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1.
Hematol Oncol ; 38(1): 34-37, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31872890

RESUMO

This report summarizes a closed workshop cosponsored by the American Association for Cancer Research, the European School of Oncology, and the 15th-International Conference on Malignant Lymphoma to discuss critical open questions on liquid biopsy in lymphoid malignancies, develops a roadmap for their analytical and clinical validation, and prioritizes research areas.


Assuntos
Biomarcadores Tumorais/genética , DNA Tumoral Circulante/sangue , Biópsia Líquida/métodos , Linfoma/sangue , DNA Tumoral Circulante/genética , Congressos como Assunto , Humanos , Linfoma/diagnóstico , Linfoma/genética , Linfoma/terapia , Manejo de Espécimes
2.
J Clin Oncol ; 37(31): 2953, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31532721
3.
Immunol Rev ; 291(1): 190-213, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31402495

RESUMO

Signals emanating from the B-cell receptor (BCR) promote proliferation and survival in diverse forms of B-cell lymphoma. Precision medicine strategies targeting the BCR pathway have been generally effective in treating lymphoma, but often fail to produce durable responses in diffuse large B-cell lymphoma (DLBCL), a common and aggressive cancer. New insights into DLBCL biology garnered from genomic analyses and functional proteogenomic studies have identified novel modes of BCR signaling in this disease. Herein, we describe the distinct roles of antigen-dependent and antigen-independent BCR signaling in different subtypes of DLBCL. We highlight mechanisms by which the BCR cooperates with TLR9 and mutant isoforms of MYD88 to drive sustained NF-κB activity in the activated B-cell-like (ABC) subtype of DLBCL. Finally, we discuss progress in detecting and targeting oncogenic BCR signaling to improve the survival of patients with lymphoma.

4.
J Clin Oncol ; 37(28): 2584-2585, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31390273
5.
Cell ; 178(3): 699-713.e19, 2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31280963

RESUMO

Accurate prediction of long-term outcomes remains a challenge in the care of cancer patients. Due to the difficulty of serial tumor sampling, previous prediction tools have focused on pretreatment factors. However, emerging non-invasive diagnostics have increased opportunities for serial tumor assessments. We describe the Continuous Individualized Risk Index (CIRI), a method to dynamically determine outcome probabilities for individual patients utilizing risk predictors acquired over time. Similar to "win probability" models in other fields, CIRI provides a real-time probability by integrating risk assessments throughout a patient's course. Applying CIRI to patients with diffuse large B cell lymphoma, we demonstrate improved outcome prediction compared to conventional risk models. We demonstrate CIRI's broader utility in analogous models of chronic lymphocytic leukemia and breast adenocarcinoma and perform a proof-of-concept analysis demonstrating how CIRI could be used to develop predictive biomarkers for therapy selection. We envision that dynamic risk assessment will facilitate personalized medicine and enable innovative therapeutic paradigms.

6.
Hematol Oncol ; 37 Suppl 1: 70-74, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31187522

RESUMO

ctDNA provides an important new strategy that will aid in the treatment of non-Hodgkin's lymphoma. Immunoglobulin sequencing provides a tumor specific marker for disease activity with a sensitivity equivalent to one tumor cell per 10-6. Furthermore, it can provide an estimate of tumor bulk and tumor response dynamics during treatment. Interim monitoring can identify patients at high risk of treatment failure and surveillance monitoring can identify patients months before radiographic disease progression. Tumor specific mutations can also be detected in ctDNA and may reflect an averaging of mutations present within multiple tumor masses. Such analysis may aid in the molecular characterization of tumors and selection of targeted treatments for precision medicine.


Assuntos
Biópsia Líquida , Linfoma não Hodgkin/diagnóstico , Biomarcadores Tumorais , DNA Tumoral Circulante , Humanos , Biópsia Líquida/métodos , Linfoma não Hodgkin/etiologia , Linfoma não Hodgkin/terapia , Técnicas de Diagnóstico Molecular , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patologia
8.
J Clin Oncol ; 37(21): 1790-1799, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-30939090

RESUMO

PURPOSE: Alliance/CALGB 50303 (NCT00118209), an intergroup, phase III study, compared dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) with standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as frontline therapy for diffuse large B-cell lymphoma. PATIENTS AND METHODS: Patients received six cycles of DA-EPOCH-R or R-CHOP. The primary objective was progression-free survival (PFS); secondary clinical objectives included response rate, overall survival (OS), and safety. RESULTS: Between 2005 and 2013, 524 patients were registered; 491 eligible patients were included in the final analysis. Most patients (74%) had stage III or IV disease; International Prognostic Index (IPI) risk groups included 26% IPI 0 to 1, 37% IPI 2, 25% IPI 3, and 12% IPI 4 to 5. At a median follow-up of 5 years, PFS was not statistically different between the arms (hazard ratio, 0.93; 95% CI, 0.68 to 1.27; P = .65), with a 2-year PFS rate of 78.9% (95% CI, 73.8% to 84.2%) for DA-EPOCH-R and 75.5% (95% CI, 70.2% to 81.1%) for R-CHOP. OS was not different (hazard ratio, 1.09; 95% CI, 0.75 to 1.59; P = .64), with a 2-year OS rate of 86.5% (95% CI, 82.3% to 91%) for DA-EPOCH-R and 85.7% (95% CI, 81.4% to 90.2%) for R-CHOP. Grade 3 and 4 adverse events were more common (P < .001) in the DA-EPOCH-R arm than the R-CHOP arm, including infection (16.9% v 10.7%, respectively), febrile neutropenia (35.0% v 17.7%, respectively), mucositis (8.4% v 2.1%, respectively), and neuropathy (18.6% v 3.3%, respectively). Five treatment-related deaths (2.1%) occurred in each arm. CONCLUSION: In the 50303 study population, the more intensive, infusional DA-EPOCH-R was more toxic and did not improve PFS or OS compared with R-CHOP. The more favorable results with R-CHOP compared with historical controls suggest a potential patient selection bias and may preclude generalizability of results to specific risk subgroups.

11.
Leuk Lymphoma ; 60(8): 2062-2066, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30626252

RESUMO

To evaluate the feasibility and clinical efficacy of the combination of alemtuzumab with dose-adjusted etoposide/cyclophosphamide/doxorubicin/vincristine/prednisone (DA-EPOCH) as upfront therapy for untreated aggressive T and NK cell lymphomas, a phase 1/2 trial was conducted. Thirty patients were treated with the study regimen, consisting of alemtuzumab on day 1 of a 21 day cycle with standard dosing of DA-EPOCH for 6-8 cycles. Alemtuzumab 30 mg IV was used for the phase 2 component. Of 30 treated patients, 17 had a complete response (CR) and eight had a partial response (83.3% overall response rate). The median overall survival and progression-free survival were 20.2 and 6.6 months, respectively. There were five treatment-related deaths on study mainly due to infectious complications, including one case each of disseminated toxoplasmosis and pneumonia and two cases of sepsis. Alemtuzumab with DA-EPOCH is of limited clinical utility due to unacceptable toxicity, despite the high rate of CR.

12.
Blood ; 133(12): 1313-1324, 2019 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-30617194

RESUMO

Although generally curable with intensive chemotherapy in resource-rich settings, Burkitt lymphoma (BL) remains a deadly disease in older patients and in sub-Saharan Africa. Epstein-Barr virus (EBV) positivity is a feature in more than 90% of cases in malaria-endemic regions, and up to 30% elsewhere. However, the molecular features of BL have not been comprehensively evaluated when taking into account tumor EBV status or geographic origin. Through an integrative analysis of whole-genome and transcriptome data, we show a striking genome-wide increase in aberrant somatic hypermutation in EBV-positive tumors, supporting a link between EBV and activation-induced cytidine deaminase (AICDA) activity. In addition to identifying novel candidate BL genes such as SIN3A, USP7, and CHD8, we demonstrate that EBV-positive tumors had significantly fewer driver mutations, especially among genes with roles in apoptosis. We also found immunoglobulin variable region genes that were disproportionally used to encode clonal B-cell receptors (BCRs) in the tumors. These include IGHV4-34, known to produce autoreactive antibodies, and IGKV3-20, a feature described in other B-cell malignancies but not yet in BL. Our results suggest that tumor EBV status defines a specific BL phenotype irrespective of geographic origin, with particular molecular properties and distinct pathogenic mechanisms. The novel mutation patterns identified here imply rational use of DNA-damaging chemotherapy in some patients with BL and targeted agents such as the CDK4/6 inhibitor palbociclib in others, whereas the importance of BCR signaling in BL strengthens the potential benefit of inhibitors for PI3K, Syk, and Src family kinases among these patients.


Assuntos
Biomarcadores Tumorais/genética , Linfoma de Burkitt/genética , Infecções por Vírus Epstein-Barr/complicações , Genes de Imunoglobulinas , Genoma Humano , Mutação , Transcriptoma , Adolescente , Adulto , Linfoma de Burkitt/patologia , Linfoma de Burkitt/virologia , Criança , Pré-Escolar , Estudos de Coortes , Citidina Desaminase/genética , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/virologia , Feminino , Seguimentos , Herpesvirus Humano 4/isolamento & purificação , Humanos , Lactente , Recém-Nascido , Masculino , Fenótipo , Prognóstico , Adulto Jovem
15.
Lancet Haematol ; 5(12): e609-e617, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30501868

RESUMO

BACKGROUND: MYC gene rearrangement is present in approximately 10% of aggressive B-cell lymphomas, with half also harbouring a BCL2 gene rearrangement. Multiple retrospective studies of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone or prednisolone) have shown a worse outcome in patients with MYC rearrangement (alone or with rearrangement of BCL2 or BCL6, or both) than in patients without MYC rearrangement, and suggest improved outcomes after more intensive treatment. We aimed to determine the outcome of dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab; DA-EPOCH-R), an intensive infusional treatment regimen, in untreated aggressive B-cell lymphoma with MYC rearrangement. METHODS: We present the final analysis of a prospective, multicentre, single-arm, phase 2 study of DA-EPOCH-R in patients with untreated aggressive B-cell lymphoma with MYC rearrangement. DA-EPOCH-R was scheduled to be administered with CNS prophylaxis for six cycles. Primary endpoints included event-free and overall survival. This study is registered with ClinicalTrials.gov (NCT01092182). FINDINGS: 53 patients were enrolled, with median age of 61 years (range 29-80; IQR 50-70); 43 (81%) patients had stage III-IV disease and 26 (49%) had high-intermediate or high international prognostic index (IPI) scores. 19 patients had confirmed MYC rearrangement alone (single-hit) and 24 also had rearrangement of BCL2, BCL6, or both (double-hit), with similar characteristics between these two groups. After a median follow-up of 55·6 months (IQR 50·5-61·1), 48-month event-free survival was 71·0% (95% CI 56·5-81·4) and 48-month overall survival was 76·7% (95% CI 62·6-86·1) for all patients. Toxicity included grade 4 neutropenia in 160 (53%) of 301 cycles, grade 4 thrombocytopenia in 40 (13%) cycles, and any grade of fever with neutropenia in 56 (19%) cycles. There were three treatment-related deaths (all infections). INTERPRETATION: In this study, DA-EPOCH-R produced durable remission in patients with MYC-rearranged aggressive B-cell lymphomas and should be considered for the treatment of these diseases. FUNDING: Cancer Trials Support Unit and Center for Cancer Research of the National Cancer Institute and Genentech.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Rearranjo Gênico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Proteínas Proto-Oncogênicas c-myc/genética , Rituximab/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Ciclofosfamida/uso terapêutico , Relação Dose-Resposta a Droga , Doxorrubicina/uso terapêutico , Etoposídeo/uso terapêutico , Feminino , Humanos , Linfoma Difuso de Grandes Células B/genética , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Resultado do Tratamento , Vincristina/uso terapêutico
16.
Best Pract Res Clin Haematol ; 31(3): 285-292, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30213398

RESUMO

Recent guidelines have de-emphasized the role of routine surveillance computed tomography (CT) scans for diffuse large B-cell lymphoma (DLBCL) patients who achieve a complete response to front-line therapy. This shift in practice recommendations was prompted by retrospective studies that failed to demonstrate clear clinical utility for surveillance CT in unselected DLBCL patients. Controversy remains, however, over the role of routine surveillance CT in the highest risk patients for treatment failure who would remain candidates for aggressive salvage therapies. Novel high-throughput sequencing methods can non-invasively monitor tumor-specific DNA in the blood and offers clear advantages designed to overcome fundamental limitations of CT scans. This review will discuss the current controversies surrounding monitoring clinical outcomes in aggressive B-cell lymphomas, with a specific emphasis on DLBCL. Fundamental limitations of imaging scans will be addressed and the potential of monitoring circulating tumor DNA as an adjunct or replacement for CT scans will be discussed.


Assuntos
DNA Tumoral Circulante/sangue , Linfoma Difuso de Grandes Células B , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X , Humanos , Linfoma Difuso de Grandes Células B/sangue , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/terapia
18.
J Clin Oncol ; 36(28): 2845-2853, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30125215

RESUMO

PURPOSE: Outcomes for patients with diffuse large B-cell lymphoma remain heterogeneous, with existing methods failing to consistently predict treatment failure. We examined the additional prognostic value of circulating tumor DNA (ctDNA) before and during therapy for predicting patient outcomes. PATIENTS AND METHODS: We studied the dynamics of ctDNA from 217 patients treated at six centers, using a training and validation framework. We densely characterized early ctDNA dynamics during therapy using cancer personalized profiling by deep sequencing to define response-associated thresholds within a discovery set. These thresholds were assessed in two independent validation sets. Finally, we assessed the prognostic value of ctDNA in the context of established risk factors, including the International Prognostic Index and interim positron emission tomography/computed tomography scans. RESULTS: Before therapy, ctDNA was detectable in 98% of patients; pretreatment levels were prognostic in both front-line and salvage settings. In the discovery set, ctDNA levels changed rapidly, with a 2-log decrease after one cycle (early molecular response [EMR]) and a 2.5-log decrease after two cycles (major molecular response [MMR]) stratifying outcomes. In the first validation set, patients receiving front-line therapy achieving EMR or MMR had superior outcomes at 24 months (EMR: EFS, 83% v 50%; P = .0015; MMR: EFS, 82% v 46%; P < .001). EMR also predicted superior 24-month outcomes in patients receiving salvage therapy in the first validation set (EFS, 100% v 13%; P = .011). The prognostic value of EMR and MMR was further confirmed in the second validation set. In multivariable analyses including International Prognostic Index and interim positron emission tomography/computed tomography scans across both cohorts, molecular response was independently prognostic of outcomes, including event-free and overall survival. CONCLUSION: Pretreatment ctDNA levels and molecular responses are independently prognostic of outcomes in aggressive lymphomas. These risk factors could potentially guide future personalized risk-directed approaches.


Assuntos
Biomarcadores Tumorais/sangue , DNA Tumoral Circulante/sangue , Linfoma Difuso de Grandes Células B/sangue , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Adulto , Idoso , Biomarcadores Tumorais/genética , Feminino , Humanos , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Intervalo Livre de Progressão , Resultado do Tratamento
20.
Nature ; 560(7718): 387-391, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29925955

RESUMO

B cell receptor (BCR) signalling has emerged as a therapeutic target in B cell lymphomas, but inhibiting this pathway in diffuse large B cell lymphoma (DLBCL) has benefited only a subset of patients1. Gene expression profiling identified two major subtypes of DLBCL, known as germinal centre B cell-like and activated B cell-like (ABC)2,3, that show poor outcomes after immunochemotherapy in ABC. Autoantigens drive BCR-dependent activation of NF-κB in ABC DLBCL through a kinase signalling cascade of SYK, BTK and PKCß to promote the assembly of the CARD11-BCL10-MALT1 adaptor complex, which recruits and activates IκB kinase4-6. Genome sequencing revealed gain-of-function mutations that target the CD79A and CD79B BCR subunits and the Toll-like receptor signalling adaptor MYD885,7, with MYD88(L265P) being the most prevalent isoform. In a clinical trial, the BTK inhibitor ibrutinib produced responses in 37% of cases of ABC1. The most striking response rate (80%) was observed in tumours with both CD79B and MYD88(L265P) mutations, but how these mutations cooperate to promote dependence on BCR signalling remains unclear. Here we used genome-wide CRISPR-Cas9 screening and functional proteomics to determine the molecular basis of exceptional clinical responses to ibrutinib. We discovered a new mode of oncogenic BCR signalling in ibrutinib-responsive cell lines and biopsies, coordinated by a multiprotein supercomplex formed by MYD88, TLR9 and the BCR (hereafter termed the My-T-BCR supercomplex). The My-T-BCR supercomplex co-localizes with mTOR on endolysosomes, where it drives pro-survival NF-κB and mTOR signalling. Inhibitors of BCR and mTOR signalling cooperatively decreased the formation and function of the My-T-BCR supercomplex, providing mechanistic insight into their synergistic toxicity for My-T-BCR+ DLBCL cells. My-T-BCR supercomplexes characterized ibrutinib-responsive malignancies and distinguished ibrutinib responders from non-responders. Our data provide a framework for the rational design of oncogenic signalling inhibitors in molecularly defined subsets of DLBCL.


Assuntos
Carcinogênese , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Complexos Multiproteicos/metabolismo , Transdução de Sinais , Animais , Biópsia , Sistemas CRISPR-Cas/genética , Carcinogênese/genética , Desenho de Drogas , Feminino , Humanos , Linfoma Difuso de Grandes Células B/genética , Camundongos , Complexos Multiproteicos/química , Mutação , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Proteômica , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Receptores de Antígenos de Linfócitos B/antagonistas & inibidores , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
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