RESUMEN
Background: Therapeutic advancements following the introduction of autologous stem cell transplantation and 'novel' agents have significantly improved clinical outcomes for patients with multiple myeloma (MM). Increased life expectancy, however, has led to renewed concerns about the long-term risk of second primary malignancies (SPMs). This review outlines the most up-to-date knowledge of possible host-, disease-, and treatment-related risk factors for the development of SPMs in patients with MM, and provides practical recommendations to assist physicians. Design: A Panel of International Myeloma Working Group members reviewed the most relevant data published in the literature as full papers, or presented at meetings of the American Society of Clinical Oncology, American Society of Hematology, European Hematology Association, or International Myeloma Workshops, up to June 2016. Here, we present the recommendations of the Panel, based on this literature review. Results: Overall, the risk of SPMs in MM is low, multifactorial, and partially related to the length of patients' survival and MM intrinsic susceptibility. Studies suggest a significantly increased incidence of SPMs when lenalidomide is administered either following, or concurrently with, oral melphalan. Increased SPM incidence has also been reported with lenalidomide maintenance following high-dose melphalan, albeit to a lesser degree. In both cases, the risk of death from MM was significantly higher than the risk of death from SPMs, with lenalidomide possibly providing a survival benefit. No increase in SPM incidence was reported with lenalidomide plus dexamethasone (without melphalan), or with bortezomib plus oral melphalan, dexamethasone, or thalidomide. Conclusion: In general, the risk of SPMs should not alter the current therapeutic decision-making process in MM. However, regimens such as lenalidomide plus dexamethasone should be preferred to prolonged exposure to lenalidomide plus oral melphalan. SPM risk should be carefully discussed with the patient in the context of benefits and risks of different treatment options.
Asunto(s)
Mieloma Múltiple/terapia , Neoplasias Primarias Secundarias/etiología , Humanos , Incidencia , Mieloma Múltiple/epidemiología , Mieloma Múltiple/patología , Neoplasias Primarias Secundarias/epidemiología , Factores de RiesgoRESUMEN
BACKGROUND: The IFM2009-02 trial studied pomalidomide (4 mg daily, 21/28 versus 28/28) and dexamethasone in very advanced relapsed or refractory multiple myeloma (RRMM). We observed that 40% of patients had a prolonged progression-free survival (PFS) and subsequently overall survival (OS). We sought to analyze the characteristics of these patients and study the effect of long exposure to pomalidomide. DESIGN: We separated the studied population into two groups: 3 months to 1 year (<1 year) and more than 1 year (≥1 year) of treatment with pomalidomide and dexamethasone based on clinical judgment and historical control studies. We then analyzed the characteristics of patients according to duration of treatment. RESULTS: The overall response rate (ORR) for the <1-year group was 43%, the median PFS 4.6 months [95% confidence interval (95% CI) 3.8-6.4] with only 6% at 12 months, and the median OS was 15 months (11.7-20.3) and 40% at 18 months. For the ≥1-year group, the response rate and survival were strikingly different, ORR at 83%, median PFS 20.7 months (14.7-35.4), median OS not reached, and 91% at 18 months. CONCLUSION: Pomalidomide and dexamethasone favored prolonged and safe exposure to treatment in 40% of heavily treated and end-stage RRMM, a paradigm shift in the natural history of RRMM characterized with a succession of shorter disease-free intervals and ultimately shorter survival. Although an optimization of pomalidomide-dexamethasone regimen is warranted in advanced RRMM, we claim that pomalidomide has proven once more to change the natural history of myeloma in this series, which should be confirmed in a larger study.
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Resistencia a Antineoplásicos/efectos de los fármacos , Mieloma Múltiple/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Talidomida/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bortezomib/administración & dosificación , Bortezomib/efectos adversos , Dexametasona/administración & dosificación , Dexametasona/efectos adversos , Supervivencia sin Enfermedad , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/patología , Recurrencia Local de Neoplasia/patología , Talidomida/administración & dosificación , Talidomida/efectos adversosRESUMEN
BACKGROUND: Mycosis fungoides (MF) and pseudo-MF (or MF simulant) can be associated with B-cell malignancies, but distinction between a true neoplasm and a reactive process may be difficult. OBJECTIVES: To report seven patients with B-cell malignancy and folliculotropic MF or pseudo-MF and emphasize on criteria allowing distinction between the two conditions. METHODS: We retrospectively and prospectively included seven patients with B-cell malignancy who presented skin lesions histologically consisting in a folliculotropic T-cell infiltrate and reviewed the literature on the topic. RESULTS: Four men and three women had a chronic lymphocytic leukaemia (n = 6) or a MALT-type lymphoma (n = 1). Five patients had localized papules, and two had patches and plaques. Histological examination showed in all cases a diffuse dermal T-cell infiltrate with folliculotropic involvement and follicular mucinosis associated with clusters of the B-cell lymphoma, without significant expression of follicular helper T-cell markers. T-cell rearrangement studies showed a polyclonal pattern in the patients with papules and a monoclonal pattern in the cases of patches and plaques. Papular lesions had an indolent evolution, whereas patches and plaques persisted or worsened into transformed MF. CONCLUSION: Folliculotropic T-cell infiltrates associated with B-cell malignancies can be either a true folliculotropic MF or a pseudo-MF. The distinction between both conditions cannot rely only on the histopathological aspect, but needs both a clinical pathological correlation and the search for a dominant T-cell clone. Whether the neoplastic T and B cells derive from a common ancestor or the T-cell proliferation is promoted by the underlying B-cell lymphoma remains unsolved, but interaction between B and T cell in the skin does not appear to be dependent on a TFH differentiation of the T-cell infiltrate.
Asunto(s)
Leucemia Linfocítica Crónica de Células B/patología , Linfoma de Células B de la Zona Marginal/patología , Micosis Fungoide/patología , Seudolinfoma/patología , Neoplasias Cutáneas/patología , Linfocitos T , Anciano , Diagnóstico Diferencial , Femenino , Folículo Piloso , Humanos , Leucemia Linfocítica Crónica de Células B/complicaciones , Leucemia Linfocítica Crónica de Células B/inmunología , Linfoma de Células B de la Zona Marginal/complicaciones , Linfoma de Células B de la Zona Marginal/inmunología , Masculino , Persona de Mediana Edad , Micosis Fungoide/complicaciones , Estudios Prospectivos , Seudolinfoma/complicaciones , Estudios Retrospectivos , Neoplasias Cutáneas/complicacionesRESUMEN
Thousands of autologous and at less extent allogeneic hematopoietic stem cells (HSC) bags are cryopreserved in France. The majority of autologous HSC grafts are used within a year after collection. However, many bags are still unused and cryopreserved for many years. In France and on a European scale, the ever-growing number of cryopreserved bags represents a real economic health concern. Indeed, the cost of storage is about 100 per bag and per year. In addition, quality and therapeutic value of these long-term cryopreserved grafts needs to be evaluated. In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC) set up its fourth annual series of workshops which brought together practitioners from its member centers across France. These workshops took place in September 2013 in Lille. In this article, we addressed the issue of the destruction of long-term cryopreserved grafts be them autologous or allogeneic and provide recommendations regarding their destruction.
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Criopreservación , Células Madre Hematopoyéticas , Eliminación de Residuos Sanitarios , Costos y Análisis de Costo , Criopreservación/economía , Francia , Trasplante de Células Madre Hematopoyéticas/normas , Humanos , Control de Calidad , Sistema de Registros , Factores de Tiempo , Trasplante HomólogoRESUMEN
One hundred de novo multiple myeloma patients with t(4;14) treated with double intensive therapy according to IFM99 protocols were retrospectively analyzed. The median overall survival (OS) and event-free survival (EFS) were 41.4 and 21 months, respectively, as compared to 65 and 37 for patients included in the IFM99 trials without t(4;14) (P<10(-7)). We identified a subgroup of patients presenting at diagnosis with both low beta(2)-microglobulin <4 mg/l and high hemoglobin (Hb) >/=10 g/l (46% of the cases) with a median OS of 54.6 months and a median EFS of 26 months, respectively, which benefits from high-dose therapy (HDT); conversely patients with one or both adverse prognostic factor (high beta(2)-microglobulin and/or low Hb) had a poor outcome. The achievement of either complete response or very good partial response after HDT was also a powerful independent prognostic factor for both OS and EFS.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Heterogeneidad Genética , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genética , Translocación Genética , Adulto , Anciano , Cromosomas Humanos Par 14 , Cromosomas Humanos Par 4 , Citarabina/administración & dosificación , Dexametasona/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Hemoglobinas , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/mortalidad , Análisis Multivariante , Pronóstico , Estudios Retrospectivos , Vincristina/administración & dosificación , Microglobulina beta-2/sangreRESUMEN
Liquid biopsies including circulating tumor cells (CTCs) and cell-free DNA (cfDNA) have enabled minimally invasive characterization of many cancers, but are rarely analyzed together. Understanding the detectability and genomic concordance of CTCs and cfDNA may inform their use in guiding cancer precision medicine. Here, we report the detectability of cfDNA and CTCs in blood samples from 107 and 56 patients with multiple myeloma (MM), respectively. Using ultra-low pass whole-genome sequencing, we find both tumor fractions correlate with disease progression. Applying whole-exome sequencing (WES) to cfDNA, CTCs, and matched tumor biopsies, we find concordance in clonal somatic mutations (~99%) and copy number alterations (~81%) between liquid and tumor biopsies. Importantly, analyzing CTCs and cfDNA together enables cross-validation of mutations, uncovers mutations exclusive to either CTCs or cfDNA, and allows blood-based tumor profiling in a greater fraction of patients. Our study demonstrates the utility of analyzing both CTCs and cfDNA in MM.
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Biomarcadores de Tumor/genética , ADN Tumoral Circulante/genética , Secuenciación del Exoma/métodos , Mieloma Múltiple/genética , Células Neoplásicas Circulantes , Adulto , Anciano , Anciano de 80 o más Años , Médula Ósea/patología , Variaciones en el Número de Copia de ADN/genética , Progresión de la Enfermedad , Femenino , Humanos , Biopsia Líquida/métodos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/patología , Mutación/genética , Medicina de Precisión/métodosRESUMEN
Transplant-eligible patients with multiple myeloma (MM) now have extended survival after diagnosis owing to effective modern treatment strategies that include new agents in induction therapy, autologous stem cell transplant (ASCT), consolidation therapy and posttransplant maintenance therapy. Standard of care for newly diagnosed, fit patients includes ASCT and, often nowadays, posttransplant maintenance. Several large studies have shown the efficacy of maintenance with thalidomide, lenalidomide and bortezomib in the treatment scheme of MM with regards to prolonging progression-free survival and, to a lesser degree, overall survival. Herein we discuss the data currently available to support the use of maintenance therapy in patients after ASCT as well as the newer available agents that may be a part of its changing landscape in the years to come.
Asunto(s)
Mieloma Múltiple/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bortezomib/administración & dosificación , Bortezomib/efectos adversos , Bortezomib/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Humanos , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/efectos adversos , Factores Inmunológicos/uso terapéutico , Lenalidomida , Quimioterapia de Mantención , Terapia Molecular Dirigida , Mieloma Múltiple/mortalidad , Mieloma Múltiple/patología , Cuidados Posoperatorios , Talidomida/administración & dosificación , Talidomida/efectos adversos , Talidomida/análogos & derivados , Talidomida/uso terapéutico , Trasplante Autólogo , Resultado del TratamientoRESUMEN
During the last few years, several new drugs have been introduced for treatment of patients with multiple myeloma, which have significantly improved treatment outcome. All of these novel substances differ at least in part in their mode of action from similar drugs of the same drug class, or are representatives of new drugs classes, and as such present with very specific side effect profiles. In this review, we summarize these adverse events, provide information on their prevention, and give practical guidance for monitoring of patients and for management of adverse events.Leukemia accepted article preview online, 18 December 2017. doi:10.1038/leu.2017.353.
RESUMEN
We describe the use and outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for multiple myeloma (MM) in Europe between January 1990 and December 2012. We identified 7333 patients, median age at allo-HSCT was 51 years (range: 18-78), of whom 4539 (62%) were males. We distinguished three groups: (1) allo-HSCT upfront (n=1924), (2) tandem auto-allo-HSCT (n=2004) and (3) allo-HSCT as a second line treatment and beyond (n=3405). Overall, there is a steady increase in numbers of allo-HSCT over the years. Upfront allo-HSCT use increased up to year 2000, followed by a decrease thereafter and represented 12% of allo-HSCTs performed in 2012. Tandem auto-allo-HSCT peaked around year 2004 and contributed to 19% of allo-HSCTs in 2012. Allo-HSCT as salvage after one or two or three autografts was steadily increasing over the last years and represented 69% of allo-HSCTs in 2012. Remarkable heterogeneity in using allo-HSCT was observed among the different European countries. The 5-year survival probabilities from time of allo-HSCT for the three groups after year 2004 were 42%, 54% and 32%, respectively. These results show that the use of allo-HSCT is increasing in Europe, especially as second line treatment and beyond. There is an unmet need for well-designed prospective studies investigating allo-HSCT as salvage therapy for MM.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Mieloma Múltiple/terapia , Adolescente , Adulto , Anciano , Europa (Continente) , Femenino , Trasplante de Células Madre Hematopoyéticas/tendencias , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/mortalidad , Tasa de Supervivencia , Trasplante Homólogo , Resultado del Tratamiento , Adulto JovenRESUMEN
The prognosis for patients multiple myeloma (MM) has improved substantially over the past decade with the development of new, more effective chemotherapeutic agents and regimens that possess a high level of anti-tumor activity. In spite of this important progress, however, nearly all MM patients ultimately relapse, even those who experience a complete response to initial therapy. Management of relapsed MM thus represents a vital aspect of the overall care for patients with MM and a critical area of ongoing scientific and clinical research. This comprehensive manuscript from the International Myeloma Working Group provides detailed recommendations on management of relapsed disease, with sections dedicated to diagnostic evaluation, determinants of therapy, and general approach to patients with specific disease characteristics. In addition, the manuscript provides a summary of evidence from clinical trials that have significantly impacted the field, including those evaluating conventional dose therapies, as well as both autologous and allogeneic stem cell transplantation. Specific recommendations are offered for management of first and second relapse, relapsed and refractory disease, and both autologous and allogeneic transplant. Finally, perspective is provided regarding new agents and promising directions in management of relapsed MM.
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Mieloma Múltiple , Guías de Práctica Clínica como Asunto , Antineoplásicos/uso terapéutico , Manejo de la Enfermedad , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/patología , Mieloma Múltiple/terapia , Recurrencia , Terapia Recuperativa/métodosRESUMEN
In patients treated with allogeneic stem cell transplantation (SCT) for malignant disease who suffer from a relapse after the transplantation, the role of second allogeneic SCT is often uncertain. In a retrospective analysis, 2632 second allogeneic transplantations carried out for a relapse after the first transplantation were analyzed to define indications and identify predictive factors. Fifteen percent of the patients remained relapse-free until 5 years after the second SCT. Patients with CML had a better survival than patients with other diseases. In a multivariate analysis, factors associated with better survival were low disease burden, longer remission duration after the first transplantation, longer interval between the transplantations, younger age, absence of grade II-IV acute GvHD or chronic GvHD after the first transplantation, and later year of transplantation. The European Society for Blood and Marrow Transplantation risk score predicted the outcome. Using the same donor as in the first transplantation vs another donor had no predictive value for survival. Sibling donor was a favorable predictive factor. In conclusion, second allogeneic SCT offers a reasonable option especially for young patients with a long remission after the first transplantation and a low disease burden. The present findings do not support the usefulness of changing the donor for the second transplantation.
Asunto(s)
Neoplasias Hematológicas/terapia , Trasplante de Células Madre , Enfermedad Aguda , Adolescente , Adulto , Aloinjertos , Enfermedad Crónica , Supervivencia sin Enfermedad , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/mortalidad , Neoplasias Hematológicas/mortalidad , Humanos , Persona de Mediana Edad , Tasa de SupervivenciaRESUMEN
Autologous hematopoietic cell transplantation (AHCT) is a standard of care in multiple myeloma (MM) patients aged <65 years. To understand age-related trends in utilisation and outcome of AHCT, we analysed 53 675 MM patients who underwent a first AHCT in 31 European countries between 1991 and 2010. The number of patients undergoing AHCT increased for all age groups (<40, 40-49, 50-59, 60-64, 65-69 and ⩾70 years) throughout the observation period. The highest increase was observed for patients aged ⩾65 years, who accounted for 3% of AHCTs in 1991-1995 and for 18.8% of AHCTs in 2006-2010. Risk factors associated with survival over the entire observation period (P<0.001) were calendar period, remission status at AHCT, gender, disease duration before AHCT and age. Survival improved considerably more in older than in younger patients in recent years. In 2006-2010, median 2- and 5-year post-transplant survival ranged from 85.9 and 61.5% in patients <40 years to 80.2 and 49.7% in those ⩾70 years. All-cause day-100 mortality decreased throughout the observation period to ⩽2.4% for all age groups in 2006-2010. The results of this study demonstrate increased utilisation and safety of AHCT with improved post-transplant survival particularly in elderly MM patients in recent years in Europe.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/tendencias , Mieloma Múltiple/mortalidad , Mieloma Múltiple/terapia , Adulto , Factores de Edad , Anciano , Autoinjertos , Supervivencia sin Enfermedad , Europa (Continente)/epidemiología , Femenino , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Masculino , Persona de Mediana Edad , Sistema de Registros , Tasa de SupervivenciaRESUMEN
Previous studies have shown that obtaining complete hematologic remission (CR) in multiple myeloma is an important predictor of PFS and OS. This applies both to autologous and allogeneic transplantation. However, the importance of CR obtained before vs after second transplant or following allogeneic vs autologous transplantation is not clear. We investigated the role of CR analyzing data from the EBMT-NMAM2000 interventional prospective study comparing tandem autologous/reduced intensity conditioning allogeneic transplantation (auto/RICallo) to autologous transplantation-single or double (auto/auto). Allocation to treatment was performed according to availability of a matched sibling donor. Cox regression and multi-state models were applied. The long-term probability of survival in CR was superior in auto/RICallo, both comparing groups according to treatment allocated at start (28.8 vs 11.4% at 60 months, P=0.0004) and according to actual administration of second transplant (25.6 vs 9.6% at 60 months, P=0.008). CR achieved before the second transplant was predictive for PFS (hazard ratio (HR)=0.44, P= 0.003) and OS (HR 0.51, P=0.047) irrespective of the type of second transplant. CR achieved after auto/RICallo was more beneficial for PFS (HR=0.53, P=0.027) than CR after auto/auto (HR=0.81, P=0.390), indicating a better durability of CR obtained after an allotransplant procedure.
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Mieloma Múltiple/mortalidad , Mieloma Múltiple/terapia , Trasplante de Células Madre , Aloinjertos , Autoinjertos , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Inducción de Remisión , Tasa de SupervivenciaRESUMEN
We performed a retrospective analysis of the European Group for Blood and Marrow Transplantation database comparing the outcomes of multiple myeloma patients who received tandem autologous followed by allogeneic PSCT (auto-allo) with the outcomes of patients who underwent a reduced intensity conditioning allograft (early RIC) without prior autologous transplant. From 1996 to 2013, we identified a total of 690 patients: 517 patients were planned to receive auto-allo and 173 received an early RIC allograft without prior autologous transplant. With a median follow-up of 93 months, 5-year PFS survival was significantly better in the auto-allo group, 34% compared with 22% in the early RIC group (P<0.001). OS was also significantly improved in the auto-allo group with a 5-year rate of 59% vs 42% in the early RIC group (P=0.001). The non-relapse mortality rate was lower in the auto-allo group than in the early RIC group, with 1- and 3-year rates of 8% and 13% vs 20% and 28%, respectively (P<0.001). The relapse/progression rate was similar in the two groups, with 5-year rates of 50% for auto-allo and 46% for early RIC (P=0.42). These data suggest that planned tandem autologous allograft can improve overall survival compared with upfront RIC allograft alone in patients with multiple myeloma.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Mieloma Múltiple/mortalidad , Mieloma Múltiple/terapia , Adulto , Anciano , Aloinjertos , Autoinjertos , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: Hemorrhagic cystitis (HC) is a common complication following allogeneic stem cell transplantation (SCT). In rare cases, it can be severe, inducing kidney failure and sepsis, and become life-threatening. METHODS: We report three cases of severe HC in stem cell transplant recipients. Risk factors and the management of these patients were studied, as well as severe HC cases reported in the literature. RESULTS: All three patients received high-dose cyclophosphamide in addition to total body irradiation or busulfan in their preparative regimen. They underwent allogeneic SCT, one of them from unrelated cord blood. BK viruria was detected in two cases at the onset of hematuria. HC lasted for more than 3 months, resulting in urinary tract obstruction and sepsis. Ultimately, cystectomy was the last therapeutic procedure available to treat this life-threatening complication. CONCLUSION: We describe three patients, among a total of more than 1300 patients treated in our unit by allogeneic bone marrow transplantation, in whom HC was severe and long lasting enough to require cystectomy as a life-saving procedure.
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Cistectomía , Cistitis/etiología , Cistitis/cirugía , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Hemorragia/etiología , Hemorragia/cirugía , Adolescente , Adulto , Virus BK/aislamiento & purificación , Virus BK/patogenicidad , Ciclofosfamida/efectos adversos , Femenino , Humanos , Leucemia/terapia , Masculino , Persona de Mediana Edad , Factores de Riesgo , Trasplante HomólogoRESUMEN
BACKGROUND: T cells present in an allogeneic bone marrow transplant may produce graft-versus-host disease but also contribute to immune reconstitution and enhance engraftment. Our aim was to separate alloreactive from nonalloreactive T lymphocytes, by performing a mixed lymphocyte culture (MLC) stimulation of donor cells, followed by selective depletion of activated cells expressing the high-affinity interleukin 2 receptor. We then characterized the resulting depleted cell fraction. METHODS: Donor peripheral blood mononuclear cells were cocultured with irradiated peripheral blood mononuclear cells from HLA-nonidentical recipient stimulators in an MLC. After 3 days, CD25+ lymphocytes (alloreactive cells expressing the alpha chain of the interleukin 2 receptor) were removed by immunomagnetic separation. The depleted donor fraction and untreated cells were then rechallenged in a secondary MLC with the original irradiated stimulator cells or a third party to assess relative alloreactivity. RESULTS: Inhibition of the secondary MLC and of host-specific cytotoxic activities was observed as well as a disappearance of interleukin 2 receptor-positive cells. Alloreactivity against unrelated third-party cells was preserved. Limiting dilution analysis of residual alloantigen-reactive T lymphocytes demonstrated a 1.3 log reduction of antihost reactivity. The depletion largely removed host-specific alloreactive CD4+ cells. CONCLUSIONS: This method reduces alloreactivity while retaining reactivity against third-party targets. This approach may allow therapeutic infusion of T cells after HLA-nonidentical allografts with a reduced capacity to produce graft-versus-host disease.
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Eliminación de Componentes Sanguíneos , Isoantígenos/análisis , Monocitos/fisiología , Receptores de Interleucina-2/análisis , Linfocitos T/inmunología , Técnicas de Cocultivo , Humanos , Prueba de Cultivo Mixto de Linfocitos , Fenotipo , Linfocitos T Citotóxicos/fisiologíaRESUMEN
Glanzmann's thrombasthenia is an autosomal recessive disorder characterized by a lack of platelet aggregation due to the absence of platelet glycoprotein IIb and IIIa. Usually, the disease leads to mild hemorrhage but sometimes bleeding is severe enough to be life-threatening. We report the case of a 16-year-old girl, presenting with very severe type 1 Glanzmann's thrombasthenia, successfully treated with an HLA-identical sibling bone marrow transplant (BMT). We also update the clinical and laboratory data of her brother, who had received a BMT 16 years ago for the same disease. In the light of these two cases and two others published in the literature, we discuss the indications for BMT from HLA-identical sibling donors in Glanzmann's thrombasthenia. Alloimmunization against the missing platelet GPIIb/IIIa complex and severity of bleeding episodes may constitute sufficient criteria for allogeneic BMT after careful assessment of the risk-benefit of such a procedure, although this remains exceptional in this disease. Bone Marrow Transplantation (2000) 25, 327-330.
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Trasplante de Médula Ósea , Trombastenia/terapia , Adolescente , Plaquetas/inmunología , Niño , Femenino , Antígenos HLA/inmunología , Hemorragia , Humanos , Isoanticuerpos/sangre , Masculino , Núcleo Familiar , Linaje , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/inmunología , Trombastenia/sangre , Trombastenia/inmunologíaRESUMEN
Allogeneic bone marrow transplantation (BMT) is an effective treatment for Fanconi's anemia (FA) but it requires a dose reduction of alkylating agents used for conditioning because of the increased sensitivity of FA cells to DNA cross-linking agents. Oesophageal damage has not previously been described as a complication after allogeneic BMT for this indication. We report five cases of severe oesophagitis with stenosis in patients transplanted for FA. It occurred either early, or more surprisingly, several years after BMT and could have easily been misdiagnosed. It could be explained by hypersensitivity of the FA mucosal cells to cytotoxic agents despite the reduced doses of cyclophosphamide and irradiation or to non diagnosed congenital abnormalities of the oesophagogastric junction. However, the evolution of the oesophageal disease was favorable in all, and none of the patients developed secondary cancer. Awareness of this complication will lead to earlier diagnosis and treatment of oesophageal stenosis and related malnutrition.
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Trasplante de Médula Ósea/efectos adversos , Esofagitis/inducido químicamente , Anemia de Fanconi/complicaciones , Anemia de Fanconi/terapia , Adolescente , Adulto , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Alquilantes/efectos adversos , Niño , Preescolar , Constricción Patológica/inducido químicamente , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Esofagitis/diagnóstico , Esofagitis/patología , Femenino , Humanos , Masculino , Acondicionamiento Pretrasplante/efectos adversos , Trasplante Homólogo/efectos adversosRESUMEN
Umbilical cord blood (CB) constitutes a promising alternative to bone marrow for allogeneic transplantation and is most remarkable for the reduced severity of GVHD compared with bone marrow. We have shown that although naive the TCR beta-chain repertoire appears fully constituted at birth in terms of mean size of the complementarity-determining region 3 (CDR3) and of the usage of V and J gene segments. Its ability to respond to exogenous stimuli was tested with staphylococcal superantigens TSST-1 and SEA (toxin at 1 ng/ml for 4 days). The amount of TCR transcripts was quantified and the percentage of representation of each BV family was calculated. TSST-1 induced BV2 expansion in both adult and CB samples. SEA activation gave a more variable pattern among individuals (adults n = 6; CB n = 6). BV6, BV18, BV22 and BV24 were the most frequently expanded families. We did not observe notable differences in either the modification of the TCRBV repertoire or the kinetics of the response to SEA superantigen between adults and newborns. These data suggest that although naive, CB lymphocytes are as equally capable as adult lymphocytes of responding to superantigen stimulation.