demonstrated the prognostic importance of microRNAs (miRNAs) in AML. Here we report a potential association between miRNA expression and clinical outcome in 238 intermediate-risk cytogenetic AML (IR-AML) patients from 16 institutions in the CETLAM cooperative group. We first profiled 670 miRNAs in a subset of 85 IR-AML patients from a single institution and identified 10 outcome-related miRNAs. We then validated these 10 miRNAs by individual assays in the total cohort and confirmed the prognostic impact of 4 miRNAs. High levels of miR-196b and miR-644 were independently associated with shorter overall survival, and low levels of miR-135a and miR-409-3p with a higher risk of relapse. Interestingly, miR-135a and miR-409-3p maintained their independent prognostic value within the unfavorable molecular subcategory (wild-type NPM1 and CEBPA and/or FLT3-ITD), and miR-644 retained its value within the favorable molecular subcategory. miR-409-3p, miR-135a, miR-196b and mir-644 arose as prognostic markers for IR-AML, both overall and within specific molecular subgroups.


Assuntos
Leucemia Mieloide Aguda/genética , MicroRNAs/análise , Adolescente , Adulto , Idoso , Feminino , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/genética , Humanos , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Nucleofosmina , Prognóstico , Risco
8.
Leukemia ; 27(11): 2157-64, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23584566

RESUMO

We retrospectively assessed whether normalized bone marrow WT1 levels could be used for risk stratification in a consecutive series of 584 acute myeloid leukemia (AML) patients. A cutoff value of 5065 copies at diagnosis identified two prognostic groups (overall survival (OS): 44 ± 3 vs 36 ± 3%, P=0.023; leukemia-free survival (LFS): 47 ± 3 vs 36 ± 4%, P=0.038; and cumulative incidence of relapse (CIR): 37 ± 3 vs 47 ± 4%, P=:0.043). Three groups were identified on the basis of WT1 levels post-induction: Group 0 (WT1 between 0 and 17.5 copies, 134 patients, OS: 59 ± 4%, LFS:59 ± 4% and CIR: 26 ± 4%); Group 1 (WT1 between 17.6 and 170.5 copies, 160 patients, OS: 48 ± 5%, LFS:41 ± 4% and CIR: 45 ± 4%); and Group 2 (WT1 >170.5 copies, 71 patients, OS: 23 ± 6%, LFS: 19 ± 7% and CIR: 68 ± 8%) (P<0.001). Post-intensification samples distinguished three groups: patients with WT1 >100 copies (47 patients, 16%); an intermediate group of patients with WT1 between 10 and 100 copies (148 patients, 52%); and a third group with WT1 <10 copies (92 patients, 32%). Outcomes differed significantly in terms of OS (30 ± 7%, 59 ± 4%, 72 ± 5%), LFS (24 ± 7%, 46 ± 4%, 65 ± 5%) and relapse probability (CIR 72 ± 7%, 45 ± 4%, 25 ± 5%), all P<0.001. WT1 levels in bone marrow assayed using the standardized ELN method provide relevant prognostic information in de novo AML.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Medula Óssea/metabolismo , Recidiva Local de Neoplasia/genética , Neoplasia Residual/genética , Proteínas WT1/genética , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Medula Óssea/efeitos dos fármacos , Medula Óssea/patologia , Quimioterapia de Consolidação , Feminino , Seguimentos , Dosagem de Genes , Humanos , Imunofenotipagem , Leucemia Mieloide Aguda , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/mortalidade , Estadiamento de Neoplasias , Neoplasia Residual/diagnóstico , Neoplasia Residual/tratamento farmacológico , Neoplasia Residual/mortalidade , Reação em Cadeia da Polimerase , Prognóstico , Indução de Remissão , Estudos Retrospectivos , Taxa de Sobrevida , Proteínas WT1/metabolismo , Adulto Jovem
9.
Leuk Res ; 36(8): 990-7, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22520341

RESUMO

The study of genetic lesions in AML cells is helpful to define the prognosis of patients with this disease. This study analyzed the frequency and clinical impact of recently described gene alterations, isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) mutations, in a series of homogeneously treated patients with primary (de novo) AML. Two-hundred and seventy-five patients enrolled in the CETLAM 2003 protocol were analyzed. IDH1 and IDH2 mutations were investigated by well-established melting curve-analysis and direct sequencing (R140 IDH2 mutations). To establish the percentage of the mutated allele a pyrosequencing method was used. Patients were also studied for NPM, FLT3, MLL, CEBPA, TET2 and WT1 mutations. IDH1 or IDH2 mutations were identified in 23.3% AML cases and in 22.5% of those with a normal karyotype. In this latter group, mutations were associated with short overall survival. This adverse effect was even more evident in patients with the NPM or CEBPA mutated/FLT3 wt genotype. In all the cases analyzed, the normal allele was detected, suggesting that both mutations act as dominant oncogenes. No adverse clinical impact was observed in cases with TET2 mutations. IDH1 and IDH2 mutations are common genetic alterations in normal karyotype AML. Favourable genotype NPM or CEBPA mutated/FLT3 wt can be further categorized according to the IDH1 and IDH2 mutational status.


Assuntos
Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Mutação , Adolescente , Adulto , Idoso , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Frequência do Gene , Humanos , Isocitrato Desidrogenase/fisiologia , Cariótipo , Leucemia Mieloide Aguda/epidemiologia , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação/fisiologia , Prognóstico , Estudos Retrospectivos , Espanha/epidemiologia , Análise de Sobrevida , Adulto Jovem
10.
Ann Oncol ; 23(3): 729-735, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21693768

RESUMO

BACKGROUND: Deletions at 13q14.3 are common in chronic lymphocytic leukemia and are also present in diffuse large B-cell lymphomas (DLBCL) but never in immunodeficiency-related DLBCL. To characterize DLBCL with 13q14.3 deletions, we combined genome-wide DNA profiling, gene expression and clinical data in a large DLBCL series treated with rituximab, cyclophosphamide, doxorubicine, vincristine and prednisone repeated every 21 days (R-CHOP21). PATIENTS AND METHODS: Affymetrix GeneChip Human Mapping 250K NspI and U133 plus 2.0 gene were used. MicroRNA (miRNA) expression was studied were by real-time PCR. Median follow-up of patients was 4.9 years. RESULTS: Deletions at 13q14.3, comprising DLEU2/MIR15A/MIR16, occurred in 22/166 (13%) cases. The deletion was wider, including also RB1, in 19/22 cases. Samples with del(13q14.3) had concomitant specific aberrations. No reduced MIR15A/MIR16 expression was observed, but 172 transcripts were significantly differential expressed. Among the deregulated genes, there were RB1 and FAS, both commonly deleted at genomic level. No differences in outcome were observed in patients treated with R-CHOP21. CONCLUSIONS: Cases with 13q14.3 deletions appear as group of DLBCL characterized by common genetic and biologic features. Deletions at 13q14.3 might contribute to DLBCL pathogenesis by two mechanisms: deregulating the cell cycle control mainly due RB1 loss and contributing to immune escape, due to FAS down-regulation.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 13/genética , Perfilação da Expressão Gênica , Linfoma Difuso de Grandes Células B/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase em Tempo Real
12.
Leuk Res ; 35(2): 163-8, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20542566

RESUMO

NPM mutations are the most common genetic abnormalities found in non-promyelocytic AML. NPM-positive patients usually show a normal karyotype, a peculiar morphologic appearance with frequent monocytic traits and good prognosis in the absence of an associated FLT3 mutation. This report describes the immunophenotypic and genetic characteristics of a consecutive series of NPM-mutated de novo AML patients enroled in the CETLAM trial. Eighty-three patients were included in the study. Complete immunophenotype was obtained using multiparametric flow cytometry. Associated genetic lesions (FLT3, MLL, CEBPA and WT1 mutations) were studied by standardized methods. Real-time PCR was employed to assess the minimal residual status. The most common pattern was CD34-CD15+ and HLA-DR+. Small CD34 populations with immunophenotypic aberrations (CD15 and CD19 coexpression, abnormal SSC) were detected even in CD34 negative samples. Nearly all cases expressed CD33 (strong positivity), CD13 and CD117, and all were CD123+. The stem cell marker CD110 was also positive in most cases. Biologic parameters such as a high percentage of intermediate CD45+ (blast gate) (>75% nucleated cells), CD123+ and FLT3-ITD mutations were associated with a poor outcome. Quantitative PCR positivity had no prognostic impact either after induction or at the end of chemotherapy. Only PCR positivity (greater than 10 copies) detected in patients in haematological remission was associated with an increased relapse rate. Further studies are required to determine whether the degree of leukemic stem cell expansion (CD45+CD123+cells) increases the risk of acquisition of FLT3-ITD and/or provides selective advantages.


Assuntos
Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Mutação , Proteínas Nucleares/genética , Adulto , Idoso , Antígenos CD/biossíntese , Proteínas Estimuladoras de Ligação a CCAAT/genética , Feminino , Citometria de Fluxo , Genes do Tumor de Wilms , Histona-Lisina N-Metiltransferase , Humanos , Imunofenotipagem , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Proteína de Leucina Linfoide-Mieloide/genética , Nucleofosmina , Prognóstico , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Adulto Jovem , Tirosina Quinase 3 Semelhante a fms/genética
13.
Leukemia ; 23(3): 486-91, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19092854

RESUMO

The recently described single-nucleotide polymorphism CT60, located in the 3'-untranslated region of the CTLA4 (cytotoxic T-lymphocyte antigen 4 ) gene, has been associated with susceptibility to several autoimmune diseases and has also been shown to be involved in immune responses following allogeneic stem cell transplantation (SCT). However, the contribution of the CTLA4 genotype to the control of minimal residual disease in patients with acute myeloid leukemia (AML) has yet to be explored. We investigated the association between the CTLA4 CT60 A/G genotype and the incidence of leukemic relapse in 143 adult patients with AML in first complete remission after the same chemotherapy protocol (CETLAM LAM'03). The CT60 AA genotype was associated with a higher rate of leukemic relapse (56.4 vs 35.6%, P=0.004; hazard ratio (HR)=2.64, 95% confidence interval (CI)=1.36-5.14) and lower overall survival at 3 years (39.4 vs 68.4%, P=0.004; HR=2.80, 95% CI=1.39-5.64). This is the first study to report an association between polymorphisms at CTLA-4 and AML relapse.


Assuntos
Antígenos CD/genética , Leucemia Mieloide/tratamento farmacológico , Proteínas de Neoplasias/genética , Regiões 3' não Traduzidas/genética , Doença Aguda , Adolescente , Adulto , Antígenos CD/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno CTLA-4 , Terapia Combinada , Citarabina/administração & dosagem , Intervalo Livre de Doença , Etoposídeo/administração & dosagem , Feminino , Genótipo , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Humanos , Idarubicina/administração & dosagem , Incidência , Estimativa de Kaplan-Meier , Leucemia Mieloide/epidemiologia , Leucemia Mieloide/genética , Leucemia Mieloide/imunologia , Leucemia Mieloide/cirurgia , Masculino , Pessoa de Meia-Idade , Mitoxantrona/administração & dosagem , Proteínas de Neoplasias/imunologia , Polimorfismo de Nucleotídeo Único , Modelos de Riscos Proporcionais , Recidiva , Indução de Remissão , Adulto Jovem
14.
Eur Respir J ; 31(6): 1368-72, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18515560

RESUMO

The present study describes an adult male who has had recurrent episodes of pulmonary infiltrates with severe acute respiratory failure over a period of 10 yrs. Clinical and pathological characteristics revealed bronchiolitis obliterans with organising pneumonia (BOOP) that responded dramatically to prednisone. BOOP is characterised by inflammation of the bronchioles and surrounding tissue in the lungs. It can mimic infectious pneumonia but diagnosis is suspected when there is no response to multiple antibiotic treatment, and blood and sputum cultures are negative for microorganisms. A high proportion of double-positive (DP)-T-cells was detected in peripheral blood and in bronchoalveolar lavage, expressing CD4 and CD8alphabeta heterodimer with memory phenotype. These DP-T-lymphocytes expressed specific homing molecules that could explain their tropism to lung tissue, giving rise to the clinical symptoms. The patient did not present organomegaly, lymphadenopathy, lymphocytosis or other features of malignancy. However, T-cell receptor Vbeta chain analysis indicated clonal rearrangement, and cytogenetic studies displayed chromosomic alterations that were similar to clonal proliferation observed in ataxia-telangiectasia and T-prolymphocytic leukaemia. The findings suggest a smouldering form of lymphoproliferation, the first sign of which was bronchiolitis obliterans organising pneumonia requiring constant corticoid treatment.


Assuntos
Pneumonia em Organização Criptogênica/complicações , Leucemia de Células T/complicações , Leucemia de Células T/diagnóstico , Adulto , Anti-Inflamatórios/uso terapêutico , Líquido da Lavagem Broncoalveolar/citologia , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Pneumonia em Organização Criptogênica/sangue , Pneumonia em Organização Criptogênica/tratamento farmacológico , Humanos , Leucemia de Células T/classificação , Masculino , Prednisolona/uso terapêutico
16.
Leukemia ; 21(7): 1413-22, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17476281

RESUMO

Therapy-related myelodysplasia and acute myeloid leukemia (t-MDS/AML) is a malignancy occurring after exposure to chemotherapy and/or radiotherapy. Polymorphisms involved in chemotherapy/radiotherapy response genes could be related to an increased risk of developing this neoplasia. We have studied 11 polymorphisms in genes of drug detoxification pathways (NQO1, glutathione S-transferase pi) and DNA repair xeroderma pigmentosum, complementation group (3) (XPC(3), X-ray repair cross complementing protein (1)), Nijmegen breakage syndrome (1), excision repair cross-complementing rodent repair deficiency, complementation group (5) and X-ray repair cross complementing protein (3) and in the methylene tetrahydrofolate reductase gene (MTHFR(2), 677C>T, 1298A>C), involved in DNA synthesis. The analyzed groups were a t-MDS/AML patients group (n=81) and a matched control group (n=64) treated similarly, and they did not develop t-MDS/AML. We found no significant differences when the groups were compared globally. However, when analysis was carried out according to the primary neoplasia involved, a significant association was observed between the MTHFR haplotype (single nucleotide polymorphisms 677 and 1298) and the risk of developing t-MDS/AML in the breast cancer patients group (P=0.016) and cyclophosphamide-treated hematological disease group (P=0.005). Risk haplotype was different for each case, corresponding to the 677T1298A haplotype after breast cancer treatment and the 677C1298C haplotype after hematological malignancy treatment. We postulate that such differences are related to variations in chemotherapy schemes between hematological and breast cancers and their differential interaction with the MTHFR route.


Assuntos
Haplótipos , Leucemia/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/patologia , Humanos , Leucemia/induzido quimicamente , Leucemia/etiologia , Pessoa de Meia-Idade , Segunda Neoplasia Primária/etiologia , Segunda Neoplasia Primária/genética , Polimorfismo de Nucleotídeo Único , Fatores de Risco
17.
Leukemia ; 20(1): 87-94, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16281071

RESUMO

Most patients with acute myeloid leukemia (AML) and t(8;21) or inv(16) have a good prognosis with current anthracycline- and cytarabine-based protocols. Tandem analysis with flow cytometry (FC) and real-time RT-PCR (RQ-PCR) was applied to 55 patients, 28 harboring a t(8;21) and 27 an inv(16), including one case with a novel CBFbeta/MYH11 transcript. A total of 31% (n=17) of CR patients relapsed: seven with t(8;21) and 10 with inv(16). The mean amount of minimal residual disease (MRD) detected by FC in relapsed and nonrelapsed patients was markedly different: 0.3 vs 0.08% (P=0.002) at the end of treatment. The mean number of fusion transcript copies/ ABL x 10(4) also differed between relapsed and non-relapsed patients: 2385 vs 122 (P=0.001) after induction, 56 vs 7.6 after intensification (P=0.0001) and 75 vs 3.3 (P=0.0001) at the end of chemotherapy. Relapses were more common in patients with FC MRD level >0.1% at the end of treatment than in patients with < or = 0.1%: cumulative incidence of relapse (CIR) was 67 and 21% (P=0.03), respectively. Likewise, using RQ-PCR, a cutoff level of >10 copies at the end of treatment correlated with a high risk of relapse: CIR was 75% for patients with RQ-PCR >10 compared to 21% for patients with RQ-PCR levels < or = 10 (P=0.04). Combined use of FC and RQ-PCR may improve MRD detection, and provide useful clinical information on relapse kinetics in AML patients.


Assuntos
Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 8/genética , Leucemia Mieloide/genética , Neoplasia Residual/genética , Doença Aguda , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Inversão Cromossômica , Análise Citogenética , Feminino , Citometria de Fluxo , Seguimentos , Humanos , Cinética , Leucemia Mieloide/metabolismo , Leucemia Mieloide/terapia , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/diagnóstico , Neoplasia Residual/terapia , Prognóstico , Recidiva , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Risco , Taxa de Sobrevida
18.
Leuk Res ; 29(10): 1109-16, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16095690

RESUMO

BACKGROUND AND OBJECTIVES: A consecutive series of acute myeloid leukemias (AML) patients was analyzed in conditions which reduce the inter-assay variations (the same flow cytometer, the same observers and the same panel of monoclonal antibodies) in order to investigate the prognostic information provided by flow cytometry. DESIGN AND METHODS: Two hundred and sixty-six bone marrow (BM) samples from 326 patients enrolled in the LMA-99 protocol from the CETLAM group were studied by multiparametric flow cytometry. Immunophenotyping studies were performed on erythrocyte-lysed BM samples. Antigen expression of leukemic cells was analyzed using triple stainings with fluorochrome-conjugated combinations of monoclonal antibodies. RESULTS: CD2 was positive in 21 cases (8%); an associated inv(16) was detected in eight CD2+ cases (38%). Two-year overall survival (OS) rate for CD2+/inv(16)+ patients was 75%, whereas it was 0% for CD2+/inv(16)- patients and 47% for CD2- patients (p=0.0001). CD36 was expressed in 37% of patients (n=98). Two-year leukemia-free survival (LFS) rate was 34% for CD36+ patients and 55% for CD36- patients (p=0.001). In the multivariate analysis, CD2+ (RR=8.4; p=0.0001) and adverse karyotype (RR=10.2; p=0.0001) were associated with a lower CR rate, CD36+ (RR=1.5; p=0.03), CD2+ (RR=2; p=0.04) and adverse karyotype (RR=4; p=0.0001) were associated with a lower OS and CD36+ (RR=2; p=0.002) and adverse karyotype (RR=3.5; p=0.005) predicted a lower LFS. CONCLUSIONS: CD2+ patients had a very poor OS when CD2/inv(16)+ cases were excluded. CD36 and CD2 expression at diagnosis can provide prognostically important information in adult de novo AML.


Assuntos
Antígenos CD2/metabolismo , Antígenos CD36/metabolismo , Leucemia Mieloide/metabolismo , Doença Aguda , Adolescente , Adulto , Anticorpos Monoclonais , Medula Óssea/metabolismo , Medula Óssea/patologia , Aberrações Cromossômicas , Inversão Cromossômica , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem , Cariotipagem , Leucemia Mieloide/genética , Leucemia Mieloide/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida
19.
Acta Haematol ; 112(3): 164-6, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15345900

RESUMO

Granulocytic sarcoma of the small intestine preceding or as the presenting feature of acute myelogenous leukemia with chromosome 16 abnormalities has been observed in at least 4 patients. We report the case of a patient initially diagnosed with eosinophilic gastroenteritis, responding to corticosteroid treatment for 21 months and eventually transforming into an acute myelogenous leukemia with eosinophilia (M4Eo variant).


Assuntos
Eosinofilia/complicações , Gastroenterite/complicações , Leucemia Mieloide Aguda/complicações , Sarcoma Mieloide/complicações , Corticosteroides/uso terapêutico , Adulto , Aberrações Cromossômicas , Cromossomos Humanos Par 16 , Eosinofilia/tratamento farmacológico , Gastroenterite/tratamento farmacológico , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Sarcoma Mieloide/genética
20.
Histopathology ; 45(3): 268-74, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15330805

RESUMO

AIM: To determine the efficacy of flow cytometry (FC) in the assessment of bone marrow (BM) in B-cell non-Hodgkin lymphoma (B-NHL). FC is a common practice, but is far from being validated. METHODS AND RESULTS: Morphological analysis and FC immunophenotyping were performed on 421 samples. T-cell lymphomas, Hodgkin's disease, chronic lymphocytic leukaemia and hairy cell leukaemia were not included in the study. Clonality was assessed by the standard kappa/lambda/CD19 test. Aberrant immunophenotypes present in the B-cell subpopulation were also investigated. A double-step procedure was employed in all cases to increase the sensitivity of the FC procedure. Of 380 evaluable samples, 188 corresponded to follicular lymphoma (FL), 58 to diffuse large B-cell lymphoma (DLBCL), 57 to mantle cell lymphoma (MCL), seven to Burkitt's lymphoma and the remaining 70 samples to other low-grade lymphomas. Morphological marrow infiltration was found in 148 cases, and flow immunophenotyping identified 138 cases with BM involvement. A concordance between the two methods was detected in 298 cases (79%). There was a discordance in 82 cases (21%): morphology positive/FC negative in 46 cases and morphology negative/FC positive in 36 (61% of all cases with discordance were from FL). There was no difference in outcome when patients with discordances were compared with patients without discordances. CONCLUSIONS: Most samples showed concordance between morphological and FC results. FC identified BM involvement in the absence of morphological infiltration. Morphology/FC discordance seems to have no influence on the outcome of FL patients.


Assuntos
Medula Óssea/patologia , Citometria de Fluxo/métodos , Linfoma de Células B/patologia , Linfoma não Hodgkin/patologia , Medula Óssea/imunologia , Intervalo Livre de Doença , Humanos , Imunofenotipagem , Linfoma de Células B/imunologia , Linfoma não Hodgkin/imunologia , Análise Multivariada , Prognóstico
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