RESUMEN
OBJECTIVE: Health disparities may be driven by hospital-level factors. We assessed whether racial and ethnic composition of populations hospitals serve explain or modify disparities in hospital outcomes of children with systemic lupus erythematosus (SLE). METHODS: In this retrospective cohort study of patients 5 to 26 years old with SLE at 47 children's hospitals in the Pediatric Health Information System (2006-2021), race and ethnicity were assessed at the patient level and hospital level (proportion of total admissions composed of Black or Hispanic patients, respectively). Outcomes included intensive care unit (ICU) admission or adverse renal outcome (end-stage renal disease, dialysis, or transplant) during follow-up. We estimated racial and ethnic disparities, adjusted or stratified by hospital racial or ethnic composition. RESULTS: Of 8,125 patients with SLE, 2,293 (28%) required ICU admission, and 698 (9%) had an adverse renal outcome. Black and non-Hispanic White disparities in ICU admission were observed only at hospitals serving higher proportions of Black patients (odds ratio [OR] 1.29, 95% confidence interval [95% CI] 1.04-1.59 vs OR 1.07, 95% CI 0.83-1.38). Larger Black and non-Hispanic White disparities in adverse renal outcomes were observed at hospitals with higher Black racial composition (OR 2.0, 95% CI 1.4-2.8 vs OR 1.7, 95% CI 1.1-2.4). Conversely, Hispanic versus non-Hispanic disparities in renal outcomes persisted after adjustment for hospital-reported Hispanic ethnic composition but were observed only at hospitals with lower proportions of Hispanic patients. CONCLUSION: Worse Black and White disparities in SLE outcomes are observed at children's hospitals serving more Black children, whereas distinct patterns are observed for Hispanic and non-Hispanic disparities. Reporting of hospital characteristics related to populations served is needed to identify modifiable drivers of hospital-level variation.
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Disparidades en Atención de Salud , Hospitales Pediátricos , Lupus Eritematoso Sistémico , Humanos , Niño , Estudios Retrospectivos , Femenino , Adolescente , Masculino , Lupus Eritematoso Sistémico/etnología , Lupus Eritematoso Sistémico/terapia , Lupus Eritematoso Sistémico/diagnóstico , Disparidades en Atención de Salud/etnología , Preescolar , Adulto Joven , Hispánicos o Latinos/estadística & datos numéricos , Disparidades en el Estado de Salud , Estados Unidos/epidemiología , Adulto , Negro o Afroamericano , Población BlancaRESUMEN
BACKGROUND: In patients with newly diagnosed multiple myeloma, the effect of adding autologous stem-cell transplantation (ASCT) to triplet therapy (lenalidomide, bortezomib, and dexamethasone [RVD]), followed by lenalidomide maintenance therapy until disease progression, is unknown. METHODS: In this phase 3 trial, adults (18 to 65 years of age) with symptomatic myeloma received one cycle of RVD. We randomly assigned these patients, in a 1:1 ratio, to receive two additional RVD cycles plus stem-cell mobilization, followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Both groups received lenalidomide until disease progression, unacceptable side effects, or both. The primary end point was progression-free survival. RESULTS: Among 357 patients in the RVD-alone group and 365 in the transplantation group, at a median follow-up of 76.0 months, 328 events of disease progression or death occurred; the risk was 53% higher in the RVD-alone group than in the transplantation group (hazard ratio, 1.53; 95% confidence interval [CI], 1.23 to 1.91; P<0.001); median progression-free survival was 46.2 months and 67.5 months. The percentage of patients with a partial response or better was 95.0% in the RVD-alone group and 97.5% in the transplantation group (P = 0.55); 42.0% and 46.8%, respectively, had a complete response or better (P = 0.99). Treatment-related adverse events of grade 3 or higher occurred in 78.2% and 94.2%, respectively; 5-year survival was 79.2% and 80.7% (hazard ratio for death, 1.10; 95% CI, 0.73 to 1.65). CONCLUSIONS: Among adults with multiple myeloma, RVD plus ASCT was associated with longer progression-free survival than RVD alone. No overall survival benefit was observed. (Funded by the National Heart, Lung, and Blood Institute and others; DETERMINATION ClinicalTrials.gov number, NCT01208662.).
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Protocolos de Quimioterapia Combinada Antineoplásica , Quimioterapia de Mantención , Mieloma Múltiple , Trasplante de Células Madre , Adulto , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bortezomib/administración & dosificación , Bortezomib/efectos adversos , Dexametasona/administración & dosificación , Dexametasona/efectos adversos , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Humanos , Lenalidomida/administración & dosificación , Lenalidomida/efectos adversos , Quimioterapia de Mantención/métodos , Melfalán/administración & dosificación , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/cirugía , Trasplante AutólogoRESUMEN
To understand the mechanisms that mediate germline genetic leukemia predisposition, we studied the inherited ribosomopathy Shwachman-Diamond syndrome (SDS), a bone marrow failure disorder with high risk of myeloid malignancies at an early age. To define the mechanistic basis of clonal hematopoiesis in SDS, we investigate somatic mutations acquired by patients with SDS followed longitudinally. Here we report that multiple independent somatic hematopoietic clones arise early in life, most commonly harboring heterozygous mutations in EIF6 or TP53. We show that germline SBDS deficiency establishes a fitness constraint that drives selection of somatic clones via two distinct mechanisms with different clinical consequences. EIF6 inactivation mediates a compensatory pathway with limited leukemic potential by ameliorating the underlying SDS ribosome defect and enhancing clone fitness. TP53 mutations define a maladaptive pathway with enhanced leukemic potential by inactivating tumor suppressor checkpoints without correcting the ribosome defect. Subsequent development of leukemia was associated with acquisition of biallelic TP53 alterations. These results mechanistically link leukemia predisposition to germline genetic constraints on cellular fitness, and provide a rational framework for clinical surveillance strategies.
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Hematopoyesis Clonal/genética , Hematopoyesis Clonal/fisiología , Síndrome de Shwachman-Diamond/genética , Síndrome de Shwachman-Diamond/metabolismo , Adolescente , Adulto , Enfermedades de la Médula Ósea/genética , Enfermedades de la Médula Ósea/metabolismo , Niño , Preescolar , Factores Eucarióticos de Iniciación/genética , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Mutación , Ribosomas/genética , Proteína p53 Supresora de Tumor/genética , Adulto JovenRESUMEN
Quality of response to immunosuppressive therapy and long-term outcomes for pediatric severe aplastic anemia remain incompletely characterized. Contemporary evidence to inform treatment of relapsed or refractory severe aplastic anemia for pediatric patients is also limited. The clinical features and outcomes for 314 children treated from 2002 to 2014 with immunosuppressive therapy for acquired severe aplastic anemia were analyzed retrospectively from 25 institutions in the North American Pediatric Aplastic Anemia Consortium. The majority of subjects (n=264) received horse anti-thymocyte globulin (hATG) plus cyclosporine (CyA) with a median 61 months follow up. Following hATG/CyA, 71.2% (95%CI: 65.3,76.6) achieved an objective response. In contrast to adult studies, the quality of response achieved in pediatric patients was high, with 59.8% (95%CI: 53.7,65.8) complete response and 68.2% (95%CI: 62.2,73.8) achieving at least a very good partial response with a platelet count ≥50×109L. At five years post-hATG/CyA, overall survival was 93% (95%CI: 89,96), but event-free survival without subsequent treatment was only 64% (95%CI: 57,69) without a plateau. Twelve of 171 evaluable patients (7%) acquired clonal abnormalities after diagnosis after a median 25.2 months (range: 4.3-71 months) post treatment. Myelodysplastic syndrome or leukemia developed in 6 of 314 (1.9%). For relapsed/refractory disease, treatment with a hematopoietic stem cell transplant had a superior event-free survival compared to second immunosuppressive therapy treatment in a multivariate analysis (HR=0.19, 95%CI: 0.08,0.47; P=0.0003). This study highlights the need for improved therapies to achieve sustained high-quality remission for children with severe aplastic anemia.
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Anemia Aplásica/tratamiento farmacológico , Suero Antilinfocítico/administración & dosificación , Ciclosporina/administración & dosificación , Terapia de Inmunosupresión , Anemia Aplásica/epidemiología , Anemia Aplásica/patología , Suero Antilinfocítico/efectos adversos , Preescolar , Ciclosporina/efectos adversos , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Estudios Retrospectivos , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: High-dose chemotherapy plus autologous stem-cell transplantation has been the standard treatment for newly diagnosed multiple myeloma in adults up to 65 years of age. However, promising data on the use of combination therapy with lenalidomide, bortezomib, and dexamethasone (RVD) in this population have raised questions about the role and timing of transplantation. METHODS: We randomly assigned 700 patients with multiple myeloma to receive induction therapy with three cycles of RVD and then consolidation therapy with either five additional cycles of RVD (350 patients) or high-dose melphalan plus stem-cell transplantation followed by two additional cycles of RVD (350 patients). Patients in both groups received maintenance therapy with lenalidomide for 1 year. The primary end point was progression-free survival. RESULTS: Median progression-free survival was significantly longer in the group that underwent transplantation than in the group that received RVD alone (50 months vs. 36 months; adjusted hazard ratio for disease progression or death, 0.65; P<0.001). This benefit was observed across all patient subgroups, including those stratified according to International Staging System stage and cytogenetic risk. The percentage of patients with a complete response was higher in the transplantation group than in the RVD-alone group (59% vs. 48%, P=0.03), as was the percentage of patients in whom minimal residual disease was not detected (79% vs. 65%, P<0.001). Overall survival at 4 years did not differ significantly between the transplantation group and the RVD-alone group (81% and 82%, respectively). The rate of grade 3 or 4 neutropenia was significantly higher in the transplantation group than in the RVD-alone group (92% vs. 47%), as were the rates of grade 3 or 4 gastrointestinal disorders (28% vs. 7%) and infections (20% vs. 9%). No significant between-group differences were observed in the rates of treatment-related deaths, second primary cancers, thromboembolic events, and peripheral neuropathy. CONCLUSIONS: Among adults with multiple myeloma, RVD therapy plus transplantation was associated with significantly longer progression-free survival than RVD therapy alone, but overall survival did not differ significantly between the two approaches. (Supported by Celgene and others; IFM 2009 Study ClinicalTrials.gov number, NCT01191060 .).
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bortezomib/administración & dosificación , Dexametasona/administración & dosificación , Trasplante de Células Madre , Talidomida/análogos & derivados , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bortezomib/efectos adversos , Terapia Combinada , Dexametasona/efectos adversos , Supervivencia sin Enfermedad , Femenino , Humanos , Quimioterapia de Inducción , Estimación de Kaplan-Meier , Lenalidomida , Quimioterapia de Mantención , Masculino , Persona de Mediana Edad , Mieloma Múltiple/tratamiento farmacológico , Terapia Recuperativa , Talidomida/administración & dosificación , Talidomida/efectos adversos , Trasplante AutólogoRESUMEN
Patterns of myeloid growth factor (GF) usage and febrile neutropenia (FN) were examined in patients >60 years of age with diffuse large B-cell non-Hodgkin lymphoma (DLBCL) enrolled on CALGB 9793/ECOG-SWOG 4494, receiving initial therapy with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or rituximab + CHOP (R-CHOP). Myeloid GFs were administered to 256/520 (49%) patients. Indications for use were: prevent dose reduction/dose delay (81%, 207/256); treat FN or non-febrile neutropenia (NFN) (19%, 48/256). One or more FN episodes occurred in 41% (212/520) of patients, with FN most often in cycle 1 (38% of episodes). In multivariate analysis, risk factors for FN included age >65 years (odds ratio (OR) = 2.6, 95% CI: [1.4, 4.9]) and anemia (hemoglobin <12 g/dl) (OR =2.2, 95% confidence intervals (CI): [1.4, 3.5]. Myeloid GF use was common in this older DLBCL population receiving CHOP-based therapy, as was FN, especially during cycle one. Risk factors predictive for FN should be used prospectively to identify patients for whom myeloid GFs are best utilized.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Factores Estimulantes de Colonias/uso terapéutico , Neutropenia Febril/tratamiento farmacológico , Neutropenia Febril/etiología , Linfoma de Células B Grandes Difuso/complicaciones , Factores de Edad , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Factores Estimulantes de Colonias/administración & dosificación , Ciclofosfamida/efectos adversos , Ciclofosfamida/uso terapéutico , Doxorrubicina/efectos adversos , Doxorrubicina/uso terapéutico , Neutropenia Febril/diagnóstico , Neutropenia Febril/epidemiología , Femenino , Humanos , Incidencia , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/mortalidad , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Prednisona/efectos adversos , Prednisona/uso terapéutico , Estudios Retrospectivos , Factores de Riesgo , Rituximab , Factores de Tiempo , Resultado del Tratamiento , Vincristina/efectos adversos , Vincristina/uso terapéuticoRESUMEN
Everolimus, an oral mammalian target of rapamycin (mTOR) inhibitor, has been studied in multiple myeloma (MM) but lacks significant single agent activity. Based on preclinical studies showing synergistic activity of mTOR inhibitors with lenalidomide, we studied the combination of lenalidomide and everolimus in relapsed or refractory MM in a phase I clinical trial. We assessed patient samples using gene expression, Western blotting and immunohistochemistry to probe the mTOR pathway. Twenty-six patients were evaluable for toxicity. Dose-limiting toxicities included grade 4 neutropenia and thrombocytopenia. The maximum tolerated dose was lenalidomide 15 mg and everolimus 5 mg for 21 d with a 7 d rest period. Grade 3/4 adverse events included thrombocytopenia (35%) and neutropenia (42%). The overall response rate was 65% (1 complete response + 4 partial response + 10 minimal response). The median progression-free survival was 5·5 months and median overall survival was 29·5 months. Biomarker data demonstrated downregulation of phosphorylated p70S6K. Gene expression profiling suggested activation of mTOR in responders versus non-responders. The combination of lenalidomide and everolimus was well tolerated with predictable toxicities and showed responses in a heavily pretreated population. When confirmed with larger patient numbers, this analysis may guide patient selection for future clinical trials of mTOR inhibition in MM.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Everolimus , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Lenalidomida , Masculino , Persona de Mediana Edad , Mieloma Múltiple/genética , Mieloma Múltiple/metabolismo , Mieloma Múltiple/mortalidad , Recurrencia , Sirolimus/administración & dosificación , Sirolimus/análogos & derivados , Talidomida/administración & dosificación , Talidomida/análogos & derivados , Resultado del TratamientoRESUMEN
PURPOSE: The Programmed Death-1 (PD-1) immune checkpoint pathway may be usurped by tumors, including diffuse large B-cell lymphoma (DLBCL), to evade immune surveillance. The reconstituting immune landscape after autologous hematopoietic stem-cell transplantation (AHSCT) may be particularly favorable for breaking immune tolerance through PD-1 blockade. PATIENTS AND METHODS: We conducted an international phase II study of pidilizumab, an anti-PD-1 monoclonal antibody, in patients with DLBCL undergoing AHSCT, with correlative studies of lymphocyte subsets. Patients received three doses of pidilizumab beginning 1 to 3 months after AHSCT. RESULTS: Sixty-six eligible patients were treated. Toxicity was mild. At 16 months after the first treatment, progression-free survival (PFS) was 0.72 (90% CI, 0.60 to 0.82), meeting the primary end point. Among the 24 high-risk patients who remained positive on positron emission tomography after salvage chemotherapy, the 16-month PFS was 0.70 (90% CI, 0.51 to 0.82). Among the 35 patients with measurable disease after AHSCT, the overall response rate after pidilizumab treatment was 51%. Treatment was associated with increases in circulating lymphocyte subsets including PD-L1E-bearing lymphocytes, suggesting an on-target in vivo effect of pidilizumab. CONCLUSION: This is the first demonstration of clinical activity of PD-1 blockade in DLBCL. Given these results, PD-1 blockade after AHSCT using pidilizumab may represent a promising therapeutic strategy in this disease.
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Anticuerpos Monoclonales/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Tolerancia Inmunológica/efectos de los fármacos , Linfoma de Células B Grandes Difuso/terapia , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/inmunología , Chile , Terapia Combinada , Supervivencia sin Enfermedad , Esquema de Medicación , Fatiga/etiología , Femenino , Humanos , India , Israel , Recuento de Linfocitos , Linfoma de Células B Grandes Difuso/sangre , Linfoma de Células B Grandes Difuso/inmunología , Masculino , Persona de Mediana Edad , Neutropenia/etiología , Receptor de Muerte Celular Programada 1/inmunología , Trasplante Autólogo , Resultado del Tratamiento , Estados Unidos , Adulto JovenRESUMEN
OBJECTIVE: Bisphosphonate-related osteonecrosis of the jaws is a well-established disorder in which patients treated with bisphosphonates develop exposed necrotic bone in the oral cavity. The objective of this study was to report staging and treatment outcomes in a large cohort of patients with bisphosphonate-related osteonecrosis of the jaws managed primarily with non-surgical measures. PATIENTS AND METHODS: A retrospective medical record review was conducted from 1998 to 2010 of all patients referred for the management of bisphosphonate-related osteonecrosis of the jaws. Clinical findings and staging were assessed at initial consultation and each follow-up visit. Management was provided to minimize symptoms and/or achieve resolution of lesions. Treatment responses were defined based on symptoms and/or change in staging. RESULTS: There were 120 records reviewed and 97 patients seen for follow-up (median 12months); 90% were cancer patients. Bisphosphonate-related osteonecrosis of the jaws was managed with observation (16%), antibiotics (55%), non-surgical sequestrectomy±antibiotics (14%), or surgery±antibiotics (14%). There were 14 patients (12%) who presented with stage 0 disease; 41%, 43%, and 5% of patients presented at stages 1, 2, and 3, respectively. Greater than 70% of patients improved, remained asymptomatic, and/or showed complete re-epithelialization when evaluated at 0-3, 3-6, 6-9, 9-12, and/or >12months. Seventeen patients developed non-infectious complications of BONJ including neuropathy (N=9), painful tongue ulcers (N=7), or pathologic fracture (N=1). Twelve patients with multiple myeloma underwent hematopoietic cell transplantation without infectious complications. CONCLUSIONS: A primarily non-surgical approach appears to be a successful management strategy for bisphosphonate-related osteonecrosis of the jaws. Overall, 71-80% of patients improved or remained asymptomatic with a median follow-up of 12months.
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Osteonecrosis de los Maxilares Asociada a Difosfonatos/terapia , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
To assess if immunochemotherapy influenced the prognostic value of IPI in elderly diffuse large B-cell lymphoma (DLBCL) patients, we evaluated the performance of the standard International Prognostic Index (IPI) and following modifications: age adjusted (AA)-IPI, revised (R)-IPI, and an elderly IPI with age cut-off 70 years (E-IPI) in patients > 60 years treated with RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). In 267 patients, by IPI/AA-IPI 60% were high-intermediate, 53% high and 12% low risk. With R-IPI, 60% were poor risk and none very good risk. Using E-IPI, 45% were high-intermediate/high risk and 27% low risk. No differences in outcome were seen in the low/low-intermediate groups with IPI/AA-IPI. For E-IPI, failure-free survival (FFS) and overall survival (OS) were significantly different for low/low-intermediate groups. No differences were detected in the four indices with model fit/discrimination measures; however, E-IPI ranked highest. For elderly R-CHOP treated patients, distribution of IPI/AA-IPI skewed toward high/high-intermediate risk with no differences in FFS/OS between low/low-intermediate risk. In contrast, with E-IPI, more are classified as low risk with significant differences in FFS/OS for low-intermediate compared to low risk. The R-IPI does not identify a very good risk group, thus minimizing its utility in this population. The prognostic discrimination provided by the E-IPI for low and low-intermediate elderly DLBCL patients needs validation by other datasets.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Indicadores de Salud , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Factores de Edad , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Ciclofosfamida/administración & dosificación , Ciclofosfamida/uso terapéutico , Doxorrubicina/administración & dosificación , Doxorrubicina/uso terapéutico , Esquema de Medicación , Métodos Epidemiológicos , Humanos , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/patología , Persona de Mediana Edad , Prednisona/administración & dosificación , Prednisona/uso terapéutico , Pronóstico , Rituximab , Resultado del Tratamiento , Vincristina/administración & dosificación , Vincristina/uso terapéuticoRESUMEN
PURPOSE: To prospectively investigate the prognostic significance of p21 and p53 expression in diffuse large B-cell lymphoma in the context of the U.S. Intergroup trial comparing conventional cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy to rituximab-CHOP (R-CHOP) induction, with or without maintenance rituximab. EXPERIMENTAL DESIGN: Immunohistochemical staining of 197 paraffin-embedded biopsy specimens was scored by an independent panel of experts. RESULTS: The cyclin-dependent kinase inhibitor, p21, was expressed in 55% of cases examined. In a multivariable analysis adjusting for International Prognostic Index score and BCL2 status, p21 expression was a significant, independent, favorable predictive factor for failure-free survival (relative risk, 0.3; P = 0.001) and overall survival (relative risk, 0.3; P = 0.003) for patients treated with R-CHOP. Expression of p21 was not predictive of outcome for CHOP-treated patients. Only p21-positive cases benefited from the addition of rituximab to CHOP. Among p21-positive patients, treatment with R-CHOP was associated with a higher failure-free survival rate at 5 years compared with CHOP (61% versus 24%; P = 0.01). In contrast, no significant differences were detected in failure-free survival according to treatment arm for p21-negative patients. Expression of p53, alone or in combination with p21, did not predict for outcome in univariable or multivariable analyses. CONCLUSIONS: In this study, p21 protein expression emerged as an important independent predictor of a favorable clinical outcome when rituximab was added to CHOP therapy. These data suggest that rituximab-related effects on lymphoma survival pathways may be functionally linked to p21 activity.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/metabolismo , Factores de Edad , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales de Origen Murino , Biomarcadores de Tumor/metabolismo , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Humanos , Técnicas para Inmunoenzimas , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana Edad , Prednisona/administración & dosificación , Rituximab , Tasa de Supervivencia , Resultado del Tratamiento , Vincristina/administración & dosificaciónRESUMEN
Bevacizumab is a humanized monoclonal antibody directed against vascular endothelial growth factor (VEGF-A). Non-Hodgkin's lymphoma patients with high serum VEGF levels have an inferior survival compared to patients with low VEGF levels. Bevacizumab was administered through a central line at 15 mg kg(-1) IV on day 1 followed by rituximab (R) and CHOP on day 2 for cycle 1 and day 1 for cycles 2 - 8. Serum levels of bevacizumab and R were measured at specified time points to assess pharmacokinetics (PK). Plasma and urine samples were also analysed for VEGF. Tumor samples were stained for VEGF, CD31 and factor VIII by immunohistochemistry. Thirteen patients with newly-diagnosed DLBCL received a total of 88 cycles (range 2 - 8, median 7). Best response included five CR, six PR, one SD and one PD with an overall response rate of 85% and complete response rate of 38%. The 12-month PFS is 77% and a median follow-up of 16.9 months for the surviving patients. All tumor samples stained strongly positive for VEGF and there was a marginal association between baseline plasma VEGF and response (p = 0.04). Patients with higher plasma VEGF levels were generally younger and had bulky disease. Micro-vessel density did not correlate with presenting disease characteristics, VEGF expression or response. The PK of bevacizumab and rituximab were not influenced by combined treatment. In this patient population, treatment with RA-CHOP did not result in any episodes of grade 3 or 4 proteinuria, heart failure or hemorrhage. The RA-CHOP combination was generally well tolerated and safe.
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Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Biomarcadores de Tumor/metabolismo , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Adulto , Inhibidores de la Angiogénesis/farmacología , Anticuerpos Monoclonales Humanizados , Anticuerpos Monoclonales de Origen Murino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab , Estudios de Cohortes , Ciclofosfamida/uso terapéutico , Doxorrubicina/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neovascularización Patológica , Prednisona/uso terapéutico , Rituximab , Vincristina/uso terapéuticoRESUMEN
PURPOSE: To address early and late treatment failures in older patients with diffuse large B-cell lymphoma (DLBCL), we designed a two-stage randomized trial of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) versus rituximab plus CHOP (R-CHOP), with a second random assignment to maintenance rituximab (MR) or observation in responding patients. PATIENTS AND METHODS: Untreated DLBCL patients who were 60 years or older were randomly assigned to R-CHOP (n = 318) or CHOP (n = 314); 415 responders were randomly assigned to MR (n = 207) or observation (n = 208). The primary end point was failure-free survival (FFS). All P values were two sided. RESULTS: Three-year FFS rate was 53% for R-CHOP patients and 46% for CHOP patients (P = .04) at a median follow-up time of 3.5 years. Two-year FFS rate from second random assignment was 76% for MR compared with 61% for observation (P = .009). No significant differences in survival were seen according to induction or maintenance therapy. FFS was prolonged with MR after CHOP (P = .0004) but not after R-CHOP (P = .81) with 2-year FFS rates from second random assignment of 77%, 79%, 74%, and 45% for R-CHOP, R-CHOP + MR, CHOP + MR, and CHOP, respectively. In a secondary analysis excluding MR patients, R-CHOP alone reduced the risks of treatment failure (P = .003) and death (P = .05) compared with CHOP alone. CONCLUSION: Rituximab administered as induction or maintenance with CHOP chemotherapy significantly prolonged FFS in older DLBCL patients. After R-CHOP, no benefit was provided by MR. These results, which are consistent with an additive effect of rituximab, suggest that future studies could focus on maintenance strategies with novel agents as well as new induction therapies.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Factores de Edad , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales de Origen Murino , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Ciclofosfamida/administración & dosificación , Progresión de la Enfermedad , Doxorrubicina/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prednisona/administración & dosificación , Estudios Prospectivos , Rituximab , Análisis de Supervivencia , Resultado del Tratamiento , Vincristina/administración & dosificaciónRESUMEN
Bcl-6 protein expression, a marker of germinal center origin, has been associated with a favorable prognosis in diffuse large B-cell lymphoma (DLBCL). To determine the prognostic significance of this marker when rituximab (R) was added to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy, we prospectively studied Bcl-6 protein expression by immunohistochemical staining of 199 paraffin-embedded specimens from patients enrolled in the US Intergroup phase 3 trial comparing R-CHOP to CHOP with or without maintenance R. In Bcl-6(-) patients, failure-free survival (FFS) and overall survival (OS) were prolonged for those treated with R-CHOP alone compared to CHOP alone (2-year FFS 76% versus 9%, P < .001; 2-year OS 79% versus 17%, P < .001). In contrast, no differences in FFS and OS were detected between treatment arms for Bcl-6(+) cases. In the multivariate analysis, treatment arm (CHOP versus R-CHOP) was the major determinant of both FFS (P < .001) and OS (P < .001) for the Bcl-6(-) subset, whereas the International Prognostic Index risk group was the only significant predictor of outcome among Bcl-6(+) cases. Bcl-2 protein expression was not predictive of outcome in either group. In this study, we observed a reduction in treatment failures and death with the addition of R to CHOP in Bcl-6(-) DLBCL cases only. Our finding that Bcl-6(+) cases did not benefit from the addition of R to CHOP requires independent confirmation.