RESUMEN
Previous randomized trials have demonstrated that rituximab maintenance (R-maintenance) can prolong time to progressive disease in patients with follicular lymphoma (FL). The phase IIIb MAXIMA study (NCT00430352) was a large prospective evaluation of R-maintenance in a daily care setting. The primary objective was safety. Secondary objectives included progression-free survival, overall survival, time to next lymphoma treatment, and partial response (PR) to complete response/unconfirmed (CR/CRu) conversion rate. Patients (n = 545) with first-line or relapsed FL who responded to 8 cycles of rituximab-based induction received R-maintenance every 2 months for 2 years. At study entry, 380 patients had CR or CRu, and 165 had PR. The median age was 57.0 years. The most common non-hematologic adverse events (AEs, excluding infusion-related reactions) were cough (9.9 % of patients), fatigue (7.5 %), nasopharyngitis (7.1 %), back pain (6.5 %), diarrhea (6.9 %), arthralgia (6.0 %), headache and hypertension (5.2 % each), and pyrexia (5.1 %). The majority of AEs were grade 1 or 2. Grade 3, 4, and 5 infections occurred in 21 (3.9 %), 2 (0.4 %), and 1 (0.2 %) patient, respectively. Fifty-one hematologic AEs occurred in 6.6 % (n = 35) of patients. Grade 3/4 prolonged neutropenia and hypogammaglobulinemia occurred in 13 (2.4 %) and 5 (0.9 %) patients, respectively. All cases of prolonged neutropenia or hypogammaglobulinemia were manageable and resolved. Fast infusion did not alter the safety profile. Efficacy was comparable with results from previous trials. R-maintenance is safe in a daily care setting for patients with first-line or relapsed FL.
Asunto(s)
Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Antineoplásicos/uso terapéutico , Inmunosupresores/uso terapéutico , Linfoma Folicular/tratamiento farmacológico , Quimioterapia de Mantención , Infecciones Oportunistas/etiología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Estimación de Kaplan-Meier , Linfoma Folicular/complicaciones , Quimioterapia de Mantención/efectos adversos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Inducción de Remisión , RituximabRESUMEN
We retrospectively analyzed the p.V158F polymorphism of Fcγ-receptor IIIA (FCGR3A, CD16) in patients with PTLD treated with rituximab monotherapy. Previous reports had indicated that the lower affinity F allele affects rituximab-mediated antibody-dependent cellular cytotoxicity (ADCC) and is linked to inferior outcome of rituximab monotherapy in B cell malignancies. 25 patients with PTLD after solid organ transplantation were included in this analysis. They had received 4 weekly doses of rituximab as part of two clinical trials, which had a rituximab monotherapy induction regimen in common. 16/25 patients received further treatment with CHOP-21 after rituximab monotherapy (PTLD-1, NCT01458548). The FCGR3A status was correlated to the response after 4 cycles of rituximab monotherapy. Response to rituximab monotherapy was not affected by F carrier status. This is in contrast to previous findings in B cell malignancies where investigators found a predictive impact of FCGR3A status on outcome to rituximab monotherapy. One explanation for this finding could be that ADCC is impaired in transplant recipients receiving immunosuppression. These results suggest that carrying a FCRG3A F allele does not negatively affect rituximab therapy in immunosuppressed patients.
Asunto(s)
Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Antineoplásicos/uso terapéutico , Trastornos Linfoproliferativos/tratamiento farmacológico , Trastornos Linfoproliferativos/etiología , Polimorfismo Genético , Receptores de IgG/genética , Adolescente , Adulto , Anciano , Alelos , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Huésped Inmunocomprometido , Masculino , Persona de Mediana Edad , Trasplante de Órganos/efectos adversos , Rituximab , Resultado del Tratamiento , Adulto JovenRESUMEN
PURPOSE: Most patients with chronic lymphocytic leukemia (CLL) are elderly and/or have comorbidities that may make them ineligible for fludarabine-based treatment. For this population, chlorambucil monotherapy is an appropriate therapeutic option; however, response rates with chlorambucil are low, and more effective treatments are needed. This trial was designed to assess how the addition of rituximab to chlorambucil (R-chlorambucil) would affect safety and efficacy in patients with CLL. PATIENTS AND METHODS: Patients with first-line CLL were treated with rituximab (375 mg/m(2) on day 1, cycle one, and 500 mg/m(2) thereafter) plus chlorambucil (10 mg/m(2)/d all cycles; day 1 through 7) for six 28-day cycles. For patients not achieving complete response (CR), six additional cycles of chlorambucil alone could be administered. The primary end point of the study was safety. RESULTS: A total of 100 patients were treated with R-chlorambucil, with a median follow-up of 30 months. Median age of patients was 70 years (range, 43 to 86 years), with patients having a median of seven comorbidities. Hematologic toxicities accounted for most grade 3/4 adverse events reported, with neutropenia and lymphopenia both occurring in 41% of patients and leukopenia in 23%. Overall response rates were 84%, with CR achieved in 10% of patients. Median progression-free survival was 23.5 months; median overall survival was not reached. CONCLUSION: These results compare favorably with previously published results for chlorambucil monotherapy, suggesting that the addition of rituximab to chlorambucil may improve efficacy with no unexpected adverse events. R-chlorambucil may improve outcome for patients who are ineligible for fludarabine-based treatments.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Clorambucilo/administración & dosificación , Clorambucilo/efectos adversos , Comorbilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Rituximab , Resultado del TratamientoRESUMEN
BACKGROUND: Burkitt lymphoma post-transplantation lymphoproliferative disorder (Burkitt-PTLD) is a rare form of monomorphic B-cell PTLD for which no standard treatment has been established. Currently, the treatment of Burkitt lymphoma outside the post-transplantation setting involves high doses of alkylating agents, frequent dosing, and intrathecal and/or systemic central nervous system prophylaxis. In PTLD, however, such protocols are associated with considerable toxicity and mortality. METHODS: The authors present a retrospective series of 8 adult patients with Burkitt-PTLD. Six patients were reported to the prospective German PTLD registry or were enrolled in the PTLD-1 trial, and 2 patients had received treatment before 2000, thus allowing for comparison with the pre-rituximab era. RESULTS: Seven of the 8 patients were men. The median age at presentation was 38 years, and the median time since transplantation was 5.7 years. Five of 8 patients had histologically established, Epstein-Barr virus-associated disease, and 7 of 7 patients were positive for a MYC translocation. Five of 8 patients received sequential immunochemotherapy (4 courses of rituximab [R] followed by 4 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisolone [CHOP] or R plus CHOP [R-CHOP]). In this group, 5 of 5 patients reached complete remission (CR), and their overall survival (OS) was significantly longer (P = .008) compared with the OS for 2 of 8 patients who received first-line CHOP and did not respond. One of 8 patients (who had stage IV disease with meningiosis) received combination therapy (cyclophosphamide pretreatment, rituximab, intrathecal chemotherapy, whole-brain irradiation, and radioimmunotherapy) and reached CR. Overall, 6 of 8 patients reached CR; and, after a median follow-up of 4.7 years (range, 1.7-4.8 years), the median OS was 36.7 months. There was no treatment-related mortality under first-line therapy. CONCLUSIONS: In the largest adult case series in Burkitt-PTLD to date, sequential immunochemotherapy with rituximab followed by standard CHOP or R-CHOP was a both safe and effective treatment.
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Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma de Burkitt/tratamiento farmacológico , Linfoma de Burkitt/inmunología , Factores Inmunológicos/uso terapéutico , Trasplante de Órganos , Adulto , Anciano , Algoritmos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Biomarcadores de Tumor/análisis , Linfoma de Burkitt/química , Linfoma de Burkitt/patología , Linfoma de Burkitt/virología , Irradiación Craneana , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Infecciones por Virus de Epstein-Barr/complicaciones , Femenino , Estudios de Seguimiento , Alemania , Humanos , Hibridación Fluorescente in Situ , Inyecciones Espinales , Masculino , Persona de Mediana Edad , Prednisona/administración & dosificación , Sistema de Registros , Inducción de Remisión , Estudios Retrospectivos , Rituximab , Resultado del Tratamiento , Vincristina/administración & dosificaciónRESUMEN
BACKGROUND: Post-transplantation lymphoproliferative disorder (PTLD) develops in 1-10% of transplant recipients and can be Epstein-Barr virus (EBV) associated. To improve long-term efficacy after rituximab monotherapy and to avoid the toxic effects of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy seen in first-line treatment, we initiated a phase 2 trial to test whether the subsequent use of rituximab and CHOP would improve the outcome of patients with PTLD. METHODS: In this international multicentre open-label phase 2 trial, treatment-naive adult solid-organ transplant recipients diagnosed with CD20-positive PTLD who had failed to respond to upfront immunosuppression reduction received four courses of rituximab (375 mg/m(2) intravenously) once a week followed by 4 weeks without treatment and four cycles of CHOP every 3 weeks. In case of disease progression during rituximab monotherapy, CHOP was started immediately. Supportive therapy with granulocyte-colony stimulating factor after chemotherapy was mandatory and antibiotic prophylaxis was recommended. The primary endpoint was treatment efficacy measured as response rates in all patients who completed treatment with rituximab and CHOP, per protocol, and response duration, in all patients who completed all planned therapy and responded. Secondary endpoints were frequency of infections, treatment-related mortality, and overall survival. This study is registered at ClinicalTrials.gov, number NCT01458548. FINDINGS: 74 patients were enrolled between Dec 12, 2002 and May 5, 2008, of whom 70 patients were eligible to receive treatment. PTLD was of late type in 53 (76%) of 70 patients, monomorphic in 67 (96%) of 70, and histologically EBV associated in 29 (44%) of 66 cases. Four of 70 patients did not receive CHOP. 53 of 59 patients had a complete or partial response (90%, 95% CI 79-96), of which 40 (68%, 55-78) were complete responses. At data cutoff (June 1, 2011) median response duration in the 53 patients who had responded to treatment had not yet been reached (>79·1 months). The main adverse events were grade 3-4 leucopenia in 42 of 62 patients (68%, 55-78) and infections of grade 3-4 in 26 of 64 patients (41%, 29-53). Seven of 66 patients (11%, 5-21) had CHOP-associated treatment-related mortality. Median overall survival was 6·6 years (95% CI 2·8-10·4; n=70). INTERPRETATION: Our results support the use of sequential immunochemotherapy with rituximab and CHOP in PTLD. FUNDING: F Hoffmann-La Roche, Amgen Germany, Chugaï France.
Asunto(s)
Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trastornos Linfoproliferativos/tratamiento farmacológico , Trasplante de Órganos/efectos adversos , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Antígenos CD20/inmunología , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Ciclofosfamida/administración & dosificación , Ciclofosfamida/uso terapéutico , Doxorrubicina/administración & dosificación , Doxorrubicina/uso terapéutico , Infecciones por Virus de Epstein-Barr/diagnóstico , Infecciones por Virus de Epstein-Barr/terapia , Femenino , Francia , Alemania , Herpesvirus Humano 4/patogenicidad , Humanos , Trastornos Linfoproliferativos/etiología , Trastornos Linfoproliferativos/patología , Masculino , Persona de Mediana Edad , Trasplante de Órganos/patología , Prednisolona/administración & dosificación , Prednisolona/uso terapéutico , Estudios Prospectivos , Rituximab , Vincristina/administración & dosificación , Vincristina/uso terapéuticoRESUMEN
INTRODUCTION: Treatment of chronic lymphocytic leukemia of the B-cell-lineage is strongly based upon clinical staging because of the heterogeneous clinical course of this disease. CASE PRESENTATION: We describe a 62-year-old patient with newly diagnosed chronic lymphocytic leukemia of the B-cell-lineage who did not respond to several chemotherapy regimens including chlorambucil, fludarabine and cyclophosphamide, developing a marked neutropenia and thrombocytopenia with life-threatening infections. Further chemotherapy appeared not feasible because of bone marrow toxicity. The patient was treated with 600 mg/m2 rituximab weekly followed by eight courses of biweekly therapy and then by long-term maintenance therapy, achieving almost complete remission of the symptoms and disease control. CONCLUSION: After resistance to standard chemotherapy with chlorambucil and fludarabine, a patient with chronic lymphocytic leukemia of the B-cell-lineage was successfully treated with rituximab.
RESUMEN
BACKGROUND: Posttransplant lymphoproliferative disorder (PTLD) is a life-threatening complication after organ transplantation. The identification of risk factors for PTLD development is important for disease management. It has been shown that cytokine gene polymorphisms are associated with lymphoma and Epstein-Barr virus (EBV)-associated diseases in nonimmunosuppressed patients. In the present case-control study, we analyzed the impact of -1082 interleukin (IL)-10, -308 tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta1 (codon 10, 25), and +874 interferon (IFN)-gamma gene single-nucleotide polymorphisms on the late onset EBV-associated PTLD. METHODS: Out of 1,765 solid organ recipients, 38 patients with late-onset EBV-associated PTLD and 408 matched solid organ recipients were selected and enrolled in the study. Single nucleotide polymorphisms (SNPs) for -1082IL-10, -308TNF-alpha, TGF-beta1 (codon 10, 25), and +874IFN-gamma genes were analyzed by a sequence specific primer polymerase chain reaction and were related to the PTLD development, and the disease course and outcome. RESULTS: The TGF-beta1 (codon 25) GG genotype was detected more frequently in controls than in PTLD patients (odds ratio=0.34, 95% confidence interval: 0.17-0.69, P=0.0022). The frequency of -1082 IL-10 GG genotype was also significantly higher in controls than in PTLD patients (odds ratio=0.5, 95% confidence interval: 0.25-1.0, P=0.044). There were no associations between -308TNF-alpha, TGF-beta1 codon 10, and +874IFN-gamma SNPs and PTLD. Disease course and outcome were not associated with any cytokine SNPs. CONCLUSIONS: Polymorphisms in two key anti-inflammatory cytokines, IL-10 and TGF-beta, are associated with susceptibility to EBV-associated PTLD, suggesting that a shift in pro-/anti-inflammatory response is involved in the pathogenesis of PTLD.
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Predisposición Genética a la Enfermedad/genética , Interleucina-10/genética , Trastornos Linfoproliferativos/genética , Trasplante de Órganos/efectos adversos , Factor de Crecimiento Transformador beta1/genética , Adulto , Estudios de Casos y Controles , Progresión de la Enfermedad , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/genética , Femenino , Genotipo , Humanos , Interferón gamma/genética , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
The introduction of single-agent rituximab has markedly changed the approach to therapy of patients with post-transplantation lymphoproliferative disorder (PTLD), but response to treatment varies substantially between patients. In the current report, we analyze long-term efficacy of single-agent rituximab in 60 patients and present factors predictive of progression-free and overall survival. Twelve months after completing first-line treatment, 34 of 60 patients (57%) had progressive disease, resulting in a median progression-free survival of 6.0 months at a median follow-up of 16.3 months. Using multivariate Cox regression analysis, the following factors were identified as significantly predictive of overall survival: age at diagnosis, performance status, lactate dehydrogenase (LDH), and time from transplantation to PTLD. Stage of disease and Epstein-Barr virus association of PTLD did not influence overall survival. LDH and time from transplantation to PTLD were also predictive of progression-free survival. The international prognostic index was shown to be of limited predictive value in these patients, but a PTLD-specific prognostic index separated low-, intermediate-, and high-risk patients with high significance: 2-year overall survival rates after first-line treatment with single-agent rituximab were 88, 50, and 0%, respectively. Thus, prognostic indices can be useful tools for prediction of treatment outcome and for the development of risk-adapted treatment strategies in patients with PTLD and may also provide the basis for interstudy comparisons.
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Anticuerpos Monoclonales/administración & dosificación , Trastornos Linfoproliferativos/prevención & control , Trasplante de Órganos/efectos adversos , Adulto , Factores de Edad , Anciano , Anticuerpos Monoclonales de Origen Murino , Antineoplásicos/administración & dosificación , Femenino , Humanos , Trastornos Linfoproliferativos/etiología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Rituximab , Análisis de Supervivencia , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Single-agent rituximab has demonstrated encouraging efficacy and tolerability in posttransplant lymphoproliferative disorders (PTLDs) failing to respond to immunosuppression reduction (IR). This retrospective analysis was undertaken to determine the efficacy and safety of salvage therapy in recipients of solid organ transplants with progression of PTLD after rituximab first-line therapy. METHODS: Eleven patients who had received IR and single-agent rituximab were analyzed. Of these, 10 had received CHOP salvage chemotherapy. One patient with limited disease received tumor irradiation and further IR. Most patients (73%) had late PTLD (median onset of disease 145 months posttransplant), and most (83%) had monomorphic histology; 36% had EBV-association. RESULTS: IR and irradiation therapy re-induced complete remission (CR) and allowed long-term disease control in a patient with polymorphic PTLD relapse. CHOP therapy achieved CR in five (50%) and partial remission (PR) in two (20%) patients. Four of five (80%) patients achieving CR remained in CR at a median follow-up of 44.2 months. Of the patients achieving PR, one is currently alive, and the second died from transplant rejection after converting to CR after consolidative chemotherapy. Patients with stable disease (two) and progressive disease (one) have died from PTLD. There was one possible CHOP-associated death (acute cardiac event) and two patients had to be switched to less-toxic monotherapies. Median overall survival was 46.5 months (95% confidence interval: 23.6-49.1 months). CONCLUSIONS: CHOP salvage therapy achieved a favorable overall response rate of 70% in this setting, indicating that PTLD generally remains chemotherapy-sensitive after progression following first-line rituximab.
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Anticuerpos Monoclonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Factores Inmunológicos/uso terapéutico , Trasplante de Riñón/inmunología , Trasplante de Hígado/efectos adversos , Trasplante de Hígado/inmunología , Trastornos Linfoproliferativos/tratamiento farmacológico , Trastornos Linfoproliferativos/etiología , Neoplasias/tratamiento farmacológico , Adulto , Anticuerpos Monoclonales de Origen Murino , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Humanos , Trasplante de Riñón/efectos adversos , Trastornos Linfoproliferativos/mortalidad , Masculino , Persona de Mediana Edad , Trasplante de Páncreas/efectos adversos , Trasplante de Páncreas/inmunología , Prednisona/administración & dosificación , Recurrencia , Estudios Retrospectivos , Rituximab , Análisis de Supervivencia , Vincristina/administración & dosificaciónRESUMEN
Post transplant lymphoproliferative disease (PTLD) in solid organ transplant (SOT) recipients is assumed to be the result of impaired Epstein-Barr Virus (EBV)-specific cellular immunity. We analyzed the absolute CD4 and CD8 T cell counts as well as the EBV-specific CD4 and CD8 T cell responses in relation to EBV load in SOT recipients with PTLD. A prospective, single center study was initiated and 10 immunosuppressed patients with diagnosis of PTLD were analyzed and compared to 3 patients without PTLD (2 SOT recipients with EBV-reactivation, 1 patient with Infectious Mononucleosis) and 6 healthy EBV positive controls. EBV-specific CD8 T cells were enumerated using HLA class I tetramers and the IFN-gamma cytokine secretion assay. EBNA1-specific CD4 T cells were analyzed after protein stimulation and EBV load was quantified by real-time PCR. Absolute CD8 T cell counts were highly variable in all 19 cases analyzed. In contrast, the absolute EBV-specific CD8 T cell count was found to be low in 7/9 patients with PTLD (<5/microl whole blood). These frequencies were similar to absolute EBV-specific CD8 T cell numbers observed in healthy EBV positive donors, but much lower compared to patients with EBV reactivation but no PTLD. Absolute CD4 T cell counts were significantly lower in PTLD patients (mean: 336/microl+/-161 vs. controls 1008/microl+/-424, p=0.0001), with EBNA1-specific CD4 T cell responses being also low, but highly variable. Moreover, low absolute CD4 T cell counts (<230/microl) were associated with an elevated EBV load (>1000 copies/microg DNA). We conclude that SOT recipients with PTLD have an inadequate functional EBV-specific T cell response. Our data suggest that the frequency and function of circulating EBV-specific CD8 T cells are dependent on absolute CD4 T cell counts. Further studies are needed to verify if a low absolute CD4 T cell count presents a risk factor for the development of PTLD in SOT recipients.
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Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Infecciones por Virus de Epstein-Barr/inmunología , Trastornos Linfoproliferativos/virología , Trasplante de Órganos/efectos adversos , Adulto , Anciano , Recuento de Células , Niño , Antígenos Nucleares del Virus de Epstein-Barr/inmunología , Femenino , Herpesvirus Humano 4 , Humanos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/inmunología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Carga ViralRESUMEN
There is no definitive treatment for post-transplant lymphoproliferative disorder (PTLD) that does not respond to reduction of immunosuppression. With a median follow-up of 8.8 years, the current retrospective analysis of standard CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) in 26 adults with PTLD demonstrated an overall response rate of 65% and median overall and progression-free survivals of 13.9 and 42 months, respectively.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trastornos Linfoproliferativos/tratamiento farmacológico , Trasplante de Órganos/métodos , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Estudios de Cohortes , Ciclofosfamida/administración & dosificación , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Femenino , Humanos , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Prednisona/administración & dosificación , Estudios Retrospectivos , Resultado del Tratamiento , Vincristina/administración & dosificaciónRESUMEN
Currently no standard treatment exists for patients with posttransplant lymphoproliferative disorders relapsed or refractory to chemotherapy after failure of reduction in immunosuppression. We have analyzed the effects of single-agent rituximab treatment in eight patients (seven adult, one pediatric) in this setting. Three patients had been salvaged with rituximab several times. In the seven adults, rituximab salvage therapy achieved complete remission (CR) in three patients (43%) and partial remission in one (14%). In the pediatric patient, a PR was obtained that could be reinduced on relapse with repeated administrations of rituximab. Patients achieving CR either remained in CR or were successfully salvaged again with single-agent rituximab. At a median follow-up of 69 months, median progression-free survival was 9 months and no relevant therapy-associated toxicity was observed. Single-agent rituximab salvage therapy is an effective treatment option in this setting of intensively pretreated patients, with virtually no therapy-associated toxicity.
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Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Trastornos Linfoproliferativos/complicaciones , Trastornos Linfoproliferativos/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Adulto , Anticuerpos Monoclonales de Origen Murino , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/administración & dosificación , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Humanos , Terapia de Inmunosupresión , Trastornos Linfoproliferativos/etiología , Neoplasias/mortalidad , Prednisona/administración & dosificación , Rituximab , Terapia Recuperativa , Análisis de Supervivencia , Sobrevivientes , Insuficiencia del Tratamiento , Resultado del Tratamiento , Vincristina/administración & dosificaciónRESUMEN
BACKGROUND: Posttransplant lymphoproliferative disease (PTLD) after solid organ transplantation (SOT) is commonly characterized by Epstein-Barr virus (EBV)-driven proliferation of recipient B cells due to impaired immune surveillance in the context of immunosuppression. Because EBV-specific T-cell responses are focused on the level of EBV antigen and epitope choice depending on the individual human leukocyte antigen (HLA) alleles, we hypothesized that certain HLA alleles or a distinct HLA haplotype may influence the risk of development of PTLD after SOT. METHODS: A multicenter case-control study was performed comparing a group of 155 recipients after SOT with development of PTLD with a group of 1996 recipients after SOT without development of PTLD. Alleles, genotypes, and three locus haplotypes were compared of SOT recipients with and without PTLD. RESULTS: The bivariate analysis showed that carrying HLA-A03 was negatively associated (odds ratio [OR] 0.61, confidence interval [CI] 0.40-0.92, P < 0.02) whereas carrying of HLA-B18 (OR 1.79, CI 1.18-2.73, P < 0.006) and HLA-B21 (OR 2.08, CI 1.14-3.77, P < 0.02) were positively associated with PTLD after SOT. HLA-DR analysis demonstrated a significant negative association between the expression of HLA-DR7 (OR 0.46, CI 0.28-0.78, P < 0.004) and PTLD. Three locus haplotype analysis underlined the relevance of a dominant protective effect of HLA-DR7 expression concerning the risk of PTLD development. CONCLUSIONS: Our data suggest an influence of HLA variants on the risk of the development of PTLD. We hypothesize that HLA genes or non-HLA genes within the HLA loci confer a risk modification for the individual patient.
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Antígenos HLA/química , Trastornos Linfoproliferativos/inmunología , Trasplante de Órganos/métodos , Adulto , Presentación de Antígeno , Linfocitos B/inmunología , Estudios de Casos y Controles , Epítopos/química , Femenino , Antígenos HLA/inmunología , Haplotipos , Herpesvirus Humano 4/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias , Estudios Retrospectivos , RiesgoRESUMEN
Posttransplant lymphoproliferative disease (PTLD) is closely linked to primary Epstein-Barr virus (EBV) infection. A defect of EBV specific cellular immunity is postulated to play a pivotal role in the etiology of PTLD, but there is some debate as to whether EBV load in the peripheral blood of transplant patients predicts onset of PTLD or relapse after treatment. The current prospective, single-center study was undertaken to investigate the impact of therapy on EBV load in adult patients with PTLD. Fifteen patients with PTLD after solid organ transplantation were included and of these, seven had EBV-associated PTLD. All 15 patients received Rituximab as primary therapy. In cases of treatment failure or relapse after Rituximab treatment, patients received polychemotherapy according to the cyclophosphamide, vincristine, doxorubicin, and prednisone regimen. At onset of PTLD, the median EBV load in the peripheral blood of patients was higher in EBV-associated PTLD than PTLD with no associated EBV infection. After Rituximab therapy, four of seven patients with EBV-associated PTLD achieved long-lasting complete remissions. However, in two of these patients, EBV load increased to reach levels as high as those recorded at onset of PTLD. Another patient showed a dramatic decline of EBV load after the first dose of Rituximab while suffering from progressive disease. The other patient relapsed after Rituximab monotherapy, but his viral load stayed low. In total, discordance in EBV load and clinical course was observed in five of the seven patients with EBV-associated PTLD. We conclude that in adult patients with PTLD, EBV load does not correlate with treatment response and is not suitable as a predictive marker for PTLD relapse.
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Herpesvirus Humano 4/genética , Trastornos Linfoproliferativos/virología , Trasplante de Órganos/efectos adversos , ARN Viral/sangre , Adulto , Biopsia , Femenino , Trasplante de Corazón/efectos adversos , Herpesvirus Humano 4/aislamiento & purificación , Humanos , Trasplante de Riñón/efectos adversos , Trasplante de Hígado/efectos adversos , Trastornos Linfoproliferativos/patología , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/patología , ARN Viral/genética , Carga ViralRESUMEN
Adult Wilms' tumor (AWT) is a very rare and aggressive malignancy, and little information is available on effective therapy in adults. Although mutations in WT1 have been found in 10% to 15% of childhood Wilms' tumor patients, to date WT1 mutations in AWT patients have not been described. The authors describe a 47-year-old man with relapsed AWT and a novel germline alteration in intron 1 of WT1: IVS1-6 C-->A. This alteration may reduce the splicing efficiency for exon 2 and possibly results in exon skipping. The effective salvage chemotherapy contained ifosfamide, carboplatin, and etoposide and was followed by a high-dose chemotherapy that contained melphalan, carboplatin, and etoposide. Both chemotherapy regimens showed moderate treatment-related toxicity. This report is the first that indicates that adult nephroblastoma patients also may carry WT1 germline mutations.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Genes del Tumor de Wilms , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genética , Tumor de Wilms/tratamiento farmacológico , Tumor de Wilms/genética , Carboplatino/administración & dosificación , Relación Dosis-Respuesta a Droga , Etopósido/administración & dosificación , Mutación de Línea Germinal , Humanos , Masculino , Melfalán/administración & dosificación , Persona de Mediana Edad , Terapia Recuperativa , Trasplante de Células Madre , Trasplante Autólogo , Resultado del TratamientoRESUMEN
This pilot study assessed the feasibility and efficacy of salvage chemotherapy (carboplatin and etoposide; CE) supported by granulocyte colony-stimulating factor (GCSF) in patients with refractory or relapsed post-transplant lymphoproliferative disorder (PTLD) following solid organ transplantation. Intensified salvage regimens were not feasible for these patients, due to their immunosuppressive conditions and potential organ (especially kidney and bone marrow) malfunctions. Salvage chemotherapy consisted of carboplatin [area under the curve (AUC) 4], on day 1, etoposide (120 mg/m2), on days 1-3 and GCSF (5 microg/kg) starting on day 5. This therapeutic regimen was planned to be repeated every 21 d. Nine patients (seven with refractory, two with relapsed disease) were enrolled. Five patients were heart transplant recipients, three liver transplant recipients and one patient had been a double lung transplant recipient. Five patients achieved a complete remission (CR), with follow-up at 92, 39, 55+, 17 and 9+ months. One patient showed stable disease after two cycles of CE and one patient had progressive disease. Two patients experienced early deaths, after the first and third cycles of chemotherapy respectively. One died of septic complications and one because of a perforated intestine, which had been infiltrated by lymphoma. In respect of the difficulties experienced in treating patients with refractory or relapsed PTLD after solid organ transplantation, the combination of carboplatin and etopoide with GCSF support (filgrastim) proved to be an effective regimen.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trastornos Linfoproliferativos/tratamiento farmacológico , Trasplante de Órganos , Adulto , Anciano , Carboplatino/administración & dosificación , Etopósido/administración & dosificación , Estudios de Factibilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Terapia Recuperativa , Resultado del TratamientoRESUMEN
Epstein-Barr virus (EBV)-associated B-cell lymphoproliferations may arise in solid organ transplant recipients. In these patients, an insufficient control of EBV-infected B cells commonly occurs. Antiviral treatment against EBV may represent a causal, relatively low-toxic treatment option. Treatment with foscarnet, an inhibitor of viral-DNA polymerase, in three patients with EBV-associated post-transplant lymphoproliferative disease (PTLD) after heart (n = 2) and heart/kidney transplantation (n = 1), who did not respond to, or were not eligible for reduction of immunosuppression, resulted in complete remission (48+, 27 and 15 months respectively). Response of PTLD to antiviral treatment correlated with the expression of lytic phase antigen BZLF1/ZEBRA protein, an early antigen of lytic EBV-activity, in the biopsied PTLD specimens.
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Antivirales/uso terapéutico , Proteínas de Unión al ADN/análisis , Infecciones por Virus de Epstein-Barr/tratamiento farmacológico , Foscarnet/uso terapéutico , Trasplante de Corazón , Linfoma de Células B/virología , Transactivadores/análisis , Proteínas Virales , Adulto , Reordenamiento Génico , Humanos , Inmunohistoquímica , Trasplante de Riñón , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/genética , Masculino , Complicaciones Posoperatorias/tratamiento farmacológicoRESUMEN
The incidence of malignant lymphomas is significantly higher in patients who have congenital or acquired immunodeficiencies. Although there are some differences between these immunodeficiency-associated lymphoproliferative disorders (IALD), they share several features: a tendency to present in extranodal sites, particularly the central nervous system and gastrointestinal tract, rapid clinical progression when untreated, diffuse large cell histology, B-cell origin and association with the Epstein-Barr virus (EBV). In the presence of disturbed T-cell function EBV may induce not only prolonged proliferation but also transformation of B-cells. In patients with primary, congenital immunodeficiency the incidence of IALD ranges from 0.7% for patients with X-linked agammaglobulinemia to 12-15% in patients with ataxia telangiectasia. In patients with post-transplant lymphoproliferative disorders (PT-LPD) the incidence varies from 0.5% after bone marrow transplantation to 10% after heart-lung transplantation. PT-LPD are often characterized by a polymorphic cell population. Recent studies identified three categories: plasmacytic hyperplasia, polymorphic lymphoproliferation and B-cell non-Hodgkin's lymphoma (NHL). The plasmacytic hyperplasias are of polyclonal composition, while polymorphic lymphoproliferations and NHL are monoclonal. The precise risk of lymphoma development in HIV infection is not defined, but estimates suggest a prevalence of 3-4%. HIV-related NHLs are divisible by site of manifestation into systemic, primary central nervous system and body-cavity lymphomas, and by pathology into Burkitt's and Burkitt's-like lymphoma, and diffuse large cell lymphoma (DLCL). In about 90% of cases these lymphomas are of monoclonal B-cell composition. Recent experiences suggest a link between therapy with immunosuppressive drugs (methotrexate, azathioprine, cyclophospamide, etc.) and development of IALD, best supported by the increased rate of IALD in patients with rheumatoid arthritis who receive methotrexate therapy. The occurrence of IALD demonstrates the importance of competent immunosurveillance in the development of lymphoid neoplasias, which may have therapeutic relevance too.
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Síndromes de Inmunodeficiencia/inmunología , Trastornos Linfoproliferativos/inmunología , Monitorización Inmunológica , HumanosRESUMEN
Epstein-Barr virus (EBV)-associated lymphoproliferations may arise in individuals with hereditary or acquired immunodeficiencies. T-cell dysfunction and resulting insufficient control of EBV infection is common to all these patients in whom EBV-associated lymphoproliferations develop. EBV is an oncogenic virus which induces proliferation and transformation of B-lymphocytes. Antiviral treatment may represent a causal treatment option with relatively low toxicity. Among the different antiviral drugs aciclovir and ganciclovir are not the drugs of choice, because in EBV-associated lymphoproliferations the viral thymidine kinase enzyme is not encoded regularly. The agent arginine butyrate has the ability to selectively activate EBV thymidine kinase genes in EBV-infected lymphoma cells. In combination with ganciclovir it has demonstrated efficacy in patients with EBV-associated lymphoproliferations after solid organ transplantation. The action of foscarnet, another antiviral agent, is directed against the viral DNA, independent of the presence of the viral thymidine kinase. In our experience treatment with foscarnet resulted in continuous complete remissions in patients with EBV-associated lymphoproliferations. These clinical experiences demonstrate the efficacy of antiviral treatment in EBV-associated lymphoproliferations.