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Antibody-secreting plasma cells (PCs) are generated in secondary lymphoid organs but are reported to reside in an emerging range of anatomical sites. Analysis of the transcriptome of different tissue-resident (Tr)PC populations revealed that they each have their own transcriptional signature indicative of functional adaptation to the host tissue environment. In contrast to expectation, all TrPCs were extremely long-lived, regardless of their organ of residence, with longevity influenced by intrinsic factors like the immunoglobulin isotype. Analysis at single-cell resolution revealed that the bone marrow is unique in housing a compendium of PCs generated all over the body that retain aspects of the transcriptional program indicative of their tissue of origin. This study reveals that extreme longevity is an intrinsic property of TrPCs whose transcriptome is imprinted by signals received both at the site of induction and within the tissue of residence.
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Médula Ósea , Células Plasmáticas , Células de la Médula ÓseaRESUMEN
ABSTRACT: Plasmablastic lymphoma (PBL) is a rare and aggressive non-Hodgkin lymphoma associated with immunodeficiency, characterized by uncertain treatment approaches and an unfavorable prognosis. We conducted a multicenter, international, retrospective cohort study, aiming to characterize the clinical features, risk factors, and outcomes of patients with PBL. Data were collected from 22 institutions across 4 countries regarding patients diagnosed with PBL between 1 January 1999 and 31 December 2020. Survival risk factors were analyzed using both univariate and multivariate regression models. Overall survival (OS) was calculated using Kaplan-Meier statistics. First-line treatment regimens were stratified into standard- and higher-intensity regimens, and based on whether they incorporated a proteasome inhibitor (PI). A total of 281 patients (median age, 55 years) were included. Immunodeficiency of any kind was identified in 144 patients (51%), and 99 patients (35%) had HIV-positive results. The 5-year OS for the entire cohort was 36% (95% confidence interval, 30%-42%). In multivariate analysis, inferior OS was associated with Epstein-Barr virus-negative lymphoma, poor performance status, advanced stage, and bone marrow involvement. In an independent univariate analysis, the international prognostic index was associated with OS outcomes. Neither immunosuppression nor HIV infection, specifically, influenced OS. Among patients treated with curative intent (n = 234), the overall response rate was 72%. Neither the intensity of the treatment regimen nor the inclusion of PIs in first-line therapy was associated with OS. In this large retrospective study of patients with PBL, we identified novel risk factors for survival. PBL remains a challenging disease with poor long-term outcomes.
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Infecciones por Virus de Epstein-Barr , Infecciones por VIH , Linfoma Plasmablástico , Humanos , Persona de Mediana Edad , Linfoma Plasmablástico/patología , Estudios Retrospectivos , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Infecciones por Virus de Epstein-Barr/complicaciones , Herpesvirus Humano 4 , PronósticoRESUMEN
Coronavirus disease 2019 (COVID-19) infection in patients with haematological neoplasms has been associated with increased mortality; however, many studies in this patient group were reported early in the pandemic. The authors evaluated outcomes of COVID-19 infection in patients with haematological conditions following widespread vaccination, newer viral variants and increasingly effective antiviral therapies. A 4% mortality rate was found and contemporary risk factors for hospitalisation including older age, nonvaccination or partial COVID-19 vaccination status and infection with non-Omicron strain were identified.
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COVID-19 , Neoplasias Hematológicas , Hematología , Humanos , SARS-CoV-2 , Vacunas contra la COVID-19 , Neoplasias Hematológicas/terapiaRESUMEN
BACKGROUND: Histologic transformation (HT) is an important event with adverse prognosis in the natural history of indolent lymphomas. There are minimal data on HT in the Australian setting. AIMS: To characterise patients with biopsy-proven HT and their outcomes identified at a tertiary Australian Hospital. METHODS: All patients with biopsy-proven HT during a 15-year period (2002-2017) were included. Clinico-pathological data were systematically collected from review of patient records. Survival estimates were assessed using the Kaplan-Meier method and compared using the log-rank test. Associations between variables and clinical outcomes were evaluated using Cox's proportional hazards model. RESULTS: A cohort of 45 patients was identified with a median age of 66 years and the majority (59%) having high-risk disease (Revised-International Prognostic Index score ≥3). R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) induction was used in 69%, with an overall response rate of 82% (complete response (CR), 75%). Sixty-one percent of these induction responders received consolidation, with autologous stem cell transplant (ASCT) performed in only 17% and rituximab maintenance given to 31%. With a median follow up of 47 months (range: 4-136), the 5-year overall survival (OS) was 69% (95% CI: 52%, 81%). Chemotherapy-naivety at HT was associated with a superior rate of CR (84% vs 54%, P = 0.057) and 5-year OS (82% vs 46%, P = 0.012). Rituximab maintenance was associated with a durable progression-free survival in induction responders. CONCLUSIONS: Excellent OS was observed in this modern cohort of patients treated with rituximab-containing induction and low rate of consolidation by ASCT, particularly in those who were chemotherapy-naïve at HT.
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Trasplante de Células Madre Hematopoyéticas , Linfoma no Hodgkin , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Australia/epidemiología , Ciclofosfamida , Supervivencia sin Enfermedad , Doxorrubicina , Humanos , Recurrencia Local de Neoplasia , Prednisona , Rituximab , Trasplante Autólogo , VincristinaRESUMEN
Recent studies have demonstrated that the immunomodulatory drugs (IMiDs) lead to the degradation of the transcription factors Ikaros and Aiolos. However, why their loss subsequently leads to multiple myeloma (MM) cell death remains unclear. Using CRISPR-Cas9 genome editing, we have deleted IKZF1/Ikaros and IKZF3/Aiolos in human MM cell lines to gain further insight into their downstream gene regulatory networks. Inactivation of either factor alone recapitulates the cell intrinsic action of the IMiDs, resulting in cell cycle arrest and induction of apoptosis. Furthermore, evaluation of the transcriptional changes resulting from their loss demonstrates striking overlap with lenalidomide treatment. This was not dependent on reduction of the IRF4-MYC "axis," as neither protein was consistently downregulated, despite cell death occurring, and overexpression of either factor failed to rescue for Ikaros loss. Importantly, Ikaros and Aiolos repress the expression of interferon-stimulated genes (ISGs), including CD38, and their loss led to the activation of an interferon-like response, contributing to MM cell death. Ikaros/Aiolos repressed CD38 expression through interaction with the nucleosome remodeling and deacetylase complex in MM. IMiD-induced loss of Ikaros or treatment with interferon resulted in an upregulation of CD38 surface expression on MM cells, priming for daratumumab-induced NK cell-mediated antibody-dependent cellular cytotoxicity. These results give further insight into the mechanism of action of the IMiDs and provide mechanistic rationale for combination with anti-CD38 monoclonal antibodies.
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Anticuerpos Monoclonales/farmacología , Antineoplásicos/farmacología , Sistemas CRISPR-Cas , Factor de Transcripción Ikaros/genética , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genética , Citotoxicidad Celular Dependiente de Anticuerpos/efectos de los fármacos , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , HumanosRESUMEN
Antibody Secreting Cells (ASCs) are a fundamental component of humoral immunity, however, deregulated or excessive antibody production contributes to the pathology of autoimmune diseases, while transformation of ASCs results in the malignancy Multiple Myeloma (MM). Despite substantial recent improvements in treating these conditions, there is as yet no widely used ASC-specific therapeutic approach, highlighting a critical need to identify novel methods of targeting normal and malignant ASCs. Surface molecules specifically expressed by the target cell population represent ideal candidates for a monoclonal antibody-based therapy. By interrogating the ASC gene signature that we previously defined we identified three surface proteins, Plpp5, Clptm1l and Itm2c, which represent potential targets for novel MM treatments. Plpp5, Clptm1l and Itm2c are highly and selectively expressed by mouse and human ASCs as well as MM cells. To investigate the function of these proteins within the humoral immune system we have generated three novel mouse strains, each carrying a loss-of-function mutation in either Plpp5, Clptm1l or Itm2c. Through analysis of these novel strains, we have shown that Plpp5, Clptm1l and Itm2c are dispensable for the development, maturation and differentiation of B-lymphocytes, and for the production of antibodies by ASCs. As adult mice lacking either protein showed no apparent disease phenotypes, it is likely that targeting these molecules on ASCs will have minimal on-target adverse effects.
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Células Productoras de Anticuerpos/inmunología , Proteínas de la Membrana/genética , Mieloma Múltiple/inmunología , Proteínas de Neoplasias/genética , Fosfatidato Fosfatasa/genética , Células Plasmáticas/inmunología , Transcriptoma , Animales , Linfocitos B/inmunología , Células de la Médula Ósea/citología , Células de la Médula Ósea/inmunología , Línea Celular Tumoral , Humanos , Inmunidad Humoral , Proteínas de la Membrana/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mieloma Múltiple/genética , Mutación , Proteínas de Neoplasias/fisiología , Fosfatidato Fosfatasa/fisiología , Células Plasmáticas/citología , Cultivo Primario de CélulasAsunto(s)
COVID-19 , Mieloma Múltiple , Personal de Salud , Humanos , Mieloma Múltiple/diagnóstico , SARS-CoV-2RESUMEN
BACKGROUND: Demand for platelet (PLT) and plasma transfusions is increasing. Improved clinical supply and contingency planning requires greater understanding of usage profiles and urgency of clinical requirement. STUDY DESIGN AND METHODS: This study was a random-sample survey of PLT and plasma units produced in Victoria, Australia, to determine product disposition, recipient demographics, clinical indications for transfusion, and urgency (or "deferability") of need. PLTs and fresh-frozen plasma (FFP) were tagged with a case report form before distribution. RESULTS: A total of 1252 PLT and 1837 FFP units were tagged, comprising 8.3 and 13.3% of all products issued during the study period. The fate of 1243 PLT and 1808 FFP units was determined. Of products issued, 72.2% of PLTs and 87.8% of FFP were transfused. Hematologic and oncologic disorders accounted for 63.9% of PLT transfusions, with acute myeloid leukemia alone accounting for 26%. Conversely, surgical patients received the largest proportion of FFP (40.4%), predominantly for cardiothoracic, solid organ transplant, and vascular surgery. Approximately 15% of PLT transfusions and 35% of plasma transfusions were required within 1 hour, and 80% of PLT transfusions and 90% of FFP transfusions were required within 24 hours. Wastage rates were higher in regional blood banks. CONCLUSION: The PUPPY study is a comprehensive and detailed population-based assessment of PLT and plasma usage, including urgency of use. It identifies specific clinical areas with high demand for PLT and FFP transfusion and demonstrates the high urgency of need for both products. These data inform clinical supply and contingency planning activities.
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Transfusión de Componentes Sanguíneos/estadística & datos numéricos , Plaquetas , Técnicas de Planificación , Plasma , Bancos de Sangre/normas , Enfermedades Hematológicas/terapia , Humanos , Neoplasias/terapia , Procedimientos Quirúrgicos Operativos , Encuestas y Cuestionarios , Almacenamiento de Sangre/métodosAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bortezomib/administración & dosificación , Linfoma Plasmablástico/tratamiento farmacológico , Linfoma Plasmablástico/mortalidad , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bortezomib/efectos adversos , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Etopósido/administración & dosificación , Etopósido/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Linfoma Plasmablástico/patología , Prednisona/administración & dosificación , Prednisona/efectos adversos , Estudios Retrospectivos , Tasa de Supervivencia , Vincristina/administración & dosificación , Vincristina/efectos adversosAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Adulto , Anciano , Bortezomib/administración & dosificación , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mieloma Múltiple/patología , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Factores de Tiempo , Resultado del TratamientoAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bortezomib/administración & dosificación , Infusiones Subcutáneas , Linfoma Plasmablástico/diagnóstico , Linfoma Plasmablástico/tratamiento farmacológico , Anciano , Ciclofosfamida/administración & dosificación , Relación Dosis-Respuesta a Droga , Doxorrubicina/administración & dosificación , Etopósido/administración & dosificación , Humanos , Infusiones Subcutáneas/métodos , Masculino , Prednisona/administración & dosificación , Resultado del Tratamiento , Vincristina/administración & dosificaciónRESUMEN
The last decade has seen a significant leap in our understanding of the wide range of genetic lesions underpinning acute lymphoblastic leukaemia (ALL). Next generation sequencing has led to the identification of driver mutations with significant implications on prognosis and has defined entities such as BCR-ABL-like ALL, where targeted therapies such as tyrosine kinase inhibitors (TKIs) and JAK inhibitors may play a role in its treatment. In Philadelphia positive ALL, the introduction of TKIs into frontline treatment regimens has already transformed patient outcomes. In B-ALL, agents targeting surface receptors CD19, CD20 and CD22, including monoclonal antibodies, bispecific T cell engagers, antibody drug conjugates and chimeric antigen receptor (CAR) T cells, have shown significant activity but come with unique toxicities and have implications for how treatment is sequenced. Advances in T-ALL have lagged behind those seen in B-ALL. However, agents such as nelarabine, bortezomib and CAR T cell therapy targeting T cell antigens have been examined with promising results seen. As our understanding of disease biology in ALL grows, as does our ability to target pathways such as apoptosis, through BH3 mimetics, chemokines and epigenetic regulators. This review aims to highlight a range of available and emerging targeted therapeutics in ALL, to explore their mechanisms of action and to discuss the current evidence for their use.
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Multiple myeloma is an incurable and fatal cancer of immunoglobulin-secreting plasma cells. Most conventional therapies aim to induce apoptosis in myeloma cells but resistance to these drugs often arises and drives relapse. In this study, we sought to identify the best adjunct targets to kill myeloma cells resistant to conventional therapies using deep profiling by mass cytometry (CyTOF). We validated probes to simultaneously detect 26 regulators of cell death, mitosis, cell signaling, and cancer-related pathways at the single-cell level following treatment of myeloma cells with dexamethasone or bortezomib. Time-resolved visualization algorithms and machine learning random forest models (RFMs) delineated putative cell death trajectories and a hierarchy of parameters that specified myeloma cell survival versus apoptosis following treatment. Among these parameters, increased amounts of phosphorylated cAMP response element-binding protein (CREB) and the pro-survival protein, MCL-1, were defining features of cells surviving drug treatment. Importantly, the RFM prediction that the combination of an MCL-1 inhibitor with dexamethasone would elicit potent, synergistic killing of myeloma cells was validated in other cell lines, in vivo preclinical models and primary myeloma samples from patients. Furthermore, CyTOF analysis of patient bone marrow cells clearly identified myeloma cells and their key cell survival features. This study demonstrates the utility of CyTOF profiling at the single-cell level to identify clinically relevant drug combinations and tracking of patient responses for future clinical trials.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/patología , Transducción de Señal , Algoritmos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apoptosis/efectos de los fármacos , Bortezomib/farmacología , Bortezomib/uso terapéutico , Línea Celular Tumoral , Supervivencia Celular , Dexametasona/farmacología , Dexametasona/uso terapéutico , Sinergismo Farmacológico , Citometría de Flujo , Humanos , Aprendizaje Automático , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Transducción de Señal/efectos de los fármacos , Análisis de la Célula Individual , Factores de TiempoAsunto(s)
Mieloma Múltiple/diagnóstico , Estadificación de Neoplasias , Microglobulina beta-2/sangre , Técnicas de Laboratorio Clínico/normas , Humanos , Luminiscencia , Nefelometría y Turbidimetría/normas , Pronóstico , Estudios Prospectivos , Estándares de Referencia , Reproducibilidad de los ResultadosRESUMEN
The transcription factor interferon regulatory factor 4 (IRF4) is critical for the development, maintenance, and function of plasma cells. The mechanism by which IRF4 exerts its action in mature plasma cells has been elusive due to the death of all such cells upon IRF4 loss. While we identify apoptosis as a critical pathway for the death of plasma cells caused by IRF4 loss, we also determine that IRF4 did not regulate the intrinsic apoptotic pathway directly. By using an inducible IRF4 deletion system in the presence of the overexpression of anti-apoptotic BCL2, we identify genes whose expression is coordinated by IRF4 and that in turn specify plasma cell identity and mitochondrial homeostasis.
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Factores Reguladores del Interferón/genética , Factores Reguladores del Interferón/metabolismo , Mitocondrias/genética , Mitocondrias/metabolismo , Células Plasmáticas/fisiología , Animales , Línea Celular Tumoral , Homeostasis , Humanos , Ratones , Mieloma Múltiple/genética , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Células Plasmáticas/metabolismo , Células Plasmáticas/patología , Plasmacitoma/genética , Plasmacitoma/metabolismo , Plasmacitoma/patología , Transcripción GenéticaRESUMEN
There is limited data describing dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP) in relapsed refractory multiple myeloma (RRMM). We reviewed 65 patients with RRMM receiving DCEP between 2005 and 2017 in two Melbourne Hospitals. Patients had received a mean of three prior treatment lines (range, 1-11). The mean number of cycles of DCEP was two (range, 1-4). Overall response rate (ORR) was 55% whilst 19% achieved MR and SD. Median overall survival (OS) was 9.6 months. Those bridged to autologous stem cell transplant (ASCT) had significantly improved OS compared to those who were not (median 32.8 vs. 10.7 months, p=.0004). Significant treatment-related mortality (TRM) was observed (9.7%), mostly attributable to grade 3-4 neutropenia and febrile neutropenia. Mandatory use of G-CSF is, therefore, warranted to prevent septic complications. In heavily pretreated RRMM, DCEP is an effective bridge to definitive therapy but in the absence of the latter, its value is questionable.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neutropenia Febril Inducida por Quimioterapia/mortalidad , Mieloma Múltiple/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Anciano , Neutropenia Febril Inducida por Quimioterapia/etiología , Neutropenia Febril Inducida por Quimioterapia/prevención & control , Cisplatino/uso terapéutico , Ciclofosfamida/uso terapéutico , Dexametasona/uso terapéutico , Resistencia a Antineoplásicos , Etopósido/uso terapéutico , Femenino , Estudios de Seguimiento , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mieloma Múltiple/mortalidad , Mieloma Múltiple/patología , Recurrencia Local de Neoplasia/mortalidad , Supervivencia sin ProgresiónRESUMEN
BACKGROUND: Daclizumab is a humanized monoclonal antibody that blocks CD25, the high affinity alpha subunit of the interleukin-2 receptor. Daclizumab therapy targets T regulatory cell and activated effector T cell proliferation to suppress autoimmune disease activity, in inflammatory conditions like relapsing and remitting multiple sclerosis. Here, we present the first report of agranulocytosis with daclizumab therapy in a patient with relapsing and remitting multiple sclerosis. CASE PRESENTATION: Our patient was a 24-year-old Australian female with a clinical history of atopy, lymphocytic enteritis complicated by B12 deficiency, relapsing and remitting multiple sclerosis, recurrent lower respiratory tract infections, vulval/cervical intraepithelial neoplasia and melanoma. She was commenced on daclizumab therapy after failing several lines of treatment for relapsing and remitting multiple sclerosis. During a hospital admission for lymphocytic enteritis, she was incidentally diagnosed with combined immunodeficiency with hypogammaglobulinaemia and declined proposed regular intravenous immunoglobulin infusions. Following six months of daclizumab therapy, our patient presented to hospital with febrile neutropenia. No clear infective cause was found, despite numerous investigations. However, bone marrow biopsy revealed agranulocytosis with an apparent maturation block at the myeloblasts stage. Neustrophil recovery occurred following cessation of daclizumab and the initiation of T cell immunosuppressive agents including systemic corticosteroids and methotrexate. The patient was further investigated for combined immunodeficiency and whole exome sequencing revealed a novel heterozygous missense variant in cytotoxic T lymphocyte antigen 4 (CTLA4), leading to a diagnosis of CTLA-4 haploinsufficiency with autoimmune infiltration (CHAI). CONCLUSION: This case demonstrates that autoimmune disease may be the presenting feature of primary immunodeficiency and should be appropriately investigated prior to the commencement of immunotherapy. Genetic clarification of underlying primary immunodeficiency may provide critical clinical information that alters the safety of the proposed treatment strategy.