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1.
Blood Coagul Fibrinolysis ; 30(5): 239-242, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31157683

RESUMO

: Acquired von Willebrand syndrome (AVWS) is a rare hemorrhagic condition that poses both a diagnostic and a therapeutic challenge. Here we report a singular case of AVWS with two associated conditions, small lymphocytic lymphoma (SLL) and Sjögren's syndrome. The patient presented with recurrent and severe digestive bleeding that forced us to raise a curative attempt of AVWS. A first immunosuppressive therapy with immunoglobulins was unsuccessful and it was later decided to treat lymphoproliferative entity with bendamustine and rituximab effectively achieving SLL and AVWS remission. On the basis of our case and through literature review, we discuss potential strategies to achieve AVWS remission when it appears in the setting of several causative associated conditions.

2.
Blood ; 133(11): 1205-1216, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30602617

RESUMO

Recent evidence suggests that complex karyotype (CK) defined by the presence of ≥3 chromosomal aberrations (structural and/or numerical) identified by using chromosome-banding analysis (CBA) may be relevant for treatment decision-making in chronic lymphocytic leukemia (CLL). However, many challenges toward the routine clinical application of CBA remain. In a retrospective study of 5290 patients with available CBA data, we explored both clinicobiological associations and the clinical impact of CK in CLL. We found that patients with ≥5 abnormalities, defined as high-CK, exhibit uniformly dismal clinical outcomes, independently of clinical stage, TP53 aberrations (deletion of chromosome 17p and/or TP53 mutations [TP53abs]), and the expression of somatically hypermutated (M-CLL) or unmutated immunoglobulin heavy variable genes. Thus, they contrasted with CK cases with 3 or 4 aberrations (low-CK and intermediate-CK, respectively) who followed aggressive disease courses only in the presence of TP53abs. At the other end of the spectrum, patients with CK and +12,+19 displayed an exceptionally indolent profile. Building upon CK, TP53abs, and immunoglobulin heavy variable gene somatic hypermutation status, we propose a novel hierarchical model in which patients with high-CK exhibit the worst prognosis, whereas those with mutated CLL lacking CK or TP53abs, as well as CK with +12,+19, show the longest overall survival. Thus, CK should not be axiomatically considered unfavorable in CLL, representing a heterogeneous group with variable clinical behavior. High-CK with ≥5 chromosomal aberrations emerges as prognostically adverse, independent of other biomarkers. Prospective clinical validation is warranted before ultimately incorporating high-CK in risk stratification of CLL.

3.
Blood Adv ; 2(20): 2755-2765, 2018 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-30348671

RESUMO

Genomic rearrangements in the MYC locus occur in ∼12% of lymphomas with diffuse large B-cell lymphoma (DLBCL) morphology and are associated with inferior outcome. Previous studies exploring MYC rearrangements have primarily used fluorescence in situ hybridization (FISH) assays to characterize break-apart status but have rarely examined breakpoint location, and in some cases have not examined partner identity. We performed targeted sequencing of MYC, BCL2, BCL6, and the immunoglobulin (IG) loci in 112 tumors with DLBCL morphology harboring MYC rearrangement. We characterized the location of the MYC rearrangement at base pair resolution and identified the partner in 88 cases. We observed a cluster of breakpoints upstream of the MYC coding region and in intron 1 (the "genic cluster"). Genic cluster rearrangements were enriched for translocations involving IGH (80%), whereas nongenic rearrangements occurred mostly downstream of the MYC gene with a variety of partners, including IGL and IGK Other recurrent partners included BCL6, ZCCHC7, and RFTN1, which has not previously been described as a MYC partner. We compared 2 commercially available FISH break-apart assays for the MYC locus and observed discordant results in 32% of cases examined, including some with MYC-IGL and MYC-IGK rearrangements. In cases of high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement (HGBL-DH), so-called "double-hit" lymphomas, the majority of MYC rearrangements had non-IG partners (65%), with breakpoints outside the genic cluster (72%). In patients with de novo HGBL-DH of DLBCL morphology, MYC-IG rearrangements showed a trend toward inferior time to progression and overall survival compared with MYC-non-IG rearrangements. Our data reveal clinically relevant architecture of MYC rearrangements in lymphomas with DLBCL morphology.

5.
Oncoimmunology ; 7(6): e1432328, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29872562

RESUMO

Analysis of the T cell receptor (TR) repertoire of chronic lymphocytic leukemia-like monoclonal B cell lymphocytosis (CLL-like MBL) and early stage CLL is relevant for understanding the dynamic interaction of expanded B cell clones with bystander T cells. Here we profiled the T cell receptor ß chain (TRB) repertoire of the CD4+ and CD8+ T cell fractions from 16 CLL-like MBL and 13 untreated, Binet stage A/Rai stage 0 CLL patients using subcloning analysis followed by Sanger sequencing. The T cell subpopulations of both MBL and early stage CLL harbored restricted TRB gene repertoire, with CD4+ T cell clonal expansions whose frequency followed the numerical increase of clonal B cells. Longitudinal analysis in MBL cases revealed clonal persistence, alluding to persistent antigen stimulation. In addition, the identification of shared clonotypes among different MBL/early stage CLL cases pointed towards selection of the T cell clones by common antigenic elements. T cell clonotypes previously described in viral infections and immune disorders were also detected. Altogether, our findings evidence that antigen-mediated TR restriction occurs early in clonal evolution leading to CLL and may further increase together with B cell clonal expansion, possibly suggesting that the T cell selecting antigens are tumor-related.

7.
Oncotarget ; 8(33): 54297-54303, 2017 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-28903342

RESUMO

Genomic complexity identified by chromosome banding analysis (CBA) predicts a worse clinical outcome in CLL patients treated either with standard or new treatments. Herein, we analyzed the clinical impact of complex karyotypes (CK) with or without high-risk FISH deletions (ATM and/or TP53, HR-FISH) in a cohort of 1045 untreated MBL/CLL patients. In all, 99/1045 (9.5%) patients displayed a CK. Despite ATM and TP53 deletions were more common in CK (25% vs 7%; P < 0.001; 40% vs 5%; P < 0.001, respectively), only 44% (40/90) patients with TP53 deletions showed a CK. CK group showed a significant higher two-year cumulative incidence of treatment (48% vs 20%; P < 0.001), as well as a shorter overall survival (OS) (79 mo vs not reached; P < 0.001). When patients were categorized regarding CK and HR-FISH, those with both characteristics showed the worst median OS (52 mo) being clearly distinct from those non-CK and non-HR-FISH (median not reached), but no significant differences were detected between cases with only CK or HR-FISH. Both CK and TP53 deletion remained statistically significant in the multivariate analysis for OS. In conclusion, CK group is globally associated with advanced disease and poor prognostic markers. Further investigation in larger cohorts with CK lacking HR-FISH is needed to elucidate which mechanisms underlie the poor outcome of this subgroup.

8.
Sci Rep ; 7(1): 12262, 2017 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-28947822

RESUMO

Chronic lymphocytic leukemia (CLL) cells are highly dependent on microenvironment, being the BCR pathway one key player in this crosstalk. Among proteins participating, ZAP-70 enhances response to microenvironmental stimuli. MicroRNA-21 (miR-21) is overexpressed in diverse neoplasias including CLL, where it has been associated to refractoriness to fludarabine and to shorter time to progression and survival. To further elucidate the role of ZAP-70 in the biology of CLL, we studied its involvement in miR-21 regulation. MiR-21 expression was higher in CLL cells with high ZAP-70. Ectopic expression of ZAP-70 induced transcription of miR-21 via MAPK and STAT3, which subsequently induced downregulation of tumor suppressors targeted by miR-21. The co-culture of primary CLL cells mimicking the microenvironment induced ZAP-70 and miR-21 expression, as well as downregulation of miR-21 targets. Interestingly, the increase in miR-21 after co-culture was significantly impaired by ibrutinib, indicating that the BCR signaling pathway is involved in its regulation. Finally, survival of CLL cells induced by the co-culture correlated with miR-21 upregulation. In conclusion, stimuli from the microenvironment regulate miR-21 and its targeted tumor suppressor genes via a signaling pathway involving ZAP-70, thus contributing to the cytoprotection offered by the microenvironment particularly observed in CLL cells expressing ZAP-70.

9.
J Clin Oncol ; 35(31): 3529-3537, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-28796588

RESUMO

Purpose Rituximab (R) plus CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy is the standard of care in previously untreated diffuse large B-cell lymphoma (DLBCL). Obinutuzumab (G) is a glycoengineered, type II, anti-CD20 monoclonal antibody. GOYA was a randomized phase III study that compared G-CHOP with R-CHOP in patients with previously untreated advanced-stage DLBCL. Methods Patients (N = 1,418) were randomly assigned to receive eight 21-day cycles of G (n = 706) or R (n = 712), plus six or eight cycles of CHOP. Primary end point was investigator-assessed progression-free survival (PFS). Results After median observation of 29 months, the number of investigator-assessed PFS events was similar between G (201; 28.5%) and R (215; 30.2%), stratified hazard ratio was 0.92 (95% CI, 0.76 to 1.11; P = .39), and 3-year PFS rates were 70% and 67%, respectively. Secondary end points of independently reviewed PFS, other time-to-event end points, and tumor response rates were similar between arms. In exploratory subgroup analyses, patients with germinal-center B cell-like subtype had a better PFS than did patients with activated B cell-like subtype, irrespective of treatment. Frequencies of grade 3 to 5 adverse events (AEs; 73.7% v 64.7%, respectively) and serious AEs (42.6% v 37.6%, respectively) were higher with G-CHOP compared with R-CHOP. Fatal AE frequencies were 5.8% for G-CHOP and 4.3% for R-CHOP. The most common AEs were neutropenia (G-CHOP, 48.3%; R-CHOP, 40.7%), infusion-related reactions (G-CHOP, 36.1%; R-CHOP, 23.5%), nausea (G-CHOP, 29.4%; R-CHOP, 28.3%), and constipation (G-CHOP, 23.4%; R-CHOP, 24.5%). Conclusion G-CHOP did not improve PFS compared with R-CHOP in patients with previously untreated DLBCL. AEs reported with G were consistent with the known safety profile. Biomarker analyses may help define a future role for G in DLBCL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Murinos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Rituximab/administração & dosagem , Vincristina/administração & dosagem , Adulto Jovem
10.
Med. clín (Ed. impr.) ; 148(8): 381.e1-381.e9, abr. 2017. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-161625

RESUMO

Antecedentes y objetivo: El amplio arsenal terapéutico junto con la heterogeneidad biológica de los pacientes hace que sea difícil estandarizar el tratamiento de la leucemia linfocítica crónica (LLC) en la práctica clínica. Estas consideraciones han motivado la preparación del presente documento de consenso, que se trata de una actualización de la versión publicada en 2013, prestando especial atención a las estrategias de tratamiento que han aparecido en los últimos 5 años, como los inhibidores del receptor de células B (ibrutinib e idelalisib), los nuevos anticuerpos monoclonales anti-CD20 (ofatumumab y obinutuzumab) y los inhibidores de Bcl-2 (venetoclax). Material y métodos: Un grupo de expertos del Grupo Español de Leucemia Linfocítica Crónica ha revisado la bibliografía publicada entre 2010 y 2016 para poder establecer una serie de recomendaciones basadas en la evidencia clínica. En aquellas áreas donde no se encontró una evidencia científica, el grupo de expertos estableció recomendaciones por consenso con base en sus experiencias clínicas. Resultados: Como resultado del proyecto se ha establecido un conjunto de recomendaciones de carácter práctico que facilitarán el diagnóstico, el tratamiento y el seguimiento de los pacientes con LLC. Conclusiones: Existen muchos aspectos del tratamiento de la LLC que resultan ser temas controvertidos sobre los que no hay estudios apropiados para generar recomendaciones de forma consensuada (AU)


Background and objective: The broad therapeutic arsenal and the biological heterogeneity of patients with chronic lymphocytic leukemia (CLL) makes it difficult to standardize treatment for CLL patients with specific clinical settings in routine clinical practice. These considerations prompted us to elaborate the present consensus document, which constitutes an update of the previous version published in 2013, mainly focusing on novel treatment strategies that have been developed over last 5 years, namely B-cell receptor inhibitors (ibrutinib and idelalisib), anti-CD20 monoclonal antibodies (ofatumumab and obinutuzumab), and Bcl-2 inhibitors (venetoclax). Material and methods: A group of experts from the Spanish Chronic Lymphocytic Leukemia Group reviewed all published literature from January 2010 to January 2016, in order to provide recommendations based on clinical evidence. For those areas without strong scientific evidence, the panel of experts established consensus criteria based on their clinical experience. Results: The project has resulted in several practical recommendations that will facilitate the diagnosis, treatment, and follow-up of patients with CLL. Conclusions: There are many controversial issues in the management of CLL with no appropriate studies for making consensus recommendations (AU)


Assuntos
Humanos , Masculino , Feminino , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/terapia , Anticorpos Monoclonais/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/uso terapêutico , Antígenos CD20/análise , Medicina Baseada em Evidências/métodos , Consenso , Prognóstico , Qualidade de Vida , Grupos de Risco
11.
J Clin Oncol ; 35(15): 1668-1677, 2017 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-28291392

RESUMO

Purpose Mantle cell lymphoma is an aggressive B-cell neoplasm that displays heterogeneous outcomes after treatment. In 2003, the Lymphoma/Leukemia Molecular Profiling Project described a powerful biomarker-the proliferation signature-using gene expression in fresh frozen material. Herein, we describe the training and validation of a new assay that measures the proliferation signature in RNA derived from routinely available formalin-fixed paraffin-embedded (FFPE) biopsies. Methods Forty-seven FFPE biopsies were used to train an assay on the NanoString platform, using microarray gene expression data of matched fresh frozen biopsies as a gold standard. The locked assay was applied to pretreatment FFPE lymph node biopsies from an independent cohort of 110 patients uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. Seventeen biopsies were tested across three laboratories to assess assay reproducibility. Results The MCL35 assay, which contained a 17-gene proliferation signature, yielded gene expression of sufficient quality to assign an assay score and risk group in 108 (98%) of 110 archival FFPE biopsies. The MCL35 assay assigned patients to high-risk (26%), standard-risk (29%), and low-risk (45%) groups, with different lengths of overall survival (OS): a median of 1.1, 2.6, and 8.6 years, respectively (log-rank for trend, P < .001). In multivariable analysis, these risk groups and the Mantle Cell Lymphoma International Prognostic Index were independently associated with OS ( P < .001 for both variables). Concordance of risk assignment across the three independent laboratories was 100%. Conclusion The newly developed and validated MCL35 assay for FFPE biopsies uses the proliferation signature to define groups of patients with significantly different OS independent of the Mantle Cell Lymphoma International Prognostic Index. Importantly, the analytic and clinical validity of this assay defines it as a reliable biomarker to support risk-adapted clinical trials.


Assuntos
Biópsia/métodos , Linfoma de Célula do Manto/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Proliferação de Células/fisiologia , Feminino , Formaldeído , Perfilação da Expressão Gênica , Humanos , Linfoma de Célula do Manto/genética , Masculino , Pessoa de Meia-Idade , Inclusão em Parafina , Reprodutibilidade dos Testes , Fixação de Tecidos
12.
Med Clin (Barc) ; 148(8): 381.e1-381.e9, 2017 Apr 21.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-28236475

RESUMO

BACKGROUND AND OBJECTIVE: The broad therapeutic arsenal and the biological heterogeneity of patients with chronic lymphocytic leukemia (CLL) makes it difficult to standardize treatment for CLL patients with specific clinical settings in routine clinical practice. These considerations prompted us to elaborate the present consensus document, which constitutes an update of the previous version published in 2013, mainly focusing on novel treatment strategies that have been developed over last 5 years, namely B-cell receptor inhibitors (ibrutinib and idelalisib), anti-CD20 monoclonal antibodies (ofatumumab and obinutuzumab), and Bcl-2 inhibitors (venetoclax). MATERIAL AND METHODS: A group of experts from the Spanish Chronic Lymphocytic Leukemia Group reviewed all published literature from January 2010 to January 2016, in order to provide recommendations based on clinical evidence. For those areas without strong scientific evidence, the panel of experts established consensus criteria based on their clinical experience. RESULTS: The project has resulted in several practical recommendations that will facilitate the diagnosis, treatment, and follow-up of patients with CLL. CONCLUSIONS: There are many controversial issues in the management of CLL with no appropriate studies for making consensus recommendations.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Humanos , Leucemia Linfocítica Crônica de Células B/complicações , Leucemia Linfocítica Crônica de Células B/diagnóstico , Purinas/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Quinazolinonas/uso terapêutico , Sulfonamidas/uso terapêutico
13.
Oncotarget ; 8(1): 742-756, 2017 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-27888629

RESUMO

Proliferation and survival of chronic lymphocytic leukemia (CLL) cells depend on microenvironmental signals coming from lymphoid organs. One of the key players involved in the crosstalk between CLL cells and the microenvironment is the B-cell receptor (BCR). Syk protein, a tyrosine kinase essential for BCR signaling, is therefore a rational candidate for targeted therapy in CLL. Against this background, we tested the efficacy of the highly specific Syk inhibitor TAK-659 in suppressing the favorable signaling derived from the microenvironment. To ex vivo mimic the microenvironment found in the proliferation centers, we co-cultured primary CLL cells with BM stromal cells (BMSC), CD40L and CpG ODN along with BCR stimulation. In this setting, TAK-659 inhibited the microenvironment-induced activation of Syk and downstream signaling molecules, without inhibiting the protein homologue ZAP-70 in T cells. Importantly, the pro-survival, proliferative, chemoresistant and activation effects promoted by the microenvironment were abrogated by TAK-659, which furthermore blocked CLL cell migration toward BMSC, CXCL12, and CXCL13. Combination of TAK-659 with other BCR inhibitors showed synergistic effect in inducing apoptosis, and the sequential addition of TAK-659 in ibrutinib-treated CLL cells induced significantly higher cytotoxicity. These findings provide a strong rationale for the clinical development of TAK-659 in CLL.


Assuntos
Leucemia Linfocítica Crônica de Células B/metabolismo , Pirimidinas/farmacologia , Pirrolidinonas/farmacologia , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Quinase Syk/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Biomarcadores , Linfoma de Burkitt/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quimiotaxia , Técnicas de Cocultura , Resistencia a Medicamentos Antineoplásicos , Humanos , Imunofenotipagem , Leucemia Linfocítica Crônica de Células B/patologia , Inibidores de Proteínas Quinases/farmacologia , Microambiente Tumoral/efeitos dos fármacos
14.
Oncotarget ; 7(49): 80916-80924, 2016 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-27821812

RESUMO

Patients with chronic lymphocytic leukemia (CLL) harboring TP53 aberrations (TP53abs; chromosome 17p deletion and/or TP53 mutation) exhibit an unfavorable clinical outcome. Chromosome 8 abnormalities, namely losses of 8p (8p-) and gains of 8q (8q+) have been suggested to aggravate the outcome of patients with TP53abs. However, the reported series were small, thus hindering definitive conclusions. To gain insight into this issue, we assessed a series of 101 CLL patients harboring TP53 disruption. The frequency of 8p- and 8q+ was 14.7% and 17.8% respectively. Both were associated with a significantly (P < 0.05) higher incidence of a complex karyotype (CK, ≥3 abnormalities) detected by chromosome banding analysis (CBA) compared to cases with normal 8p (N-8p) and 8q (N-8q), respectively. In univariate analysis for 10-year overall survival (OS), 8p- (P = 0.002), 8q+ (P = 0.012) and CK (P = 0.009) were associated with shorter OS. However, in multivariate analysis only CK (HR = 2.47, P = 0.027) maintained independent significance, being associated with a dismal outcome regardless of chromosome 8 abnormalities. In conclusion, our results highlight the association of chromosome 8 abnormalities with CK amongst CLL patients with TP53abs, while also revealing that CK can further aggravate the prognosis of this aggressive subgroup.


Assuntos
Biomarcadores Tumorais/genética , Deleção Cromossômica , Cromossomos Humanos Par 8 , Cariótipo , Leucemia Linfocítica Crônica de Células B/genética , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Distribuição de Qui-Quadrado , Feminino , Predisposição Genética para Doença , Humanos , Estimativa de Kaplan-Meier , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/patologia , Leucemia Linfocítica Crônica de Células B/terapia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Mutação , Fenótipo , Modelos de Riscos Proporcionais , Fatores de Risco , Espanha , Fatores de Tempo , Resultado do Tratamento
15.
PLoS One ; 10(11): e0143073, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26630574

RESUMO

To analyze the impact of the 11q deleted (11q-) cells in CLL patients on the time to first therapy (TFT) and overall survival (OS), 2,493 patients with CLL were studied. 242 patients (9.7%) had 11q-. Fluorescence in situ hybridization (FISH) studies showed a threshold of 40% of deleted cells to be optimal for showing that clinical differences in terms of TFT and OS within 11q- CLLs. In patients with ≥40% of losses in 11q (11q-H) (74%), the median TFT was 19 months compared with 44 months in CLL patients with <40% del(11q) (11q-L) (P<0.0001). In the multivariate analysis, only the presence of 11q-L, mutated IGHV status, early Binet stage and absence of extended lymphadenopathy were associated with longer TFT. Patients with 11q-H had an OS of 90 months, while in the 11q-L group the OS was not reached (P = 0.008). The absence of splenomegaly (P = 0.02), low LDH (P = 0.018) or ß2M (P = 0.006), and the presence of 11q-L (P = 0.003) were associated with a longer OS. In addition, to detect the presence of mutations in the ATM, TP53, NOTCH1, SF3B1, MYD88, FBXW7, XPO1 and BIRC3 genes, a select cohort of CLL patients with losses in 11q was sequenced by next-generation sequencing of amplicons. Eighty % of CLLs with 11q- showed mutations and fewer patients with low frequencies of 11q- had mutations among genes examined (50% vs 94.1%, P = 0.023). In summary, CLL patients with <40% of 11q- had a long TFT and OS that could be associated with the presence of fewer mutated genes.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 11 , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/genética , Mutação , Proteínas de Neoplasias/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Hibridização in Situ Fluorescente , Cariótipo , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/imunologia , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida
18.
J Clin Oncol ; 33(26): 2848-56, 2015 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-26240231

RESUMO

PURPOSE: To evaluate the prognostic impact of cell-of-origin (COO) subgroups, assigned using the recently described gene expression-based Lymph2Cx assay in comparison with International Prognostic Index (IPI) score and MYC/BCL2 coexpression status (dual expressers). PATIENTS AND METHODS: Reproducibility of COO assignment using the Lymph2Cx assay was tested employing repeated sampling within tumor biopsies and changes in reagent lots. The assay was then applied to pretreatment formalin-fixed paraffin-embedded tissue (FFPET) biopsies from 344 patients with de novo diffuse large B-cell lymphoma (DLBCL) uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) at the British Columbia Cancer Agency. MYC and BCL2 protein expression was assessed using immunohistochemistry on tissue microarrays. RESULTS: The Lymph2Cx assay provided concordant COO calls in 96% of 49 repeatedly sampled tumor biopsies and in 100% of 83 FFPET biopsies tested across reagent lots. Critically, no frank misclassification (activated B-cell-like DLBCL to germinal center B-cell-like DLBCL or vice versa) was observed. Patients with activated B-cell-like DLBCL had significantly inferior outcomes compared with patients with germinal center B-cell-like DLBCL (log-rank P < .001 for time to progression, progression-free survival, disease-specific survival, and overall survival). In pairwise multivariable analyses, COO was associated with outcomes independent of IPI score and MYC/BCL2 immunohistochemistry. The prognostic significance of COO was particularly evident in patients with intermediate IPI scores and the non-MYC-positive/BCL2-positive subgroup (log-rank P < .001 for time to progression). CONCLUSION: Assignment of DLBCL COO by the Lymph2Cx assay using FFPET biopsies identifies patient groups with significantly different outcomes after R-CHOP, independent of IPI score and MYC/BCL2 dual expression.


Assuntos
Linfoma Difuso de Grandes Células B/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biópsia , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Expressão Gênica , Humanos , Linfoma Difuso de Grandes Células B/química , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Inclusão em Parafina , Prednisona/uso terapêutico , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-2/análise , Proteínas Proto-Oncogênicas c-myc/análise , Análise Serial de Tecidos , Vincristina/uso terapêutico
19.
Clin Cancer Res ; 21(14): 3160-9, 2015 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-25840972

RESUMO

PURPOSE: This phase I expansion-cohort study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of the pan-PI3K inhibitor pilaralisib (SAR245408/XL147) in patients with chronic lymphocytic leukemia (CLL) or relapsed or refractory lymphoma. PATIENTS AND METHODS: Patients were treated with the maximum tolerated dose of pilaralisib previously determined in patients with solid tumors (600 mg capsules once daily). Adverse events (AE) and response were evaluated. Plasma pharmacokinetics and pharmacodynamic effects on cytokines and chemokines were also assessed. RESULTS: Twenty-five patients were included in the study: 10 with CLL and 15 with lymphoma. The most frequent AEs of any grade were diarrhea (92.0%), pyrexia (52.0%), and fatigue (44.0%). The most frequent grade ≥3 AEs were neutropenia (32.0%), diarrhea (20.0%), and anemia (16.0%). Pilaralisib exposure on cycle 1 day 28 was similar to exposure in patients with solid tumors. In patients with CLL, pilaralisib significantly reduced plasma levels of several cytokines and chemokines involved in B-cell trafficking. Five patients (50.0%) with CLL and 3 patients (20.0%) with lymphoma had a partial response. Six patients (60.0%) with CLL had nodal shrinkage ≥50%. Overall, 14 patients (56.0%; 7 patients with CLL and 7 patients with lymphoma) had progression-free survival ≥6 months. CONCLUSIONS: Pilaralisib demonstrated an acceptable safety profile in patients with CLL and lymphoma, generally consistent with findings in patients with solid tumors. Single-agent pilaralisib showed preliminary clinical activity in patients with CLL and lymphoma, supporting further development.


Assuntos
Antineoplásicos/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma/tratamento farmacológico , Quinoxalinas/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacocinética , Estudos de Coortes , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfoma/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Quinoxalinas/farmacocinética , Sulfonamidas/farmacocinética
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