RESUMEN
The objective of this study is to externally validate the clinical positron emission tomography (PET) model developed in the HOVON-84 trial and to compare the model performance of our clinical PET model using the international prognostic index (IPI). In total, 1195 patients with diffuse large B-cell lymphoma (DLBCL) were included in the study. Data of 887 patients from 6 studies were used as external validation data sets. The primary outcomes were 2-year progression-free survival (PFS) and 2-year time to progression (TTP). The metabolic tumor volume (MTV), maximum distance between the largest lesion and another lesion (Dmaxbulk), and peak standardized uptake value (SUVpeak) were extracted. The predictive values of the IPI and clinical PET model (MTV, Dmaxbulk, SUVpeak, performance status, and age) were tested. Model performance was assessed using the area under the curve (AUC), and diagnostic performance, using the positive predictive value (PPV). The IPI yielded an AUC of 0.62. The clinical PET model yielded a significantly higher AUC of 0.71 (P < .001). Patients with high-risk IPI had a 2-year PFS of 61.4% vs 51.9% for those with high-risk clinical PET, with an increase in PPV from 35.5% to 49.1%, respectively. A total of 66.4% of patients with high-risk IPI were free from progression or relapse vs 55.5% of patients with high-risk clinical PET scores, with an increased PPV from 33.7% to 44.6%, respectively. The clinical PET model remained predictive of outcome in 6 independent first-line DLBCL studies, and had higher model performance than the currently used IPI in all studies.
Asunto(s)
Linfoma de Células B Grandes Difuso , Recurrencia Local de Neoplasia , Humanos , Pronóstico , Estudios Retrospectivos , Tomografía de Emisión de Positrones , Linfoma de Células B Grandes Difuso/diagnóstico , Factores de Riesgo , Fluorodesoxiglucosa F18RESUMEN
For elderly frail patients with diffuse large B-cell lymphoma (DLBCL), an attenuated chemo-immunotherapy strategy of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-miniCHOP) was introduced as a treatment option as from 2014 onward in the Netherlands. Although R-miniCHOP is more tolerable, reduction of chemotherapy could negatively affect survival compared to R-CHOP. The aim of this analysis was to assess survival of patients treated with R-miniCHOP compared to R-CHOP. DLBCL patients ≥65 years, newly diagnosed in 2014-2020, who received ≥1 cycle of R-miniCHOP or R-CHOP were identified in the Netherlands Cancer Registry, with survival follow-up through 2022. Patients were propensity-score-matched for baseline characteristics. Main endpoints were progression-free survival (PFS), overall survival (OS), and relative survival (RS). The use of R-miniCHOP in DLBCL increased from 2% in 2014 to 15% in 2020. In total, 384 patients treated with R-miniCHOP and 384 patients treated with R-CHOP were included for comparison (median age; 81 years, stage 3-4; 68%). The median number of R-(mini)CHOP cycles was 6 (range, 1-8). The 2-year PFS, OS and RS were inferior for patients treated with R-miniCHOP compared to R-CHOP (PFS 51% vs. 68%, p < .01; OS 60% vs. 75%, p < .01; RS 69% vs. 86%, p < .01). In multivariable analysis, patients treated with R-miniCHOP had higher risk of all-cause mortality compared to patients treated with R-CHOP (HR 1.73; 95%CI, 1.39-2.17). R-miniCHOP is effective for most elderly patients. Although survival is inferior compared to R-CHOP, the use of R-miniCHOP as initial treatment is increasing. Therefore, fitness needs to be carefully weighed in treatment selection.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma de Células B Grandes Difuso , Humanos , Anciano , Rituximab , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Vincristina/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Doxorrubicina/efectos adversos , Ciclofosfamida , Prednisona/efectos adversos , Resultado del TratamientoRESUMEN
PURPOSE: MYC gene rearrangements in diffuse large B-cell lymphoma (DLBCL) patients are associated with poor prognosis. Our aim was to compare patterns of 2[18F]fluoro-2-deoxy-D-glucose positron emission tomography computed tomography (PET/CT) response in MYC + and MYC- DLBCL patients. METHODS: Interim PET/CT (I-PET) and end of treatment PET/CT (EoT-PET) scans of 81 MYC + and 129 MYC- DLBCL patients from 2 HOVON trials were reviewed using the Deauville 5-point scale (DS). DS1-3 was regarded as negative and DS4-5 as positive. Standardized uptake values (SUV) and metabolic tumor volume (MTV) were quantified at baseline, I-PET, and EoT-PET. Negative (NPV) and positive predictive values (PPV) were calculated using 2-year overall survival. RESULTS: MYC + DLBCL patients had significantly more positive EoT-PET scans than MYC- patients (32.5 vs 15.7%, p = 0.004). I-PET positivity rates were comparable (28.8 vs 23.8%). In MYC + patients 23.2% of the I-PET negative patients converted to positive at EoT-PET, vs only 2% for the MYC- patients (p = 0.002). Nine (34.6%) MYC + DLBCL showed initially uninvolved localizations at EoT-PET, compared to one (5.3%) MYC- patient. A total of 80.8% of EoT-PET positive MYC + patients showed both increased lesional SUV and MTV compared to I-PET. In MYC- patients, 31.6% showed increased SUV and 42.1% showed increased MTV. NPV of I-PET and EoT-PET was high for both MYC subgroups (81.8-94.1%). PPV was highest at EoT-PET for MYC + patients (61.5%). CONCLUSION: MYC + DLBCL patients demonstrate aberrant PET response patterns compared to MYC- patients with more frequent progression during treatment after I-PET negative assessment and new lesions at sites that were not initially involved. TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION: HOVON-84: EudraCT: 2006-005,174-42, retrospectively registered 01-08-2008. HOVON-130: EudraCT: 2014-002,654-39, registered 26-01-2015.
Asunto(s)
Linfoma de Células B Grandes Difuso , Tomografía Computarizada por Tomografía de Emisión de Positrones , Fluorodesoxiglucosa F18 , Reordenamiento Génico , Humanos , Linfoma de Células B Grandes Difuso/diagnóstico por imagen , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/terapia , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Tomografía de Emisión de Positrones , Pronóstico , Estudios RetrospectivosRESUMEN
Burkitt lymphoma is an aggressive B cell malignancy accounting for 1-2% of all adult lymphomas. Treatment with dose-intensive, multi-agent chemotherapy is effective but associated with considerable toxicity. In this observational study, we compared real-world efficacy, toxicity, and costs of four frequently employed treatment strategies for Burkitt lymphoma: the Lymphome Malins B (LMB), the Berlin-Frankfurt-Münster (BFM), the HOVON, and the CODOX-M/IVAC regimens. We collected data from 147 adult patients treated in eight referral centers. Following central pathology assessment, 105 of these cases were accepted as Burkitt lymphoma, resulting in the following treatment groups: LMB 36 patients, BFM 19 patients, HOVON 29 patients, and CODOX-M/IVAC 21 patients (median age 39 years, range 14-74; mean duration of follow-up 47 months). There was no significant difference between age, sex ratio, disease stage, or percentage HIV-positive patients between the treatment groups. Five-year progression-free survival (69%, p = 0.966) and 5-year overall survival (69%, p = 0.981) were comparable for all treatment groups. Treatment-related toxicity was also comparable with only hepatotoxicity seen more frequently in the CODOX/M-IVAC group (p = 0.004). Costs were determined by the number of rituximab gifts and the number of inpatients days. Overall, CODOX-M/IVAC had the most beneficial profile with regards to costs, treatment duration, and percentage of patients completing planned treatment. We conclude that the four treatment protocols for Burkitt lymphoma yield nearly identical results with regards to efficacy and safety but differ in treatment duration and costs. These differences may help guide future choice of treatment.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma de Burkitt/tratamiento farmacológico , Análisis Costo-Beneficio , Infecciones por VIH/tratamiento farmacológico , Adolescente , Adulto , Anciano , Linfoma de Burkitt/complicaciones , Linfoma de Burkitt/economía , Linfoma de Burkitt/mortalidad , Carmustina/economía , Carmustina/uso terapéutico , Ciclofosfamida/economía , Ciclofosfamida/uso terapéutico , Citarabina/economía , Citarabina/uso terapéutico , Etopósido/economía , Etopósido/uso terapéutico , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/economía , Infecciones por VIH/mortalidad , Humanos , Ifosfamida/economía , Ifosfamida/uso terapéutico , Masculino , Melfalán/economía , Melfalán/uso terapéutico , Metotrexato/economía , Metotrexato/uso terapéutico , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Retrospectivos , Rituximab/economía , Rituximab/uso terapéutico , Análisis de SupervivenciaRESUMEN
MYC oncogene rearrangements (MYC-R) negatively affect survival in patients with Ann Arbor stage III-IV diffuse large B-cell lymphoma (DLBCL), but their impact in limited stage (LS) I-II is unclear. Therefore, we assessed the impact of MYC-R on progression-free survival (PFS) and overall survival (OS) in LS DLBCL patients at the population level. We identified 1,434 LS DLBCL patients with known MYC-R status diagnosed between 2014 and 2020, who received R-CHOP(-like) regimens using the Netherlands Cancer Registry, with survival follow-up until February 2022. Stage I patients with (n = 83, 11%) and without (n = 650, 89%) a MYC-R had similar 2-years PFS (89% and 93%, p = 0.63) and OS (both 95%, p = 0.22). Conversely, stage II DLBCL patients with a MYC-R (n = 90, 13%) had inferior survival outcomes compared to stage II patients without a MYC-R (n = 611, 87%) (PFS 70% vs. 89%, p = 0.001; OS 79% vs. 94%, p < 0.0001). Both single MYC-R (single hit, n = 36) and concurrent BCL2 and/or BCL6 rearrangements (double/triple hit, n = 39) were associated with increased mortality and relapse risk. In conclusion, in stage II DLBCL a MYC-R is negatively associated with survival. In stage I DLBCL, however, survival outcomes are excellent irrespective of MYC-R status. This challenges the diagnostic assessment of MYC-R in stage I DLBCL patients.
Asunto(s)
Linfoma de Células B Grandes Difuso , Proteínas Proto-Oncogénicas c-bcl-2 , Humanos , Pronóstico , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-bcl-6 , Protocolos de Quimioterapia Combinada Antineoplásica , Recurrencia Local de Neoplasia , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Doxorrubicina/uso terapéuticoRESUMEN
MHC class II molecules presenting MHC class II restricted antigens play an important role in the activation of CD4+ T cells, which are the central orchestrating cells of an immune response. This review focuses on the particular role of MHC class II molecules in tumour immunology. The MHC class II antigen presentation pathway and the expression of MHC class II molecules on tumour cells related to clinical outcome is discussed. Improving the MHC class II tumour antigen presentation pathway, for instance by downregulation of the invariant chain or modulation of HLA-DO expression, offers many opportunities for developing new modalities of immunotherapy.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Antígenos de Histocompatibilidad Clase II/metabolismo , Factores Inmunológicos/metabolismo , Neoplasias/inmunología , Animales , Humanos , Neoplasias/diagnóstico , Neoplasias/metabolismo , PronósticoRESUMEN
In the past decade, patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) were treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) therapy. Standard treatment is now changing as a result of deeper understanding of underlying biologic differences of such lymphomas. One of the most powerful predictors of an adverse outcome on R-CHOP therapy is the presence of a MYC gene rearrangement (MYC+ lymphoma). Determination of MYC gene rearrangement by FISH (fluorescent in situ hybridisation) has recently become a standard diagnostic procedure. In this paper, an overview of current literature on MYC function and MYC+ lymphoma patient outcome is presented. Furthermore, we present 26 patients from our tertiary referral centre who were diagnosed with MYC+ lymphoma between 2009 and 2014. In our patient series, we confirm the dismal prognosis of MYC+ lymphoma patients. Intensification of classical chemotherapy does not lead to better overall survival, justifying new treatment modalities. First line therapy should be more specifically targeted against MYC and the genes and proteins that are deregulated by MYC. To this end, the first clinical trial in which MYC+ patients will be offered targeted treatment has recently been launched.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Reordenamiento Génico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-myc/genética , Adulto , Anciano , Femenino , Predisposición Genética a la Enfermedad , Humanos , Hibridación Fluorescente in Situ , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/mortalidad , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Selección de Paciente , Fenotipo , Medicina de Precisión , Valor Predictivo de las Pruebas , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Stem cell therapy is a promising strategy in promoting cardiac repair in the setting of ischemic heart disease. Clinical and preclinical studies have shown that cell therapy improves cardiac function. Whether autologous or allogeneic cells should be used, and the need for immunosuppression in non-autologous settings, is a matter of debate. Cyclosporin A (CsA) is frequently used in preclinical trials to reduce cell rejection after non-autologous cell therapy. The direct effect of CsA on the function and survival of stem cells is unclear. Furthermore, the appropriate daily dosage of CsA in animal models has not been established. In this review, we discuss the pros and cons of the use of CsA on an array of stem cells both in vitro and in vivo. Furthermore, we present a small collection of data put forth by our group supporting the efficacy and safety of a specific daily CsA dosage in a pig model.
Asunto(s)
Ciclosporina/administración & dosificación , Supervivencia de Injerto/efectos de los fármacos , Cardiopatías/cirugía , Inmunosupresores/administración & dosificación , Regeneración/efectos de los fármacos , Trasplante de Células Madre , Células Madre/efectos de los fármacos , Animales , Supervivencia Celular/efectos de los fármacos , Ciclosporina/efectos adversos , Modelos Animales de Enfermedad , Esquema de Medicación , Cardiopatías/inmunología , Cardiopatías/patología , Cardiopatías/fisiopatología , Humanos , Inmunosupresores/efectos adversos , Trasplante de Células Madre/efectos adversos , Células Madre/inmunología , Porcinos , Factores de Tiempo , Resultado del TratamientoRESUMEN
On behalf of the lymphoma and multiple myeloma working parties of the Dutch/Belgian Haemato-Oncology Foundation for Adults in The Netherlands (HOVON), we present a guideline for diagnosis and management of Waldenström's macroglobulinemia (WM). Considering the indolent behaviour and heterogeneous clinical presentation of WM, it is crucial to determine the right indications for treatment, as well as to individualise therapeutic options. There are significant differences from the approach to multiple myeloma or the treatment of other indolent non-Hodkgin lymphomas, and these results cannot always be extrapolated. There is a lack of large clinical trials due to the low incidence of WM. Based on the available data, we provide a practical diagnostic classification, as well as recommendations for first-line therapy and options for treating relapsed disease. Some typical clinical features of WM, such as autoimmune phenomena and 'IgM flare' after rituximab treatment, are highlighted. A more elaborate version of this guideline was published in the 'Nederlands Tijdschrift voor Hematologie' (Dutch Journal for Hematology) September 2012.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Factores Inmunológicos/uso terapéutico , Macroglobulinemia de Waldenström/diagnóstico , Médula Ósea/patología , Humanos , Gammopatía Monoclonal de Relevancia Indeterminada/diagnóstico , Gammopatía Monoclonal de Relevancia Indeterminada/terapia , Plasmaféresis , Macroglobulinemia de Waldenström/terapiaAsunto(s)
Infecciones por Acinetobacter/microbiología , Acinetobacter/enzimología , Proteínas Bacterianas/biosíntesis , beta-Lactamasas/biosíntesis , Acinetobacter/efectos de los fármacos , Acinetobacter/genética , Acinetobacter/aislamiento & purificación , Infecciones por Acinetobacter/tratamiento farmacológico , Adulto , Proteínas Bacterianas/genética , Carbapenémicos/farmacología , Niño , Farmacorresistencia Bacteriana , Femenino , Humanos , Masculino , Persona de Mediana Edad , Países Bajos , Análisis de Secuencia de ADN , beta-Lactamasas/genéticaAsunto(s)
Anemia Hemolítica Autoinmune/etiología , Autoanticuerpos/inmunología , Autoantígenos/inmunología , Sistema del Grupo Sanguíneo de Kidd/inmunología , Lupus Eritematoso Sistémico/sangre , Adulto , Anemia Hemolítica Autoinmune/inmunología , Especificidad de Anticuerpos , Autoanticuerpos/sangre , Autoantígenos/genética , Biopsia , Transfusión Sanguínea , Prueba de Coombs , Urgencias Médicas , Femenino , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Inmunoglobulinas Intravenosas/uso terapéutico , Inmunosupresores/uso terapéutico , Sistema del Grupo Sanguíneo de Kidd/genética , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/inmunología , Neumonía por Mycoplasma/complicaciones , Prednisona/uso terapéutico , Piel/patologíaRESUMEN
One of the principal responsibilities of the Chronic Lymphocytic Leukaemia (CLL) Working Party of the Dutch/Belgium Haemato-Oncology Foundation for Adults in the Netherlands (HOVON) is to create up-to-date guidelines for CLL . In this article, the revised guidelines for diagnosis and treatment are summarised. Despite recent expansion in treatment options for patients with CLL , the disease remains incurable in most cases and the optimal treatment approach for several subgroups of patients is still unclear. Therefore, it remains highly important to treat patients within clinical studies as much as possible. In this article, the current studies initiated by the HOVON CLL working party are emphasised.
Asunto(s)
Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/terapia , Antineoplásicos/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Humanos , Países Bajos , RecurrenciaRESUMEN
Activation of the TNF-related apoptosis-inducing ligand (TRAIL) pathway can induce apoptosis in a broad range of human cancer cells. Four membrane-bound receptors have been identified. TRAIL-R1 and TRAIL-R2 contain a functional death domain; TRAIL-R3 and TRAIL-R4 lack a functional death domain and function as decoy receptors. Flow-cytometric analysis revealed that acute myeloid leukemic (AML) blasts expressed significantly more pro-apoptotic receptors compared to normal blasts. However, about 20% of AML patients highly expressed decoy receptor TRAIL-R3, which was strongly correlated to a shortened overall survival. TRAIL-R3 expression was also high on CD34+/CD38- cells, the compartment that harbors the leukemia initiating stem cell. Expression levels of pro-apoptotic TRAIL receptors were not correlated to the susceptibility for soluble TRAIL, which was generally low (mean level of cell death induction 14%). Cell death could be enhanced by down-modulation of TRAIL-R3, confirming its decoy function on AML blasts. Bypassing of TRAIL-R3 by treatment with antibodies directly targeting TRAIL-R2 resulted in higher rates of induced cell death (max. 80%). In conclusion, AML blasts do express pro-apoptotic TRAIL receptors. However, co-expression of decoy receptor TRAIL-R3 results in significant shortened overall survival. AML blasts could be targeted by anti-TRAIL-R2 antibodies, yielding a new therapeutic option for AML patients.
Asunto(s)
Leucemia Mieloide Aguda/metabolismo , Células Madre Neoplásicas/metabolismo , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/biosíntesis , Receptores Señuelo del Factor de Necrosis Tumoral/biosíntesis , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados , Apoptosis/efectos de los fármacos , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/patología , Línea Celular , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Proteínas Ligadas a GPI/biosíntesis , Células HL-60 , Humanos , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Células Madre Neoplásicas/patología , Pronóstico , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/antagonistas & inhibidores , Miembro 10c de Receptores del Factor de Necrosis Tumoral , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Resultado del Tratamiento , Células U937 , Adulto JovenRESUMEN
We present a patient with acute myeloid leukaemia who developed subcutaneously disseminated aspergillosis after allogeneic peripheral stem cell transplantation (PSCT). Disseminated aspergillosis after stem cell transplantation has a high mortality despite treatment with amphotericin B or one of the azoles. Aspergillosis in our patient was refractory to amphotericin B and itraconazole but was successfully treated with caspofungin acetate.