RESUMEN
BACKGROUND: Rituximab (R) in combination with DHAP is a widely accepted salvage regimen for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). A common adverse effect of this protocol is renal toxicity which may result in treatment discontinuation. Assuming that a lower single dose of cisplatin over several days would reduce renal toxicity, our institution has chosen to administer cisplatin in a dosage of 25 mg/m(2) per day as a 3-h infusion over 4 consecutive days. METHODS: In this study, we analyzed the renal function of 122 patients with relapsed or refractory DLBCL treated with R-DHAP at our institution. Overall, 256 R-DHAP cycles were administered. 31 (25%), 61 (50%), 14 (12%) and 16 (13%) patients received one, two, three or four R-DHAP courses, respectively. RESULTS: A glomerular filtration rate (GFR) decrease was observed after each R-DHAP cycle. However, in none of the subgroups the median GFR was lower than 60 ml/min/1.73 m(2). In most patients, only renal impairment stage I and II was observed. Renal impairment stage III was seen in 10% and stage IV only in 1% of patients. CONCLUSION: We conclude that a modified R-DHAP regimen with administration of cisplatin 25 mg/m(2) over 4 consecutive cycles leads only to minimal renal toxicity.
Asunto(s)
Cisplatino/administración & dosificación , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Rituximab/administración & dosificación , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cisplatino/efectos adversos , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Humanos , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Inducción de Remisión , Rituximab/efectos adversos , Resultado del TratamientoAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma Folicular/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Anticuerpos Monoclonales de Origen Murino/economía , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/economía , Biomarcadores de Tumor , Análisis Costo-Beneficio , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Ciclofosfamida/economía , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Doxorrubicina/economía , Humanos , Estimación de Kaplan-Meier , Linfoma Folicular/economía , Linfoma Folicular/genética , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Prednisona/administración & dosificación , Prednisona/efectos adversos , Prednisona/economía , Modelos de Riesgos Proporcionales , Inducción de Remisión , Rituximab , Resultado del Tratamiento , Vincristina/administración & dosificación , Vincristina/efectos adversos , Vincristina/economía , Adulto JovenRESUMEN
Chronic lymphocytic leukemia (CLL) is characterized by apoptosis resistance and a dysfunctional immune system. Previous reports suggested a potential role of myeloid cells in mediating these defects. However, the composition and function of CLL-associated myeloid cells have not been thoroughly investigated in vivo. Using the Eµ-TCL1 mouse model, we observed severe skewing of myeloid cell populations with CLL development. Monocytes and M2-like macrophages infiltrated the peritoneal cavity of leukemic mice. Monocytes also accumulated in the spleen in a CCR2-dependent manner, and were severely skewed toward Ly6C(low) patrolling or nonclassical phenotype. In addition, the percentage of MHC-II(hi) dendritic cells and macrophages significantly dropped in the spleen. Gene expression profiling of CLL-associated monocytes revealed aberrantly high PD-L1 expression and secretion of multiple inflammatory and immunosuppressive cytokines like interleukin-10, tumor necrosis factor-α and CXCL9. In vivo myeloid cell depletion using liposomal Clodronate resulted in a significant control of CLL development accompanied by a pronounced repair of innate immune cell phenotypes and a partial resolution of systemic inflammation. In addition, CLL-associated skewing of T cells toward antigen-experienced phenotypes was repaired. The presented data suggest that targeting nonmalignant myeloid cells might serve as a novel immunotherapeutical strategy for CLL.