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Practice of pediatric aphereses - in particular when caring for low-weight children - differs from the practice of adult aphereses, since pediatric aphereses represent low numbers of procedures, which has practical implications in terms of practical training and retraining for involved healthcare personnel, as needed for habilitation and validation of ongoing competencies. A specific training is mandatory in order to ensure both the child and the staff safety during and after collection, as well as ensure high quality of the collected cell product and that its meets predefined specifications that depend on its intended use. Low and very low-weight children deserve a particular attention for a number of procedural and clinical aspects: the nature and quality of venous accesses to ensure proper operation of the cell separator, management of hemodynamic fluctuations in relation with the relative importance of the extracorporeal blood volume as compared to the total blood volume of the child, risks and clinical manifestations of citrate toxicity, minimization of stress during the procedure that may include but is not limited to pharmacological sedation. The full spectrum of competencies needed to deal with these aspects is rarely present within a single team of healthcare professionals; it most often requires the tight combination of expertise drawing from the collection facility, the pediatric department and possibly the pediatric intensive care unit ward, whether from the same or from different institutions. Interactions must be formalized in a document that accurately describes which category of actors is responsible for each category of acts (prescriptions, decisions), depending on their initial qualifications, specific competencies, and affiliations.
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Introduction: Rituximab monotherapy represents the main therapeutic option for cryoglobulinemic vasculitis (CV) with severe organ involvement. However, initial worsening of the CV, known as rituximab-associated CV flare (=CV flare), has been described and are associated with high mortality rates. The aim of the present study is to evaluate the outcomes of plasmapheresis initiated before or during rituximab treatment, as prevention of CV flare. Methods: We conducted a retrospecttive study in our tertiary referral center from 2001 to 2020. We have included all patients with CV receiving rituximab and divided them in two groups whether they had flare prevention by plasmapheresis or not. We evaluated rituximab-related CV flare incidence in both groups. CV flare was defined as the onset of a new organ involvement or worsening of the initial manifestations within 4 weeks following rituximab. Results: Among the 71 patients included, 44 received rituximab without plasmapheresis (control = CT cohort) and 27 received plasmapheresis before or during rituximab treatment (preventive plasmapheresis = PP cohort). PP was given to patients thought to have a high risk of CV flare, with significantly more severe diseases than patients in the CT cohort. Despite this, no CV flare was observed in the PP group. In the other hand, 5 flares occurred in the CT cohort. Conclusion: Our results show that plasmapheresis is efficient and well tolerated to prevent rituximab-associated CV flare. We believe that our data support the use of plasmapheresis in this indication, especially in patients with high risk of CV flare.
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INTRODUCTION: Despite the implementation of new therapeutic agents, management of relapsed multiple myeloma (MM) remains a challenge. Salvage autologous hematopoietic cell transplant (AHCT) remains a valid therapeutic option for eligible patients who achieve prolonged response after a first AHCT. However, a second graft is not always available, and these patients may need a second mobilization. PATIENTS AND METHODS: This prospective, non-interventional, multicenter study aimed to collect data on the feasibility of salvage AHCT using a plerixafor-based hematopoietic cell mobilization in relapsed MM, according to the plerixafor label in France. Adult patients with relapsed MM eligible for a second AHCT and mobilized using granulocyte- colony stimulating factor (G-CSF) and plerixafor were included. RESULTS: Of the 23 patients, 17 achieved a successful hematopoietic cell mobilization and 13 were able to proceed to a second AHCT. Median age was 62.9 years (min-max 51-71). Ten patients (77%) were male. Eleven (85%) received AHCT as a third-line treatment or more. Median time between first and second AHCT was 5.4 years (range, 2.6-16.3). Among 18 evaluable patients, mobilization was successful for 17 (94%) of them [95% CI 84-100], with no reported side effects. Among the 13 patients who underwent salvage AHCT, the median time to engraftment was 14 days (min-max 11-29). One-year progression-free and overall survival were 88.9% [95% CI 43.3-98.4] and 100%, respectively. CONCLUSION: This study demonstrated that plerixafor allows safe and efficient mobilization in relapsed MM patients who are candidates for a salvage AHCT. TRIAL REGISTRATION: NCT02439476 Registered 8 May 2015, https://clinicaltrials.gov/ct2/show/NCT02439476 .
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Background: The prevalence, prognostic role, and diagnostic value of blood pressure in immune-mediated thrombotic thrombocytopenic purpura (iTTP) and other thrombotic microangiopathies (TMAs) remain unclear. Methods: Using a national cohort of iTTP (n = 368), Shigatoxin-induced hemolytic uremic syndrome (n = 86), atypical hemolytic uremic syndrome (n = 84), and hypertension-related thrombotic microangiopathy (n = 25), we sought to compare the cohort's blood pressure profile to assess its impact on prognosis and diagnostic performances. Results: Patients with iTTP had lower blood pressure than patients with other TMAs, systolic (130 [interquartile range (IQR) 118-143] vs 161 [IQR 142-180] mmHg) and diastolic (76 [IQR 69-83] vs 92 [IQR 79-105] mmHg, both p < 0.001). The best threshold for iTTP diagnosis corresponded to a systolic blood pressure <150 mmHg. iTTP patients presenting with hypertension had a significantly poorer survival (hazard ratio 1.80, 95% confidence interval 1.07-3.04), and this effect remained significant after multivariable adjustment (hazard ratio = 1.14, 95% confidence interval 1.00-1.30). Addition of a blood pressure criterion modestly improved the French clinical score to predict a severe A disintegrin and metalloprotease with thrombospondin type 1 deficiency in patients with an intermediate score (i.e., either platelet count <30 × 109/L or serum creatinine <200 µM). Conclusions: Elevated blood pressure at admission affects the prognosis of iTTP patients and may help discriminate them from other TMA patients. Particular attention should be paid to blood pressure and its management in these patients.
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Idiopathic purpura fulminans (IPF) is a rare but severe prothrombotic coagulation disorder that can occur after chickenpox or human herpesvirus 6 (HHV-6) infection. IPF leads to an autoantibody-mediated decrease in the plasma concentration of protein S. We conducted a retrospective multicenter study involving patients with IPF from 13 French pediatric centers and a systematic review of cases in published literature. Eighteen patients were included in our case series, and 34 patients were included as literature review cases. The median age was 4.9 years, and the diagnostic delay after the first signs of viral infection was 7 days. The lower limbs were involved in 49 patients (94%) with typical lesions. In all, 41 patients (78%) had a recent history of varicella-zoster virus infection, and 7 patients (14%) had been infected by HHV-6. Most of the patients received heparin (n = 51; 98%) and fresh frozen plasma transfusions (n = 41; 79%); other treatment options were immunoglobulin infusion, platelet transfusion, corticosteroid therapy, plasmapheresis, and coagulation regulator concentrate infusion. The antithrombin level and platelet count at diagnosis seemed to be associated with severe complications. Given the rarity of this disease, the creation of a prospective international registry is required to consolidate these findings.
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Varicela , Púrpura Fulminante , Varicela/complicaciones , Niño , Preescolar , Diagnóstico Tardío/efectos adversos , Humanos , Estudios Multicéntricos como Asunto , Estudios Prospectivos , Proteína S , Púrpura Fulminante/diagnóstico , Púrpura Fulminante/etiología , Púrpura Fulminante/terapia , Estudios RetrospectivosRESUMEN
CD19-directed CAR T-cells have been remarkably successful in treating patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and transformed follicular lymphoma (t-FL). In this cohort study, we treated 60 patients with axicabtagene ciloleucel or tisagenlecleucel. Complete and partial metabolic responses (CMR/PMR) were obtained in 40% and 23% of patients, respectively. After 6.9 months of median follow-up, median progression-free survival (mPFS) and overall survival (mOS) were estimated at 3.1 and 12.3 months, respectively. Statistical analyses revealed that CMR, PFS, and OS were all significantly associated with age-adjusted international prognostic index (aaIPI, p < 0.05). T-cell subset phenotypes in the apheresis product tended to correlate with PFS. Within the final product, increased percentages of both CD4 and CD8 CAR+ effector memory cells (p = 0.02 and 0.01) were significantly associated with CMR. Furthermore, higher CMR/PMR rates were observed in patients with a higher maximal in vivo expansion of CAR T-cells (p = 0.05) and lower expression of the LAG3 and Tim3 markers of exhaustion phenotype (p = 0.01 and p = 0.04). Thus, we find that aaIPI at the time of infusion, phenotype of the CAR T product, in vivo CAR T-cell expansion, and low levels of LAG3/Tim3 are associated with the efficacy of CAR T-cell therapy in DLBCL patients.
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CONTEXT: The management of systemic auto-immune diseases (SAID) -associated thrombotic microangiopathies (TMA) [SAID-TMA] remains debated. OBJECTIVES: To provide a demographic, clinical and therapeutic picture of SAID-TMA. METHODS: A cross-sectional analysis was conducted on adult patients presenting with SAID and TMA from the French National TMA Registry over a 20-year period. Clinical features were extracted and compared to those from a historical cohort of atypical haemolytic and uremic syndrome (aHUS) patients. RESULTS: Forty-one patients with SAID-TMA were compared to 78 patients with aHUS from a historical cohort. Connective tissue diseases (CTD) were systemic lupus erythematosus (n=18), primary Sjögren's syndrome (n=7), systemic sclerosis (n=11), mixed CTD (n=2) and 2 cases of vasculitides, including 7 overlapping forms and 8 cases of primary antiphospholipid syndromes (APLS). Patients with SAID-TMA generally had pre-existing chronic kidney failure (OR= 3.17, 95%CI: 1.204 to 7.923; p= 0.016) compared to aHUS patients, though creatinine levels were significantly lower (216 [IQR, 108-334] µmol/L vs. 368 [IQR, 170-722] µmol/L; p= 0.002). Patients were less likely to recover if renal replacement therapy was needed at onset (OR= 0.07; 0.02 to 0.34; p <0.0005). Two patients died. Thirty patients responded to immunosuppressive treatment and complete remission was achieved in 25 cases. By contrast, therapeutic plasma exchange (TPE) did not have an early effect on TMA features at Day-7 nor Day-15 (p >0.05). CONCLUSION: The management of SAID-TMA implies an early initiation of immunosuppressive drugs for flares of the associated SAID, whereas TPE seem ineffective. KEY MESSAGES.
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Síndrome Antifosfolípido , Lupus Eritematoso Sistémico , Microangiopatías Trombóticas , Adulto , Síndrome Antifosfolípido/complicaciones , Síndrome Antifosfolípido/epidemiología , Estudios Transversales , Humanos , Sistema de Registros , Microangiopatías Trombóticas/epidemiologíaRESUMEN
Chimeric antigen receptor (CAR) T-cells are a new class of cancer treatments manufactured through autologous or allogeneic T cells genetic engineering to induce CAR expression directed against a membrane antigen present at the surface of malignant cells. In Europe, tisagenlecleucel (Kymriah™) has a marketing authorization for the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia in children and young adults and for the relapsed/refractory diffuse large B-cell lymphoma (DLBCL). The marketing authorization for axicabtagene ciloleucel (Yescarta™) is the treatment of relapsed/refractory DLBCL and mediastinal B-cell lymphoma. Both products are "living drugs" and genetically modified autologous T cells directed against CD19 which is an antigen expressed throughout B lymphoid differentiation and on many B malignancies. This collaborative work - part of a series of expert works on the topic - aims to provide practical advice to assist collection facilities that procure the starting material i.e. blood mononuclear cells for autologous CAR T-cell manufacturing.
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Antígenos CD19/uso terapéutico , Comercio , Consenso , Inmunoterapia Adoptiva , Leucaféresis/métodos , Receptores de Antígenos de Linfocitos T/uso terapéutico , Adolescente , Productos Biológicos , Niño , Ingeniería Genética/métodos , Humanos , Leucemia de Células B/terapia , Linfoma de Células B Grandes Difuso/terapia , Neoplasias del Mediastino/terapia , Linfocitos T , Recolección de Tejidos y Órganos/métodos , Adulto JovenRESUMEN
Following an acute thrombotic thrombocytopenic purpura (TTP) episode, patients are at risk for relapse, and a careful long-term follow-up is needed. Adherence to the follow-up by patients implies a good understanding of the disease. However, TTP literacy in patients is currently unknown. To explore the TTP literacy in patients and identify factors associated with poor disease understanding, a questionnaire was developed focusing on patient's characteristics, knowledge about TTP and patients' actions in an emergency. The questionnaire was presented to 120 TTP patients in remission from the French National Registry for Thrombotic Microangiopathies. TTP literacy was low in 24%, intermediate in 43% and high in 33% of the patients. Low TTP literacy was associated with older age and low education level. Among the knowledge gaps identified, few patients knew that plasma exchange in acute phase is mandatory and has to be done daily (39%), 47% of participants did not consider themselves at risk for relapse, and 30% of women did not know that pregnancy exposes them to a greater risk of relapse. Importantly, few patients responded about life-saving actions in an emergency. Hence, the design of educational material should pay special attention to the age and education level of the target population focusing on the events leading to TTP, the importance of the emergency treatment, controllable predisposing factors for TTP development and patient attitude in an emergency.
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Donor lymphocyte infusion (DLI) is used to prevent or treat haematological malignancies relapse after allogeneic stem cell transplantation (allo-SCT). Recombinant human granulocyte colony-stimulated factor primed DLI (gDLI) is derived from frozen aliquots of the peripheral blood stem cell collection. We compared the efficacy and safety of gDLI and classical DLI after allo-SCT. We excluded haploidentical allo-SCT. Initial diseases were acute myeloblastic leukaemia (n = 45), myeloma (n = 38), acute lymphoblastic leukaemia (n = 20), non-Hodgkin lymphoma (n = 10), myelodysplasia (n = 8), Hodgkin lymphoma (n = 8), chronic lymphocytic leukaemia (n = 7), chronic myeloid leukaemia (n = 2) and osteomyelofibrosis (n = 1). Indications for DLI were relapse (n = 96) or pre-emptive treatment (n = 43). Sixty-eight patients had classical DLI and 71 had gDLI. The response rate was 38.2%, the 5-year progression-free survival (PFS) rate was 38% (29-48) and the 5-year overall survival (OS) rate was 37% (29-47). Graft versus host disease rate was 46.7% and 10.1% of patients died from toxicity. There were no differences between classical DLI and gDLI in terms of response (p = 0.28), 5-year PFS (p = 0.90), 5-year OS (p. 0.50), GvHD (p = 0.86), treated GvHD (p = 0.81) and cause of mortality (p. 0.14). In conclusion, this study points out no major effectiveness or toxicity of gDLI compared to classical DLI.
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Older age is associated with increased mortality in immune thrombotic thrombocytopenic purpura (iTTP). Yet, data are scarce regarding iTTP occurring among older patients. To assess clinical features and long-term impact of iTTP on mortality in older patients (>60 years old), characteristics and prognoses of adult iTTP patients enrolled in the French Reference Center for Thrombotic Microangiopathies registry between 2000 and 2016 were described according to age (<60 years old or ≥60 years old). Long-term mortality of iTTP older survivors was compared with that of non-iTTP geriatric subjects. Comparing, respectively, older iTTP patients (N = 71) with younger patients (N = 340), time from hospital admission to diagnosis was longer (P < .0001); at diagnosis, delirium (P = .034), behavior impairment (P = .045), renal involvement (P < .0001), and elevated troponin level (P = .025) were more important whereas cytopenias were less profound (platelet count, 22 × 103/mm3 [9-57] vs 13 × 103/mm3 [9-21], respectively [P = .002]; hemoglobin level, 9 g/dL [8-11] vs 8 g/dL [7-10], respectively [P = .0007]). Short- and mid-term mortalities were higher (P < .0001) and increased for every 10 years of age range. Age ≥60 years, cardiac involvement, increased plasma creatinine level, and total plasma exchange volume were independently associated with 1-month mortality. Compared with a non-iTTP geriatric population, older survivors showed an increased long-term mortality (hazard ratio = 3.44; P < .001). In conclusion, older iTTP patients have atypical neurological presentation delaying the diagnosis. Age negatively impacts short-term but also long-term mortality.
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Púrpura Trombocitopénica Idiopática/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores , Terapia Combinada , Comorbilidad , Manejo de la Enfermedad , Femenino , Francia/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Pronóstico , Vigilancia en Salud Pública , Púrpura Trombocitopénica Idiopática/diagnóstico , Púrpura Trombocitopénica Idiopática/mortalidad , Púrpura Trombocitopénica Idiopática/terapia , Sistema de Registros , Análisis de Supervivencia , Evaluación de SíntomasRESUMEN
Preemptive rituximab infusions prevent relapses in immune thrombotic thrombocytopenic purpura (iTTP) by maintaining normal ADAMTS13 activity. However, the long-term outcome of these patients and the potential adverse events of this strategy need to be determined. We report the long-term outcome of 92 patients with iTTP in clinical remission who received preemptive rituximab after identification of severe ADAMTS13 deficiency (activity <10%) during the follow-up. Thirty-seven patients had >1 iTTP episode, and the median cumulative relapse incidence before preemptive rituximab was 0.33 episode per year (interquartile range [IQR], 0.23-0.66). After preemptive rituximab, the median cumulative relapse incidence in the whole population decreased to 0 episodes per year (IQR, 0-1.32; P < .001). After preemptive rituximab, ADAMTS13 activity recovery was sustained in 34 patients (37%) during a follow-up of 31.5 months (IQR, 18-65), and severe ADAMTS13 deficiency recurred in 45 patients (49%) after the initial improvement. ADAMTS13 activity usually improved with additional courses of preemptive rituximab. In 13 patients (14%), ADAMTS13 activity remained undetectable after the first rituximab course, but retreatment was efficient in 6 of 10 cases. In total, 14 patients (15%) clinically relapsed, and 19 patients (20.7%) experienced benign adverse effects. Preemptive rituximab treatment was associated with a change in ADAMTS13 conformation in respondent patients. Finally, in the group of 23 historical patients with iTTP and persistently undetectable ADAMTS13 activity, 74% clinically relapsed after a 7-year follow-up (IQR, 5-11). In conclusion, persistently undetectable ADAMTS13 activity in iTTP during remission is associated with a higher relapse rate. Preemptive rituximab reduces clinical relapses by maintaining a detectable ADAMTS13 activity with an advantageous risk-benefit balance.
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Factores Inmunológicos/uso terapéutico , Púrpura Trombocitopénica Trombótica/tratamiento farmacológico , Rituximab/uso terapéutico , Prevención Secundaria/métodos , Proteína ADAMTS13/química , Proteína ADAMTS13/deficiencia , Proteína ADAMTS13/metabolismo , Adulto , Femenino , Humanos , Factores Inmunológicos/efectos adversos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Conformación Proteica/efectos de los fármacos , Púrpura Trombocitopénica Trombótica/metabolismo , Rituximab/efectos adversos , Resultado del TratamientoRESUMEN
Thrombotic thrombocytopenic purpura (TTP) has a devastating prognosis without adapted management. Sources of misdiagnosis need to be identified to avoid delayed treatment. We studied 84 patients with a final diagnosis of severe (<10%) acquired ADAMTS13 deficiency-associated TTP from our National database that included 423 patients, who had an initial misdiagnosis (20% of all TTP). Main diagnostic errors were attributed to autoimmune thrombocytopenia, associated (51%) or not (37%) with autoimmune hemolytic anemia. At admission, misdiagnosed patients were more frequently females (P = .034) with a history of autoimmune disorder (P = .017) and had organ involvement in 67% of cases; they had more frequently antinuclear antibodies (P = .035), a low/undetectable schistocyte count (P = .001), a less profound anemia (P = .008), and a positive direct antiglobulin test (DAT) (P = .008). In multivariate analysis, female gender (P = .022), hemoglobin level (P = .028), a positive DAT (P = .004), and a low schistocytes count on diagnosis (P < .001) were retained as risk factors of misdiagnosis. Platelet count recovery was significantly longer in the misdiagnosed group (P = .041) without consequence on mortality, exacerbation and relapse. However, patients in the misdiagnosed group had a less severe disease than those in the accurately diagnosed group, as evidenced by less organ involvement at TTP diagnosis (P = .006). TTP is frequently misdiagnosed with autoimmune cytopenias. A low schistocyte count and a positive DAT should not systematically rule out TTP, especially when associated with organ failure.
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Errores Diagnósticos , Púrpura Trombocitopénica Idiopática/diagnóstico , Púrpura Trombocitopénica Trombótica/diagnóstico , Proteína ADAMTS13/deficiencia , Adulto , Anemia Hemolítica Autoinmune/diagnóstico , Anticuerpos Antinucleares/análisis , Prueba de Coombs , Diagnóstico Diferencial , Femenino , Hemoglobinas/análisis , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Factores de Riesgo , Factores SexualesRESUMEN
Autoimmune thrombotic thrombocytopenic purpura (TTP) can be associated with other autoimmune disorders, but their prevalence following autoimmune TTP remains unknown. To assess the prevalence of autoimmune disorders associated with TTP and to determine risk factors for and the time course of the development of an autoimmune disorder after a TTP episode, we performed a cross sectional study. Two-hundred sixty-one cases of autoimmune TTP were included in the French Reference Center registry between October, 2000 and May, 2009. Clinical and laboratory data available at time of TTP diagnosis were recovered. Each center was contacted to collect the more recent data and diagnosis criteria for autoimmunity. Fifty-six patients presented an autoimmune disorder in association with TTP, 9 years before TTP (median; min: 2 yr, max: 32 yr) (26 cases), at the time of TTP diagnosis (17 cases) or during follow-up (17 cases), up to 12 years after TTP diagnosis (mean, 22 mo). The most frequent autoimmune disorder reported was systemic lupus erythematosus (SLE) (26 cases) and Sjögren syndrome (8 cases). The presence of additional autoimmune disorders had no impact on outcomes of an acute TTP or the occurrence of relapse. Two factors evaluated at TTP diagnosis were significantly associated with the development of an autoimmune disorder during follow-up: the presence of antidouble stranded (ds)DNA antibodies (hazard ratio (HR): 4.98; 95% confidence interval (CI) [1.64-15.14]) and anti-SSA antibodies (HR: 9.98; 95% CI [3.59-27.76]). A follow-up across many years is necessary after an acute TTP, especially when anti-SSA or anti-dsDNA antibodies are present on TTP diagnosis, to detect autoimmune disorders early before immunologic events spread to prevent disabling complications.
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Enfermedades Autoinmunes/etiología , Púrpura Trombocitopénica Trombótica/complicaciones , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Adulto JovenRESUMEN
Epstein-Barr virus reactivation (EBV-R) frequently occurs in patients having allogeneic hematopoietic stem cell transplantation (HSCT). We evaluated the impact of controlled EBV-R on survival of 190 patients (114M/76F, median age: 51 yr, range 18-69), having HSCT for hematological malignancies (105 acute leukemias and myelodysplasias, 71 lymphoproliferative disorders, 14 others). Overall survival (OS) and progression-free survival (PFS) were compared between patients with and without EBV-R. Of 138, patients had reduced-intensity conditioning regimen. Various stem cell sources (141 PB, 33 umbilical cord blood and 16 bone marrow) were used. Patients with EBV-R had longer PFS and OS than those without EBV-R: PFS at 2 yr 69% vs. 51% and at 5 yr 47% vs. 38% (P < 0.04); OS at 2 yr 76% vs. 64% and at 5 yr 63% vs. 47%) (P < 0.001). The use of rituximab had no impact on OS and PFS, but it reduced the intensity of GVHD, despite the fact that TRM was not significantly different between the two groups of patients. So, rituximab may have an additional effect to other factors on PFS and OS. In multivariate analysis, antithymocyte globulin administration was not a significant factor for PFS (P = 0.68) and for OS (P = 0.81). Circulating NK cells were significantly increased by 22% (P = 0.03) in EBV-R patients with no differences for other parameters. Controlled EBV-R in the setting of HSCT is associated with better OS and PFS, with a significant increase in circulating NK cells.
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Infecciones por Virus de Epstein-Barr/virología , Neoplasias Hematológicas/virología , Trasplante de Células Madre Hematopoyéticas , Herpesvirus Humano 4/fisiología , Acondicionamiento Pretrasplante , Activación Viral/fisiología , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Suero Antilinfocítico/uso terapéutico , Femenino , Enfermedad Injerto contra Huésped/prevención & control , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Hematológicas/inmunología , Neoplasias Hematológicas/mortalidad , Humanos , Factores Inmunológicos/uso terapéutico , Células Asesinas Naturales/inmunología , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Rituximab , Análisis de Supervivencia , Trasplante HomólogoRESUMEN
OBJECTIVE: The ADAM (a disintegrin and metalloproteinases) and the related ADAMTS (a disintegrin and metalloproteinases with thrombospondin) motifs metalloproteinases are membrane-anchored and secreted proteins exhibiting key roles in mediating cell adhesion, proteolytic shedding, and cell signaling. Dysregulation of these proteins has been observed in some pathologic states, including cancers. Their contribution to multiple myeloma, a plasma-cell neoplasia strongly dependent on bone marrow environment, has been poorly characterized. MATERIALS AND METHODS: We analyzed the expression of genes encoding for these proteins and their inhibitors (tissue inhibitor of metalloproteinases [TIMP], reversion-inducing cysteine-rich protein with kazal motifs) in normal B-cell differentiation, primary malignant plasma cells, human myeloma cell lines, and various bone marrow environment cells. The prognostic value of the expression of these genes was analyzed in two independent series of newly diagnosed patients. RESULTS: ADAM28 and ADAMTS6 were overexpressed in normal memory B cells, ADAM10 and ADAM19 in plasmablasts, and TIMP1 and TIMP2 in normal bone marrow plasma cells. ADAMTS9 was aberrantly expressed by primary malignant plasma cells and ADAM23 expression was associated with a bad prognosis, its expression being spiked in some primary myeloma cell samples. Bone marrow environment cells displayed distinct expression profiles for genes encoding for ADAMs and their inhibitors. They expressed ADAMTSs genes at a low level, with the exception of bone marrow stromal cells. CONCLUSIONS: This study provides an overview of expression data related to ADAMs and ADAMTSs genes potentially involved in myeloma pathogenesis.
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Proteínas ADAM/genética , Células de la Médula Ósea/metabolismo , Perfilación de la Expresión Génica , Mieloma Múltiple/genética , Células Plasmáticas/metabolismo , Células de la Médula Ósea/enzimología , Línea Celular , Humanos , Mieloma Múltiple/enzimología , Células Plasmáticas/citología , Células Plasmáticas/enzimología , Células Plasmáticas/patologíaRESUMEN
In mice, the plasma cell (PC) niche in the bone marrow is close to the haematopoietic stem cell (HSC) niche. We investigated whether PCs can be mobilized into the peripheral blood (PB) in healthy donors receiving granulocyte colony-stimulating factor (G-CSF) for the induction of HSC mobilization into the PB. G-CSF increased the count of circulating PCs 6-fold, that of circulating B lymphocytes 4-fold and that of circulating HSCs 44-fold. Mobilized circulating PCs comprised CD138(-) (62·2%) and CD138(+) (37·8%) PCs, the latter being more mature based on increased CD27, CD38 and cytoplasmic immunoglobulin expression. Mobilized PCs had a phenotype close to that of steady-state PB PCs or in vitro generated PCs, but they expressed L-selectin only weakly. Finally, a median value of 0·4 × 10(6) /kg donor PCs - one-thirtieth of the overall PC count in a healthy adult - was grafted into patients, which could contribute to immune memory recovery.
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Factor Estimulante de Colonias de Granulocitos/farmacología , Movilización de Célula Madre Hematopoyética/métodos , Células Madre Hematopoyéticas/citología , Células Plasmáticas/efectos de los fármacos , Adulto , Anciano , Animales , Linfocitos B/citología , Recuento de Células , Humanos , Ratones , Persona de Mediana Edad , Células Plasmáticas/citología , Donantes de Tejidos , Adulto JovenRESUMEN
High-dose melphalan (HDM) followed by autologous stem cell transplantation (ASCT) is a standard treatment for patients with multiple myeloma. However, lymphocyte reconstitution is impaired after HDM. Recent work has suggested that the lymphopenia period occurring after various immunosuppressive or chemotherapy treatments may provide an interesting opportunity for adoptive antitumor immunotherapy. The objective of this study was to determine an immunotherapy window after HDM and ASCT, evaluating T cell lymphopenia, and measuring circulating immune cytokine concentrations in patients with multiple myeloma. The counts of T cell subpopulations reached a nadir at day 8 post-ASCT (day 10 post-HDM) and recovered by day 30. IL-6, IL-7, and IL-15 plasma levels increased on a median day 8 post-ASCT, respectively, 35-fold, 8-fold, and 10-fold compared with pre-HDM levels (p < or = 0.05). The increases in IL-7 and IL-15 levels were inversely correlated to the absolute lymphocyte count, unlike monocyte or myeloid counts. Furthermore, we have shown that CD3 T cells present in the ASC graft are activated, die rapidly when they are cultured without cytokine in vitro, and that addition of IL-7 or IL-15 could induce their survival and proliferation. In conclusion, the early lymphodepletion period, occurring 4-11 d post-HDM and ASCT, is associated with an increase of circulating immune cytokines and could be an optimal window to enhance the survival and proliferation of polyclonal T cells present in the ASC autograft and also of specific antimyeloma T cells previously expanded in vitro.
Asunto(s)
Citocinas/sangre , Depleción Linfocítica/métodos , Melfalán/farmacología , Mieloma Múltiple/terapia , Proliferación Celular , Supervivencia Celular/inmunología , Femenino , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Factores Inmunológicos , Inmunoterapia Adoptiva , Cinética , Masculino , Persona de Mediana Edad , Linfocitos T/citología , Trasplante AutólogoRESUMEN
PURPOSE: We hypothesized that granulocyte-macrophage colony-stimulating factor (GM-CSF) could potentiate the clinical activity of rituximab given its individual and cooperative effects on Fc gamma RIIa- and Fc gamma RIIIa-expressing cells. A phase II clinical study combining GM-CSF and rituximab was initiated in patients with relapsed follicular lymphoma (FL) to determine the clinical and biologic responses, as well as safety of the combination. PATIENTS AND METHODS: Thirty three patients with relapsed FL were treated with GM-CSF 5 microg/kg/d on days 1 to 8 and rituximab 375 mg/m(2) on day 5 of each 21-day cycle for four cycles. Clinical response and tolerability were examined according to international criteria. Biologic monitoring included evaluation of immune cells involved in rituximab activity. RESULTS: Of 33 evaluated patients, a 70% overall response rate (complete response plus complete response unconfirmed, 45%) and a median progression-free survival (PFS) of 16.5 months were achieved. Outcome was influenced by the quality of response and the Follicular Lymphoma International Prognostic Index (FLIPI), where low- and intermediate-risk FLIPI groups were associated with significantly better PFS. After treatment there was a significant increase in granulocyte and monocyte counts. Examination of dendritic cell response showed an overall increase in plasmacytoid dendritic cells, especially in non-complete response patients, after treatment. Addition of GM-CSF did not impair tolerance to rituximab, and adverse events were rare and mild. DISCUSSION: GM-CSF plus rituximab results in high response rates, along with a tolerable safety profile in patients with relapsed or progressive FL. The improved efficacy over rituximab monotherapy may be due to increases seen in monocyte, granulocyte, and dendritic cell populations.