RESUMEN
The exchange of genes between cells is known to play an important physiological and pathological role in many organisms. We show that circulating tumor DNA (ctDNA) facilitates cell-specific gene transfer between human cancer cells and explain part of the mechanisms behind this phenomenon. As ctDNA migrates into the nucleus, genetic information is transferred. Cell targeting and ctDNA integration require ERVL, SINE or LINE DNA sequences. Chemically manufactured AluSp and MER11C sequences replicated multiple myeloma (MM) ctDNA cell targeting and integration. Additionally, we found that ctDNA may alter the treatment response of MM and pancreatic cancer models. This study shows that retrotransposon DNA sequences promote cancer gene transfer. However, because cell-free DNA has been detected in physiological and other pathological conditions, our findings have a broader impact than just cancer. Furthermore, the discovery that transposon DNA sequences mediate tissue-specific targeting will open up a new avenue for the delivery of genes and therapies.
Asunto(s)
ADN Tumoral Circulante , Elementos Transponibles de ADN , Humanos , ADN Tumoral Circulante/genética , ADN Tumoral Circulante/sangre , Elementos Transponibles de ADN/genética , Línea Celular Tumoral , Mieloma Múltiple/genética , Mieloma Múltiple/terapia , Animales , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/terapia , Ratones , Especificidad de Órganos/genética , Retroelementos/genética , Técnicas de Transferencia de GenRESUMEN
Monoclonal antibodies are standard therapeutics for several cancers including the anti-CD20 antibody rituximab for B cell non-Hodgkin lymphoma (NHL). Rituximab and other antibodies are not curative and must be combined with cytotoxic chemotherapy for clinical benefit. Here we report the eradication of human NHL solely with a monoclonal antibody therapy combining rituximab with a blocking anti-CD47 antibody. We identified increased expression of CD47 on human NHL cells and determined that higher CD47 expression independently predicted adverse clinical outcomes in multiple NHL subtypes. Blocking anti-CD47 antibodies preferentially enabled phagocytosis of NHL cells and synergized with rituximab. Treatment of human NHL-engrafted mice with anti-CD47 antibody reduced lymphoma burden and improved survival, while combination treatment with rituximab led to elimination of lymphoma and cure. These antibodies synergized through a mechanism combining Fc receptor (FcR)-dependent and FcR-independent stimulation of phagocytosis that might be applicable to many other cancers.
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Anticuerpos Monoclonales/uso terapéutico , Antígeno CD47/inmunología , Linfoma no Hodgkin/inmunología , Linfoma no Hodgkin/terapia , Fagocitosis , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales de Origen Murino , Linfocitos B/inmunología , Línea Celular Tumoral , Humanos , Linfoma no Hodgkin/diagnóstico , Ratones , Receptores Fc/inmunología , Rituximab , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The combination of the phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor zandelisib with the Bruton's tyrosine kinase (BTK) inhibitor zanubrutinib was hypothesized to be synergistic and prevent resistance to single-agent therapy. This phase 1 study (NCT02914938) included a dose-finding stage in patients with relapsed/refractory (R/R) B-cell malignancies (n = 20) and disease-specific expansion cohorts in follicular lymphoma (FL; n = 31) or mantle cell lymphoma (MCL; n = 19). The recommended phase 2 dose was zandelisib 60 mg on Days 1-7 plus zanubrutinib 80 mg twice daily continuously in 28-day cycle. In the total population, the most common adverse events (AEs; all grades/grade 3-4) were neutropenia (35%/24%), diarrhoea (33%/2%), thrombocytopenia (32%/8%), anaemia (27%/8%), increased creatinine (25%/0%), contusion (21%/0%), fatigue (21%/2%), nausea (21%/2%) and increased aspartate aminotransferase (24%/6%). Three patients discontinued due to AEs. The overall response rate was 87% (complete response [CR] = 33%) for FL and 74% (CR = 47%) for MCL. The median duration of response and progression-free survival (PFS) were not reached in either group. The estimated 1-year PFS was 72.3% (95% confidence interval [CI], 51.9-85.1) for FL and 56.3% (95% CI, 28.9-76.7) for MCL (median follow-up: 16.5 and 10.9 months respectively). Zandelisib plus zanubrutinib was associated with high response rates and no increased toxicity compared to either agent alone.
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Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma Folicular , Linfoma de Células del Manto , Pirazoles , Pirimidinas , Humanos , Linfoma de Células del Manto/tratamiento farmacológico , Femenino , Masculino , Anciano , Persona de Mediana Edad , Linfoma Folicular/tratamiento farmacológico , Linfoma Folicular/mortalidad , Pirimidinas/efectos adversos , Pirimidinas/administración & dosificación , Pirimidinas/uso terapéutico , Pirazoles/efectos adversos , Pirazoles/uso terapéutico , Pirazoles/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Adulto , Tiazoles/efectos adversos , Tiazoles/administración & dosificación , Tiazoles/uso terapéutico , Anciano de 80 o más Años , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Resultado del Tratamiento , PiperidinasRESUMEN
To address the current and long-term unmet health needs of the growing population of non-Hodgkin lymphoma (NHL) patients, we established the Lymphoma Epidemiology of Outcomes (LEO) cohort study (NCT02736357; https://leocohort.org/). A total of 7735 newly diagnosed patients aged 18 years and older with NHL were prospectively enrolled from 7/1/2015 to 5/31/2020 at 8 academic centers in the United States. The median age at diagnosis was 62 years (range, 18-99). Participants came from 49 US states and included 538 Black/African-Americans (AA), 822 Hispanics (regardless of race), 3386 women, 716 age <40 years, and 1513 rural residents. At study baseline, we abstracted clinical, pathology, and treatment data; banked serum/plasma (N = 5883, 76.0%) and germline DNA (N = 5465, 70.7%); constructed tissue microarrays for four major NHL subtypes (N = 1189); and collected quality of life (N = 5281, 68.3%) and epidemiologic risk factor (N = 4489, 58.0%) data. Through August 2022, there were 1492 deaths. Compared to population-based SEER data (2015-2019), LEO participants had a similar distribution of gender, AA race, Hispanic ethnicity, and NHL subtype, while LEO was underrepresented for patients who were Asian and aged 80 years and above. Observed overall survival rates for LEO at 1 and 2 years were similar to population-based SEER rates for indolent B-cell (follicular and marginal zone) and T-cell lymphomas, but were 10%-15% higher than SEER rates for aggressive B-cell subtypes (diffuse large B-cell and mantle cell). The LEO cohort is a robust and comprehensive national resource to address the role of clinical, tumor, host genetic, epidemiologic, and other biologic factors in NHL prognosis and survivorship.
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Linfoma no Hodgkin , Calidad de Vida , Humanos , Femenino , Estados Unidos/epidemiología , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Linfoma no Hodgkin/diagnóstico , Linfocitos B/patología , PronósticoRESUMEN
Diffuse large B-cell lymphomas (DLBCLs) are clinically and genetically heterogeneous tumors. Deregulation of diverse biological processes specific to B cells, such as B-cell receptor (BCR) signaling and motility regulation, contribute to lymphomagenesis. Human germinal center associated lymphoma (HGAL) is a B-cell-specific adaptor protein controlling BCR signaling and B lymphocyte motility. In normal B cells, it is expressed in germinal center (GC) B lymphocytes and promptly downregulated upon further differentiation. The majority of DLBCL tumors, primarily GC B-cell types, but also activated types, express HGAL. To investigate the consequences of constitutive expression of HGAL in vivo, we generated mice that conditionally express human HGAL at different stages of hematopoietic development using 3 restricted Cre-mediated approaches to initiate expression of HGAL in hematopoietic stem cells, pro-B cells, or GC B cells. Following immune stimulation, we observed larger GCs in mice in which HGAL expression was initiated in GC B cells. All 3 mouse strains developed DLBCL at a frequency of 12% to 30% starting at age 13 months, leading to shorter survival. Immunohistochemical studies showed that all analyzed tumors were of the GC B-cell type. Exon sequencing revealed mutations reported in human DLBCL. Our data demonstrate that constitutive enforced expression of HGAL leads to DLBCL development.
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Carcinogénesis/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Linfoma de Células B Grandes Difuso/genética , Proteínas de Microfilamentos/genética , Animales , Carcinogénesis/patología , Línea Celular , Femenino , Mutación con Ganancia de Función , Regulación Neoplásica de la Expresión Génica , Centro Germinal/metabolismo , Centro Germinal/patología , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/patología , Humanos , Linfoma de Células B Grandes Difuso/patología , Ratones , Ratones Endogámicos C57BLRESUMEN
We examined adults with untreated Burkitt lymphoma (BL) from 2009 to 2018 across 30 US cancer centers. Factors associated with progression-free survival (PFS) and overall survival (OS) were evaluated in univariate and multivariate Cox models. Among 641 BL patients, baseline features included the following: median age, 47 years; HIV+, 22%; Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2 to 4, 23%; >1 extranodal site, 43%; advanced stage, 78%; and central nervous system (CNS) involvement, 19%. Treatment-related mortality was 10%, with most common causes being sepsis, gastrointestinal bleed/perforation, and respiratory failure. With 45-month median follow-up, 3-year PFS and OS rates were 64% and 70%, respectively, without differences by HIV status. Survival was better for patients who received rituximab vs not (3-year PFS, 67% vs 38%; OS, 72% vs 44%; P < .001) and without difference based on setting of administration (ie, inpatient vs outpatient). Outcomes were also improved at an academic vs community cancer center (3-year PFS, 67% vs 46%, P = .006; OS, 72% vs 53%, P = .01). In multivariate models, age ≥ 40 years (PFS, hazard ratio [HR] = 1.70, P = .001; OS, HR = 2.09, P < .001), ECOG PS 2 to 4 (PFS, HR = 1.60, P < .001; OS, HR = 1.74, P = .003), lactate dehydrogenase > 3× normal (PFS, HR = 1.83, P < .001; OS, HR = 1.63, P = .009), and CNS involvement (PFS, HR = 1.52, P = .017; OS, HR = 1.67, P = .014) predicted inferior survival. Furthermore, survival varied based on number of factors present (0, 1, 2 to 4 factors) yielding 3-year PFS rates of 91%, 73%, and 50%, respectively; and 3-year OS rates of 95%, 77%, and 56%, respectively. Collectively, outcomes for adult BL in this real-world analysis appeared more modest compared with results of clinical trials and smaller series. In addition, clinical prognostic factors at diagnosis identified patients with divergent survival rates.
Asunto(s)
Linfoma de Burkitt/sangre , Linfoma de Burkitt/tratamiento farmacológico , Adulto , Anciano , Linfoma de Burkitt/genética , Femenino , Reordenamiento Génico/genética , Humanos , Estimación de Kaplan-Meier , L-Lactato Deshidrogenasa/sangre , Masculino , Persona de Mediana Edad , Pronóstico , Supervivencia sin Progresión , Proteínas Proto-Oncogénicas c-myc/genética , Resultado del Tratamiento , Estados UnidosRESUMEN
Mosunetuzumab is a novel bispecific antibody targeting epitopes on CD3 on T cells and CD20 on B cells with the goal of inducing T-cell mediated elimination of malignant B cells. A recent pivotal phase I/II clinical trial (GO29781) demonstrated that mosunetuzumab induced an overall response rate of 80%, complete response rate of 60%, and a median progression-free survival of 17.9 months in patients with relapsed/refractory (r/r) follicular lymphoma (FL) following at least two prior lines of systemic therapy, including alkylator and anti-CD20 antibody-based therapy. Historical data from cohorts receiving therapy for r/r FL can provide some context for interpretation of single-arm trials. We compared the results from the mosunetuzumab trial to outcomes from a cohort of patients with r/r FL from the LEO Consortium for Real World Evidence (LEO CReWE). We applied clinical trial eligibility criteria to the LEO CReWE cohort and utilized matching-adjusted indirect comparison weighting to balance the clinical characteristics of the LEO CReWE cohort with those from the mosunetuzumab trial. Overall response rates (73%, 95% CI:65-80%) and complete response rates (53%, 95% CI:45-61%) observed in the weighted LEO CReWE cohort were lower than those reported on the mosunetuzumab trial (ORR=80%, 95% CI:70-88%; CR=60%, 95% CI:49-70% respectively). Progression-free survival at 12 months was similar in the weighted LEO CReWE (60%, 95% CI:51-69%) and the mosunetuzumab trial (PFS 58%, 95% CI:47-68%). Sensitivity analyses examining the impact of matching variables, selection of line of therapy, and application of eligibility criteria, provide context for best practices in this setting.
RESUMEN
Comprehensive information on clinical features and long-term outcomes of primary conjunctival extranodal marginal zone lymphoma (PCEMZL) is scarce. We present a large single-institution retrospective study of 72 patients. The median age was 64 years, and 63.9% were female. Stage I was present in 87.5%. Radiation therapy (RT) alone was the most common treatment (70.8%). Complete response (CR) was 87.5%, and 100% in RT-treated patients. With a median follow-up of 6.7 years, relapse/progression and death occurred in 19.4% each, with one relapse within the RT field. The 10-year progression-free survival (PFS) and overall survival (OS) were 68.4% (95% CI 52.8%-79.8%) and 89.4% (95% CI 77.4%-95.2%), respectively. The 10-year rate for time to progression from diagnosis was 22.5% (95% CI 11.6%-35.7%). The 10-year PFS and OS of MALT-IPI 0 versus 1-2 were 83.3% versus 51.3%, (p = .022) and 97.6% versus 76.6%, (p = .0052), respectively. The following characteristics were associated with shorter survival: age > 60 years (PFS: HR = 2.93, 95% CI 1.08-7.95; p = .035, OS: HR = 9.07, 95% CI 1.17-70.26; p = .035) and MALT-IPI 1-2 (PFS: HR = 2.67, 95% CI 1.12-6.31; p = .027, OS: HR = 6.64, 95% CI 1.45-30.37; p = .015). CR following frontline therapy was associated with longer PFS (HR = 0.13, 95% CI 0.04-0.45; p = .001), but not OS. Using the Fine and Gray regression model with death without relapse/progression as a competing risk, RT and CR after frontline therapy were associated with lower risk of relapse (SHR = 0.34, 95% CI 0.12-0.96 p = .041 and SHR = 0.11, 95% CI 0.03-0.36; p < .001, respectively). Patients with PCEMZL treated with frontline RT exhibit excellent long-term survival, and the MALT-IPI score appropriately identifies patients at risk for treatment failure.
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Linfoma de Células B de la Zona Marginal , Recurrencia Local de Neoplasia , Humanos , Femenino , Persona de Mediana Edad , Masculino , Supervivencia sin Enfermedad , Estudios Retrospectivos , Supervivencia sin Progresión , PronósticoRESUMEN
Plasmablastic lymphoma (PBL) is a rare entity, commonly associated with immunosuppressed states such as human immunodeficiency virus (HIV) infection or solid organ transplant. The clinical course is characterized by high relapse rates and a poor prognosis, leading some clinicians to recommend aggressive frontline therapy. However, a specific review of limited stage (LS) PBL patients is not available to evaluate outcomes and justify treatment recommendations. We performed a retrospective review of LS PBL cases to provide insight into this rare disease. Our cohort consisted of 80 stage I or II PBL patients from 13 US academic centers. With a median follow up of 34 months (1-196), the 3-year progression-free survival (PFS) and overall survival (OS) of the entire cohort were 72% (95% CI 62, 83) and 79% (95% CI 70, 89), respectively. The 3-year PFS and OS of patients treated with frontline chemotherapy alone was 65% (95% CI 50, 84) and 71% (95% CI 56, 89), respectively, compared to 85% (95% CI 72, 100) and 96% (95% CI 89, 100), respectively, in patients treated with combined frontline chemotherapy with radiation consolidation. Our data demonstrate favorable outcomes in LS PBL with no improvements in outcome from aggressive frontline treatment including Hyper-CVAD or auto-SCT consolidation. Multivariate regression analysis (MRA) demonstrated improved PFS for patients receiving EPOCH based frontline therapy versus CHOP (HR: 0.23; p = 0.029). Frontline chemotherapy followed by radiation consolidation versus chemotherapy alone appeared to be associated with improved relapse and survival outcomes but did not show statistical significance in MRA.
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Infecciones por VIH , Linfoma Plasmablástico , Humanos , Linfoma Plasmablástico/terapia , Linfoma Plasmablástico/patología , Estudios Retrospectivos , Recurrencia Local de Neoplasia/etiología , Protocolos de Quimioterapia Combinada Antineoplásica , Supervivencia sin Progresión , Infecciones por VIH/tratamiento farmacológico , PronósticoRESUMEN
The impact of LMO2 expression on cell lineage decisions during T-cell leukemogenesis remains largely elusive. Using genetic lineage tracing, we have explored the potential of LMO2 in dictating a T-cell malignant phenotype. We first initiated LMO2 expression in hematopoietic stem/progenitor cells and maintained its expression in all hematopoietic cells. These mice develop exclusively aggressive human-like T-ALL In order to uncover a potential exclusive reprogramming effect of LMO2 in murine hematopoietic stem/progenitor cells, we next showed that transient LMO2 expression is sufficient for oncogenic function and induction of T-ALL The resulting T-ALLs lacked LMO2 and its target-gene expression, and histologically, transcriptionally, and genetically similar to human LMO2-driven T-ALL We next found that during T-ALL development, secondary genomic alterations take place within the thymus. However, the permissiveness for development of T-ALL seems to be associated with wider windows of differentiation than previously appreciated. Restricted Cre-mediated activation of Lmo2 at different stages of B-cell development induces systematically and unexpectedly T-ALL that closely resembled those of their natural counterparts. Together, these results provide a novel paradigm for the generation of tumor T cells through reprogramming in vivo and could be relevant to improve the response of T-ALL to current therapies.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Carcinogénesis , Transformación Celular Neoplásica , Proteínas con Dominio LIM/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Animales , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Células Madre Hematopoyéticas/fisiología , Histocitoquímica , Ratones , Timo/patologíaRESUMEN
Acalabrutinib, a Bruton tyrosine kinase inhibitor, demonstrated greater selectivity and improved safety versus ibrutinib in a head-to-head trial in relapsed/refractory (R/R) chronic lymphocytic leukaemia. In the R/R marginal zone lymphoma (MZL) cohort (phase 2) of a phase 1b/2 trial (NCT02180711), 43 patients with MZL and at least one prior therapy received acalabrutinib 100 mg twice daily until disease progression or unacceptable toxicity [median age 69 years (range 42-84); median one (1-4) prior systemic regimens]. Median follow-up was 13.3 months (range 0.5-45.5). Among 40 patients evaluable for response, investigator-assessed overall response rate was 53% [95% confidence interval (CI) 36%-69%] with five (13%) complete responses. Tumour reduction occurred in 40 (93%) of the treated patients. Median time to response was 2.9 months (median duration of response not estimable). Estimated median progression-free survival (PFS) was 27.4 months (12-month PFS rate, 67%). Five patients died (disease progression, n = 4; septic shock, n = 1). Seventeen patients (40%) had grade 3 or higher adverse events (AEs), most commonly neutropenia (14%), anaemia, dyspnoea (7% each), fatigue and thrombocytopenia (5% each). Hypertension occurred in 5%; atrial fibrillation/flutter and major haemorrhage were not reported. AEs led to treatment discontinuation in three (7%) patients. Acalabrutinib was active and well tolerated in patients with R/R MZL.
Asunto(s)
Leucemia Linfocítica Crónica de Células B , Linfoma de Células B de la Zona Marginal , Adulto , Anciano , Anciano de 80 o más Años , Benzamidas , Progresión de la Enfermedad , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Linfoma de Células B de la Zona Marginal/tratamiento farmacológico , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversos , Pirazinas , Resultado del TratamientoRESUMEN
T- lymphoblastic leukemia/lymphoma (T-LL) is an aggressive malignancy of immature T-cells with poor overall survival (OS) and in need of new therapies. LIM-domain only 2 (LMO2) is a critical regulator of hematopoietic cell development that can be overexpressed in T-LL due to chromosomal abnormalities. Deregulated LMO2 expression contributes to T-LL development by inducing block of T-cell differentiation and continuous thymocyte self-renewal. However, LMO2 expression and its biologic significance in T-LL remain largely unknown. We analyzed LMO2 expression in 100 initial and follow-up biopsies of T-LL from 67 patients, including 31 (46%) early precursor T-cell (ETP)-ALL, 26 (39%) cortical and 10 (15%) medullary type. LMO2 expression was present in 50 (74.6%) initial biopsies with an average of 87% positive tumor cells (range 30-100%). LMO2 expression in ETP, medullary and cortical T-LLs was not statistically different. In patients with biopsies after initial therapy, LMO2 expression was stable. LMO2 expression was associated with longer OS (p = 0.048) regardless of T-lymphoblast stage or other clinicopathologic features. These findings indicate that LMO2 is a promising new prognostic marker that could predict patients' outcomes and potentially be targeted for novel chemotherapy, i.e. PARP1/2 inhibitors, which have been shown to enhance chemotherapy sensitivity in LMO2 expressing diffuse large B cell lymphoma (DLBCL) tumors by decreasing DNA repair efficiency.
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Proteínas con Dominio LIM , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Proteínas Adaptadoras Transductoras de Señales/genética , Humanos , Proteínas con Dominio LIM/genética , Proteínas con Dominio LIM/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Linfocitos T/patologíaRESUMEN
In relapsed/refractory Hodgkin lymphoma (R/R HL), immunotherapies such as the anti-programmed death-1 inhibitor pembrolizumab have demonstrated efficacy as monotherapy and are playing an increasingly prominent role in treatment. The CD30/CD16A-bispecific antibody AFM13 is an innate immune cell engager, a first-in-class, tetravalent antibody, designed to create a bridge between CD30 on HL cells and the CD16A receptor on natural killer cells and macrophages, to induce tumor cell killing. Early studies of AFM13 have demonstrated signs of efficacy as monotherapy for patients with R/R HL and the combination of AFM13 with pembrolizumab represents a rational new treatment modality. Here, we describe a phase 1b, dose-escalation study to assess the safety and preliminary efficacy of AFM13 in combination with pembrolizumab in patients with R/R HL. The primary objective was estimating the maximum tolerated dose; the secondary objectives were to assess safety, tolerability, antitumor efficacy, pharmacokinetics, and pharmacodynamics. In this heavily pretreated patient population, treatment with the combination of AFM13 and pembrolizumab was generally well tolerated, with similar safety profiles compared to the known profiles of each agent alone. The combination of AFM13 with pembrolizumab demonstrated an objective response rate of 88% at the highest treatment dose, with an 83% overall response rate for the overall population. Pharmacokinetic assessment of AFM13 in the combination setting revealed a half-life of up to 20.6 hours. This proof-of-concept study holds promise as a novel immunotherapy combination worthy of further investigation. This phase 1b study was registered at www.clinicaltrials.gov as NCT02665650.
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Antígenos de Neoplasias/inmunología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Enfermedad de Hodgkin/tratamiento farmacológico , Inmunoterapia , Antígeno Ki-1/antagonistas & inhibidores , Receptores de IgG/antagonistas & inhibidores , Adolescente , Adulto , Anciano , Anticuerpos Biespecíficos/administración & dosificación , Anticuerpos Biespecíficos/efectos adversos , Anticuerpos Biespecíficos/farmacocinética , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Terapia Combinada , Relación Dosis-Respuesta Inmunológica , Femenino , Semivida , Trasplante de Células Madre Hematopoyéticas , Enfermedad de Hodgkin/terapia , Humanos , Inmunidad Innata/efectos de los fármacos , Antígeno Ki-1/inmunología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Prueba de Estudio Conceptual , Receptores de IgG/inmunología , Recurrencia , Trasplante Autólogo , Adulto JovenRESUMEN
Marginal zone lymphoma (MZL) is commonly underrepresented in clinical trials collectively studying mostly nodal indolent lymphomas.In this manuscript we propose new inclusion and response criteria defined by MZL subtype and disease location for those with extranodal MZL. Progression of disease within 24 months is associated with poor outcomes in MZL and future studies should assess the efficacy of novel agents in this population.
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Linfoma de Células B de la Zona Marginal , Ensayos Clínicos como Asunto , Humanos , Linfoma de Células B de la Zona Marginal/tratamiento farmacológicoRESUMEN
Extranodal marginal zone lymphoma (EMZL) is a heterogeneous disease with a subset of patients exhibiting a more aggressive course. We previously reported that EMZL with multiple mucosal sites (MMS) at diagnosis is characterized by shorter survival. To better recognize patients with different patterns of progression-free survival (PFS) we developed and validated a new prognostic index primarily based on patient's disease characteristics. We derived the "Revised mucosa-associated lymphoid tissue International Prognostic Index" (Revised MALT-IPI) in a large data set (n = 397) by identifying candidate variables that showed highest prognostic association with PFS. The revised MALT-IPI was validated in two independent cohorts, from the University of Iowa/Mayo Clinic (n = 297) and from IELSG-19 study (n = 400). A stepwise Cox regression analysis yielded a model including four independent predictors of shorter PFS. Revised MALT-IPI has scores ranging from 0 to 5, calculated as a sum of one point for each of the following- age >60 years, elevated LDH, and stage III-IV; and two points for MMS. In the training cohort, the Revised MALT-IPI defined four risk groups: low risk (score 0, reference group), low-medium risk (score 1, HR = 1.85, p = .008), medium-high risk (score 2, HR = 3.84, p < .0001), and high risk (score 3+, HR = 8.48, p < .0001). Performance of the Revised MALT-IPI was similar in external validation cohorts. Revised MALT-IPI is a new index centered on disease characteristics that provides robust risk-stratification identifying a group of patients characterized by earlier progression of disease. Revised MALT-IPI can allow a more disease-adjusted management of patients with EMZL in clinical trials and practice.
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Linfoma de Células B de la Zona Marginal , Humanos , Persona de Mediana Edad , Estudios Retrospectivos , Linfoma de Células B de la Zona Marginal/tratamiento farmacológico , Pronóstico , Factores de RiesgoRESUMEN
Protein arginine methyltransferase 5 (PRMT5) catalyzes the symmetric di-methylation of arginine residues in histones H3 and H4, marks that are generally associated with transcriptional repression. However, we found that PRMT5 inhibition or depletion led to more genes being downregulated than upregulated, indicating that PRMT5 can also act as a transcriptional activator. Indeed, the global level of histone H3K27me3 increases in PRMT5 deficient cells. Although PRMT5 does not directly affect PRC2 enzymatic activity, methylation of histone H3 by PRMT5 abrogates its subsequent methylation by PRC2. Treating AML cells with an EZH2 inhibitor partially restored the expression of approximately 50% of the genes that are initially downregulated by PRMT5 inhibition, suggesting that the increased H3K27me3 could directly or indirectly contribute to the transcription repression of these genes. Indeed, ChIP-sequencing analysis confirmed an increase in the H3K27me3 level at the promoter region of a quarter of these genes in PRMT5-inhibited cells. Interestingly, the anti-proliferative effect of PRMT5 inhibition was also partially rescued by treatment with an EZH2 inhibitor in several leukemia cell lines. Thus, PRMT5-mediated crosstalk between histone marks contributes to its functional effects.
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Arginina/metabolismo , Histonas/metabolismo , Proteínas del Grupo Polycomb/metabolismo , Proteína-Arginina N-Metiltransferasas/metabolismo , Transcripción Genética , Animales , Ciclo Celular/genética , Línea Celular Tumoral , Eliminación de Gen , Regulación de la Expresión Génica , Células Madre Hematopoyéticas/metabolismo , Metilación , Ratones Noqueados , Modelos Biológicos , Nucleosomas/metabolismo , Proteína-Arginina N-Metiltransferasas/antagonistas & inhibidoresRESUMEN
Even in the era of highly active combination antiretroviral therapy (cART), patients with HIV have a disproportionate risk of developing aggressive lymphomas that are frequently Epstein-Barr virus (EBV)-related. Here, we investigate HIV-associated diffuse large B-cell lymphoma (HIV-DLBCL) and compare EBV-positive and EBV-negative cases. HIV-DLBCL were identified from two academic medical centres and characterised by immunohistochemistry, EBV status, fluorescence in situ hybridisation, cell of origin determination by gene expression profiling, and targeted deep sequencing using a custom mutation panel of 334 genes. We also applied the Lymphgen tool to determine the genetic subtype of each case. Thirty HIV-DLBCL were identified, with a median patient age of 46 years and male predominance (5:1). Thirteen cases (48%) were EBV-positive and 14 (52%) EBV-negative. Nine of the 16 tested cases (56%) had MYC rearrangement, three (19%) had BCL6 (two of which were double hit MYC/BCL6) and none had BCL2 rearrangements. Using the Lymphgen tool, half of the cases (15) were classified as other. All HIV-DLBCL showed mutational abnormalities, the most frequent being TP53 (37%), MYC (30%), STAT3 (27%), HIST1H1E (23%), EP300 (20%), TET2 (20%), SOCS1 (17%) and SGK1 (17%). EBV-negative cases were mostly of germinal centre B-cell (GCB) origin (62%), showed more frequent mutations per case (a median of 13·5/case) and significant enrichment of TP53 (57% vs. 15%; P = 0·046), SGK1 (36% vs. 0%; P = 0·04), EP300 (43% vs. 0%; P = 0·02) and histone-modifying gene (e.g. HIST1H1E, HIST1H1D, 79% vs. 31%; P = 0·02) mutations. EBV-positive cases were mostly of non-GCB origin (70%), with fewer mutations per case (median 8/case; P = 0·007), and these tumours were enriched for STAT3 mutations (P = 0·10). EBV-positive cases had a higher frequency of MYC mutations but the difference was not significant (36% vs. 15%; P = 0·38). EBV-association was more frequent in HIV-DLBCLs, arising in patients with lower CD4 counts at diagnosis (median 46·5 vs. 101, P = 0·018). In the era of cART, approximately half of HIV-DLBCL are EBV-related. HIV-DLBCL are enriched for MYC rearrangements, MYC mutations and generally lack BCL2 rearrangements, regardless of EBV status. Among HIV-DLBCL, tumours that are EBV-negative and EBV-positive appear to have important differences, the latter arising in context of lower CD4 count, showing frequent non-GCB origin, lower mutation burden and recurrent STAT3 mutations.
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Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por VIH/complicaciones , Quinasas Janus/genética , Linfoma de Células B Grandes Difuso/virología , Factores de Transcripción STAT/genética , Adulto , Infecciones por Virus de Epstein-Barr/genética , Infecciones por Virus de Epstein-Barr/metabolismo , Femenino , Infecciones por VIH/genética , Infecciones por VIH/metabolismo , Herpesvirus Humano 4/aislamiento & purificación , Humanos , Quinasas Janus/metabolismo , Linfoma de Células B Grandes Difuso/etiología , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/metabolismo , Masculino , Persona de Mediana Edad , Mutación , Factores de Transcripción STAT/metabolismo , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Transducción de SeñalRESUMEN
We present long-term combined results of two clinical trials implementing R-MACLO-IVAM induction followed by thalidomide or rituximab maintenance in 44 patients with untreated mantle cell lymphoma (MCL). The first 22 patients (UM-MCL1 ClinicalTrials.gov identifier NCT00450801) received maintenance with thalidomide (200 mg daily until relapse/intolerable toxicity) and a subsequent cohort of 22 patients (UM-MCL2 ClinicalTrials.gov identifier NCT00878254) received rituximab (375 mg/m2 IV weekly × 4, repeated every 6 months for 3 years). Considering all 44 patients, 41 (93.2%) achieved complete response (CR), two (4.5%) partial response (PR), and one (2.3%) was not evaluated for response. With a median follow up of 7.2 years (range < 1 month to 16 years), the 5-year progression-free survival (PFS) was 55.6% (95% CI: 38.9%-69.4%) and median PFS 7.9 years (95% CI: 3.7-11 years). The 5-year OS was 83.3% (95% CI: 68.1%-91.7%) and median OS was not reached. Patients with blastic variant (n = 6) had a 5-year PFS and OS of 20.8% and 60%, respectively. Myelosuppression was the most common adverse event during immunochemotherapy. Long-term treatment-related mortality was 6.8%. Note, R-MACLO-IVAM followed by maintenance therapy is an effective regimen to induce long-term remission in MCL without need for consolidation with ASCT.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma de Células del Manto/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ciclofosfamida/administración & dosificación , Citarabina/administración & dosificación , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Etopósido/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Ifosfamida/administración & dosificación , Estimación de Kaplan-Meier , Quimioterapia de Mantención , Masculino , Metotrexato/administración & dosificación , Persona de Mediana Edad , Supervivencia sin Progresión , Estudios Prospectivos , Inducción de Remisión , Rituximab/administración & dosificación , Talidomida/administración & dosificación , Talidomida/toxicidad , Vincristina/administración & dosificación , Adulto JovenRESUMEN
BACKGROUND: Splenic marginal zone lymphoma (SMZL) is a rare tumor without a uniform treatment approach. The authors describe a large population-based study evaluating survival outcomes of patients with SMZL according to the treatment received. METHODS: From the Surveillance, Epidemiology, and End Results database, patients were selected who had SMZL diagnosed from 1999 to 2016. Observation, splenectomy, chemotherapy, and splenectomy with chemotherapy were the evaluated treatment strategies. Cox and Fine and Gray regression models were used to evaluate overall and SMZL-specific survival, respectively. RESULTS: In total, 1671 patients were selected for the analysis. Most patients were aged >60 years (71.3%), White (89.7%), and non-Hispanic (91.7%). Transformation to diffuse large B-cell lymphoma (DLBCL) occurred in 71 patients (4.2%), and the 10-year transformation rate was 8.6% (95% CI, 6.6%-10.9%). In multivariable analysis, shorter SMZL-specific survival was associated with age ≥60 years (subdistribution hazard ratio [SHR], 1.85; 95% CI, 1.40-2.45; P < .001), Hispanic ethnicity (SHR, 1.50; 95% CI, 1.06-2.13; P = .023), DLBCL transformation (SHR, 2.10; 95% CI, 1.48-2.97; P < .001), and the presence of B-symptoms (SHR, 1.67; 95% CI, 1.23-2.27; P < .001). Compared with splenectomy, observation (SHR, 0.92; 95% CI, 0.67-1.28; P = .636), chemotherapy only (SHR, 1.28; 95% CI, 0.93-1.76; P = .127), and splenectomy plus chemotherapy (SHR, 1.43; 95% CI, 0.96-2.13; P = .089) showed no significant differences in SMZL-specific survival. Predictors of shorter overall survival were age ≥60 years (hazard ratio, 2.98; 95% CI, 2.37-3.76; P < .001) and the presence of B-symptoms (hazard ratio, 1.33; 95% CI, 1.06-1.67; P = .014). CONCLUSIONS: There were no significant differences in overall or SMZL-specific survival by treatment strategy. Older age, Hispanic ethnicity, DLBCL transformation, and B-symptoms were associated with a worse prognosis.
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Linfoma de Células B de la Zona Marginal/mortalidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Programa de VERF , Análisis de SupervivenciaRESUMEN
Neurological emergencies are frequently catastrophic events in the course of haematological malignancies (HM) that, if not promptly recognized and treated, may lead to lethal outcomes or chronic sequelae. They may occur at any time during the disease course, but are more frequently observed following relapse. Practice guidelines are lacking in the management of most central nervous system (CNS) complications in HM. Herein we review the pathophysiology, presentation and treatment of elevated intracranial pressure, spinal cord compression, status epilepticus, neurovascular complications, CNS infection, leucostasis and hyperviscosity. Further, we discuss the expanding spectrum of neurological complications of old and novel treatments in HM.