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1.
Leuk Lymphoma ; : 1-9, 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33236943

RESUMO

Navitoclax, a novel BCL-2 and BCL-XL inhibitor, demonstrated promising antitumor activity in the dose-escalation part of a phase 1/2a study (NCT00406809) in lymphoid tumors. Herein, we report the continued safety and efficacy results of the phase 2a portion. Twenty-six adult patients with relapsed/refractory follicular lymphoma (n = 11, Arm A) and other relapsed/refractory lymphoid malignancies (n = 15, Arm B) were enrolled. Navitoclax administration schedule consisted of a 150-mg 7-day lead-in dose followed by 250-mg daily dosing with the option to further increase to 325 mg after 14 days if the 250-mg dose was tolerated. All patients experienced at least 1 treatment-related adverse event (TRAE). Seventeen (65.4%) patients reported grade 3/4 TRAEs; thrombocytopenia (38.5%) and neutropenia (30.8%) were the most common. Two patients reported serious AEs; none were fatal (no deaths occurred within 30 days of last dose of study drug). The objective response rate (complete and partial) was 23.1% (6/26; Arm A: 9.1%, Arm B: 33.3%). Median progression-free survival and time to progression were identical: 4.9 months (95% CI: 3.0, 8.2); median overall survival: 24.8 months (95% CI could not be computed). Navitoclax monotherapy has an acceptable safety profile and meaningful clinical activity in a minority of patients with relapsed/refractory lymphoid malignancies.

2.
3.
J Clin Oncol ; 38(31): 3723-3724, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32931397
4.
Sci Immunol ; 5(48)2020 06 05.
Artigo em Inglês | MEDLINE | ID: covidwho-545978

RESUMO

Patients with severe COVID-19 have a hyperinflammatory immune response suggestive of macrophage activation. Bruton tyrosine kinase (BTK) regulates macrophage signaling and activation. Acalabrutinib, a selective BTK inhibitor, was administered off-label to 19 patients hospitalized with severe COVID-19 (11 on supplemental oxygen; 8 on mechanical ventilation), 18 of whom had increasing oxygen requirements at baseline. Over a 10-14 day treatment course, acalabrutinib improved oxygenation in a majority of patients, often within 1-3 days, and had no discernable toxicity. Measures of inflammation - C-reactive protein and IL-6 - normalized quickly in most patients, as did lymphopenia, in correlation with improved oxygenation. At the end of acalabrutinib treatment, 8/11 (72.7%) patients in the supplemental oxygen cohort had been discharged on room air, and 4/8 (50%) patients in the mechanical ventilation cohort had been successfully extubated, with 2/8 (25%) discharged on room air. Ex vivo analysis revealed significantly elevated BTK activity, as evidenced by autophosphorylation, and increased IL-6 production in blood monocytes from patients with severe COVID-19 compared with blood monocytes from healthy volunteers. These results suggest that targeting excessive host inflammation with a BTK inhibitor is a therapeutic strategy in severe COVID-19 and has led to a confirmatory international prospective randomized controlled clinical trial.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Pirazinas/farmacologia , Pirazinas/uso terapêutico , Tirosina Quinase da Agamaglobulinemia/metabolismo , Idoso , Idoso de 80 Anos ou mais , Infecções por Coronavirus/virologia , Estado Terminal , Feminino , Seguimentos , Humanos , Inflamação/tratamento farmacológico , Inflamação/virologia , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Pandemias , Pneumonia Viral/virologia , Estudos Prospectivos , Respiração Artificial , Resultado do Tratamento
5.
Sci Immunol ; 5(48)2020 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-32503877

RESUMO

Patients with severe COVID-19 have a hyperinflammatory immune response suggestive of macrophage activation. Bruton tyrosine kinase (BTK) regulates macrophage signaling and activation. Acalabrutinib, a selective BTK inhibitor, was administered off-label to 19 patients hospitalized with severe COVID-19 (11 on supplemental oxygen; 8 on mechanical ventilation), 18 of whom had increasing oxygen requirements at baseline. Over a 10-14 day treatment course, acalabrutinib improved oxygenation in a majority of patients, often within 1-3 days, and had no discernable toxicity. Measures of inflammation - C-reactive protein and IL-6 - normalized quickly in most patients, as did lymphopenia, in correlation with improved oxygenation. At the end of acalabrutinib treatment, 8/11 (72.7%) patients in the supplemental oxygen cohort had been discharged on room air, and 4/8 (50%) patients in the mechanical ventilation cohort had been successfully extubated, with 2/8 (25%) discharged on room air. Ex vivo analysis revealed significantly elevated BTK activity, as evidenced by autophosphorylation, and increased IL-6 production in blood monocytes from patients with severe COVID-19 compared with blood monocytes from healthy volunteers. These results suggest that targeting excessive host inflammation with a BTK inhibitor is a therapeutic strategy in severe COVID-19 and has led to a confirmatory international prospective randomized controlled clinical trial.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Pirazinas/farmacologia , Pirazinas/uso terapêutico , Tirosina Quinase da Agamaglobulinemia/metabolismo , Idoso , Idoso de 80 Anos ou mais , Infecções por Coronavirus/virologia , Estado Terminal , Feminino , Seguimentos , Humanos , Inflamação/tratamento farmacológico , Inflamação/virologia , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Pandemias , Pneumonia Viral/virologia , Estudos Prospectivos , Respiração Artificial , Resultado do Tratamento
6.
Cancer J ; 26(3): 195-205, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32496453

RESUMO

Diffuse large B-cell lymphoma (DLBCL) encompasses a group of aggressive B-cell non-Hodgkin lymphomas with striking genetic heterogeneity and variable clinical presentations. Among these is primary mediastinal B-cell lymphoma (PMBL), which has unique clinical and molecular features resembling Hodgkin lymphoma. Treatment of DLBCL is usually curative, but identifiable subsets at highest risk for treatment failure may benefit from intensified chemotherapy regimens and/or targeted agents added to frontline therapy. Recent comprehensive genomic analyses have identified distinct genetic subtypes of DLBCL with characteristic genetic drivers and signaling pathways that are targetable. Immune therapy with chimeric antigen receptor T cells and checkpoint inhibitors has revolutionized the treatment of relapsed or refractory disease, and antibody drug conjugates have weaponized otherwise intolerable cytotoxic agents. Ongoing clinical trials are further refining the specificity of these approaches in different genetic subtypes and moving them from the setting of recurrent disease to frontline treatment in high-risk patient populations.

7.
J Clin Oncol ; 38(22): 2519-2529, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32453640

RESUMO

PURPOSE: Burkitt lymphoma is an aggressive B-cell lymphoma curable with dose-intensive chemotherapy derived from pediatric leukemia regimens. Treatment is acutely toxic with late sequelae. We hypothesized that dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and rituximab (DA-EPOCH-R) may obviate the need for highly dose-intensive chemotherapy in adults with Burkitt lymphoma. METHODS: We conducted a multicenter risk-adapted study of DA-EPOCH-R in untreated adult Burkitt lymphoma. Low-risk patients received three cycles without CNS prophylaxis, and high-risk patients received six cycles with intrathecal CNS prophylaxis or extended intrathecal treatment if leptomeninges were involved. The primary endpoint was event-free survival (EFS), and secondary endpoints were toxicity and predictors of EFS and overall survival (OS). RESULTS: Between 2010 and 2017, 113 patients were enrolled across 22 centers, and 98 (87%) were high risk. The median age was 49 (range, 18-86) years, and 62% were ≥ 40 years. Bone marrow and/or CSF was involved in 29 (26%) of patients, and 28 (25%) were HIV positive. At a median follow-up of 58.7 months, EFS and OS were 84.5% and 87.0%, respectively, and EFS was 100% and 82.1% in low- and high-risk patients. Therapy was equally effective across age groups, HIV status, and International Prognostic Index risk groups. Involvement of the CSF identified the group at greatest risk for early toxicity-related death or treatment failure. Five treatment-related deaths (4%) occurred during therapy. Febrile neutropenia occurred in 16% of cycles, and tumor lysis syndrome was rare. CONCLUSION: Risk-adapted DA-EPOCH-R therapy is effective in adult Burkitt lymphoma regardless of age or HIV status and was well tolerated. Improved therapeutic strategies for adults with CSF involvement are needed (funded by the National Cancer Institute; ClinicalTrials.gov identifier: NCT01092182).

8.
Cancer Cell ; 37(4): 551-568.e14, 2020 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-32289277

RESUMO

The development of precision medicine approaches for diffuse large B cell lymphoma (DLBCL) is confounded by its pronounced genetic, phenotypic, and clinical heterogeneity. Recent multiplatform genomic studies revealed the existence of genetic subtypes of DLBCL using clustering methodologies. Here, we describe an algorithm that determines the probability that a patient's lymphoma belongs to one of seven genetic subtypes based on its genetic features. This classification reveals genetic similarities between these DLBCL subtypes and various indolent and extranodal lymphoma types, suggesting a shared pathogenesis. These genetic subtypes also have distinct gene expression profiles, immune microenvironments, and outcomes following immunochemotherapy. Functional analysis of genetic subtype models highlights distinct vulnerabilities to targeted therapy, supporting the use of this classification in precision medicine trials.


Assuntos
Biomarcadores Tumorais/genética , Heterogeneidade Genética , Linfoma Difuso de Grandes Células B/classificação , Linfoma Difuso de Grandes Células B/genética , Terapia de Alvo Molecular , Animais , Apoptose , Proliferação de Células , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Medicina de Precisão , Células Tumorais Cultivadas , Microambiente Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Blood ; 135(25): 2224-2234, 2020 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-32232481

RESUMO

As part of a randomized, prospective clinical trial in large cell lymphoma, we conducted serial fluorodeoxyglucose positron emission tomography (FDG-PET) at baseline, after 2 cycles of chemotherapy (interim PET [i-PET]), and at end of treatment (EoT) to identify biomarkers of response that are predictive of remission and survival. Scans were interpreted in a core laboratory by 2 imaging experts, using the visual Deauville 5-point scale (5-PS), and by calculating percent change in FDG uptake (change in standardized uptake value [ΔSUV]). Visual scores of 1 through 3 and ΔSUV ≥66% were prospectively defined as negative. Of 524 patients enrolled in the parent trial, 169 agreed to enroll in the PET substudy and 158 were eligible for final analysis. In this selected population, all had FDG-avid disease at baseline; by 5-PS, 55 (35%) remained positive on i-PET and 28 (18%) on EoT PET. Median ΔSUV on i-PET was 86.2%. With a median follow-up of 5 years, ΔSUV, as continuous variable, was associated with progression-free survival (PFS) (hazard ratio [HR] = 0.99; 95% confidence interval [CI], 0.97-1.00; P = .02) and overall survival (OS) (HR, 0.98; 95% CI, 0.97-0.99; P = .03). ΔSUV ≥66% was predictive of OS (HR, 0.31; 95% CI, 0.11-0.85; P = .02) but not PFS (HR, 0.47; 95% CI, 0.19-1.13; P = .09). Visual 5-PS on i-PET did not predict outcome. ΔSUV, but not visual analysis, on i-PET predicted OS in DLBCL, although the low number of events limited the statistical analysis. These data may help guide future clinical trials using PET response-adapted therapy. This trial was registered at www.clinicaltrials.gov as #NCT00118209.

10.
Blood ; 135(16): 1344-1352, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32107539

RESUMO

Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus (EBV)-driven B-cell lymphoproliferative disease (LPD). This disease is hypothesized to result from defective immune surveillance of EBV, with most patients showing evidence of immune dysfunction, despite no known primary immunodeficiency. Pathologically, LYG is graded by the number and density of EBV+ atypical B cells, and other characteristic findings include an angioinvasive/angiodestructive reactive T-cell infiltrate and various degrees of necrosis. Clinically, LYG universally involves the lungs with other common extranodal sites, including skin, central nervous system, liver, and kidneys. Nodal and/or bone marrow involvement is extremely rare and, if present, suggests an alternative diagnosis. Treatment selection is based on histologic grade and underlying pathobiology with low-grade disease hypothesized to be immune-dependent and typically polyclonal and high-grade disease to be immune-independent and typically oligoclonal or monoclonal. Methods of augmenting the immune response to EBV in low-grade LYG include treatment with interferon-α2b, whereas high-grade disease requires immunochemotherapy. Given the underlying defective immune surveillance of EBV, patients with high-grade disease may have a recurrence in the form of low-grade disease after immunochemotherapy, and those with low-grade disease may progress to high-grade disease after immune modulation, which can be effectively managed with crossover treatment. In patients with primary refractory disease or in those with multiple relapses, hematopoietic stem cell transplantation may be considered, but its efficacy is not well established. This review discusses the pathogenesis of LYG and highlights distinct histopathologic and clinical features that distinguish this disorder from other EBV+ B-cell LPDs and lymphomas. Treatment options, including immune modulation and combination immunochemotherapy, are discussed.


Assuntos
Infecções por Vírus Epstein-Barr/complicações , Granulomatose Linfomatoide/terapia , Granulomatose Linfomatoide/virologia , Animais , Herpesvirus Humano 4/isolamento & purificação , Humanos , Imunoterapia , Granulomatose Linfomatoide/diagnóstico , Granulomatose Linfomatoide/patologia , Terapia de Alvo Molecular
11.
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
12.
J Clin Oncol ; 37(31): 2953, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31532721
13.
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.


Assuntos
Leucemia Linfoide/etiologia , Leucemia Linfoide/metabolismo , Linfoma/etiologia , Linfoma/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais , Animais , Autoantígenos/imunologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Centro Germinativo/patologia , Humanos , Leucemia Linfoide/diagnóstico , Leucemia Linfoide/terapia , Linfoma/diagnóstico , Linfoma/terapia , Receptores de Antígenos de Linfócitos B/genética
14.
J Clin Oncol ; 37(28): 2584-2585, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31390273
15.
Cell ; 178(3): 699-713.e19, 2019 07 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.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Linfoma Difuso de Grandes Células B/patologia , Medicina de Precisão , Algoritmos , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/sangue , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , DNA Tumoral Circulante/sangue , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/mortalidade , Terapia Neoadjuvante , Prognóstico , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Medição de Risco , Resultado do Tratamento
17.
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
18.
J Clin Oncol ; 37(21): 1790-1799, 2019 07 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.

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