RESUMEN
OBJECTIVES: Patients with systemic lupus erythematosus (SLE) refractory to conventional immunosuppression suffer substantial morbidity and mortality due to active disease and treatment toxicity. Immunoablation followed by autologous stem cell transplantation (ASCT) is a novel therapeutic strategy that potentially offers new hope to these patients. METHODS: This retrospective survey reviews the efficacy and safety of ASCT in 28 SLE patients from eight centres reported to the European Group for Blood and Marrow Transplantation (EBMT) registry between 2001 and 2008. RESULTS: Median disease duration before ASCT was 52 (nine to 396) months, 25/28 SLE patients (89%) were female, age 29 (16-48) years. At the time of ASCT, eight (one to 11) American College of Rheumatology (ACR) diagnostic criteria for SLE were present and 17 (60%) patients had nephritis. Peripheral blood stem cells were mobilized with cyclophosphamide and granulocyte-colony stimulating factor in 93% of patients, and ex vivo CD34 stem cell selection was performed in 36%. Conditioning regimens were employed with either low (n = 10) or intermediate (18) intensities. With a median follow-up of 38 (one to 110) months after ASCT, the five-year overall survival was 81 ± 8%, disease-free survival was 29 ± 9%, relapse incidence (RI) was 56 ± 11% and non-relapse mortality was 15 ± 7%. Graft manipulation by CD34+ selection was associated with a lower RI (p = 0.001) on univariate analysis. There were five deaths within two years after ASCT: three caused by infection, one by secondary autoimmune disease and one by progressive SLE. CONCLUSIONS: Our data further support the concept of immunoablation and ASCT to re-induce long-term clinical and serologic remissions in refractory SLE patients even in the absence of maintenance therapy. This study also suggests a beneficial effect of ex vivo graft manipulation on prevention of relapses post-transplantation in SLE.
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Trasplante de Células Madre Hematopoyéticas , Lupus Eritematoso Sistémico/terapia , Adolescente , Adulto , Femenino , Encuestas de Atención de la Salud , Humanos , Masculino , Persona de Mediana Edad , Sistema de Registros , Estudios Retrospectivos , Prevención Secundaria , Trasplante Autólogo , Adulto JovenRESUMEN
OBJECTIVE: To report long-term results of a phase I/II study conducted in a single center in order to investigate the effect of hemopoietic stem cell transplantation (HSCT) in the treatment of multiple sclerosis (MS). METHODS: Clinical and MRI outcomes of 35 patients with aggressive MS treated with HSCT are reported after a median follow-up period of 11 (range 2-15) years. RESULTS: Disease progression-free survival (PFS) at 15 years is 44% for patients with active CNS disease and 10% for those without (p=0.01); median time to progression was 11 (95% confidence interval 0-22) and 2 (0-6) years. Improvements by 0.5-5.5 (median 1) Expanded Disability Status Scale (EDSS) points were observed in 16 cases lasting for a median of 2 years. In 9 of these patients, EDSS scores did not progress above baseline scores. Two patients died, at 2 months and 2.5 years, from transplant-related complications. Gadolinium-enhancing lesions were significantly reduced after mobilization but were maximally and persistently diminished post-HSCT. CONCLUSION: HSCT is not a therapy for the general population of patients with MS but should be reserved for aggressive cases, still in the inflammatory phase of the disease, and for the malignant form, in which it can be life-saving. HSCT has an impressive and sustained effect in suppressing disease activity on MRI. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that HSCT results in PFS rates of 25%. PFS rate was significantly better in patients with active MRI lesions; HSCT also resulted in a significant reduction in the number and volume of gadolinium-enhancing lesions on MRI.
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Encéfalo/cirugía , Trasplante de Células Madre Hematopoyéticas/métodos , Esclerosis Múltiple/terapia , Adulto , Encéfalo/diagnóstico por imagen , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Gadolinio , Humanos , Estimación de Kaplan-Meier , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/diagnóstico por imagen , Cintigrafía , Acondicionamiento Pretrasplante/métodos , Resultado del TratamientoRESUMEN
The chronic lymphocytic leukemia (CLL) immunoglobulin repertoire is uniquely characterized by the presence of stereotyped B-cell receptors (BCRs). A major BCR stereotype in CLL is shared by immunoglobulin G-switched cases utilizing the immunoglobulin heavy-chain variable 4-34 (IGHV4-34) gene. Increased titers of IGHV4-34 antibodies are detected in selective clinical conditions, including infection by B-cell lymphotropic viruses, particularly Epstein-Barr virus (EBV) and cytomegalovirus (CMV). In this context, we sought evidence for persistent activation by EBV and CMV in CLL cases expressing the IGHV4-34 gene. The study group included 93 CLL cases with an intentional bias for the IGHV4-34 gene. On the basis of real-time PCR results for CMV/EBV DNA, cases were assigned to three groups: (1) double-negative (59/93); (2) single-positive (CMV- or EBV-positive; 25/93); (3) double-positive (9/93). The double-negative group was characterized by heterogeneous IGHV gene repertoire. In contrast, a bias for the IGHV4-34 gene was observed in the single-positive group (9/25 cases; 36%). Remarkably, all nine double-positive cases utilized the IGHV4-34 gene; seven of nine cases expressed the major BCR stereotype as described above. In conclusion, our findings indicate that the interactions of CLL progenitor cells expressing distinctive IGHV4-34 BCRs with viral antigens/superantigens might facilitate clonal expansion and, eventually, leukemic transformation. The exact type, timing and location of these interactions remain to be determined.
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Citomegalovirus/fisiología , Herpesvirus Humano 4/fisiología , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/virología , Receptores de Antígenos de Linfocitos B/genética , Anciano , Linfocitos B/inmunología , Linfocitos B/patología , Estudios de Casos y Controles , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Genoma Viral , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Hipermutación Somática de Inmunoglobulina , Factores de Tiempo , Activación ViralRESUMEN
Malignant multiple sclerosis (MS) is a rare but clinically important subtype of MS characterized by the rapid development of significant disability in the early stages of the disease process. These patients are refractory to conventional immunomodulatory agents and the mainstay of their treatment is plasmapheresis or immunosuppression with mitoxantrone, cyclophosphamide, cladribine or, lately, bone marrow transplantation. We report on the case of a 17-year old patient with malignant MS who was treated with high-dose chemotherapy plus anti-thymocyte globulin followed by autologous stem cell transplantation. This intervention resulted in an impressive and long-lasting clinical and radiological response. It is concluded that intensive immunosuppression followed by autologous stem cell transplantation is a viable therapeutic option in patients with malignant MS unresponsive to conventional forms of treatment.
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Esclerosis Múltiple/terapia , Recuperación de la Función , Trasplante de Células Madre , Adolescente , Suero Antilinfocítico/uso terapéutico , Terapia Combinada , Humanos , Inmunosupresores/uso terapéutico , Imagen por Resonancia Magnética , Masculino , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/patología , Trasplante AutólogoRESUMEN
Natalizumab (Tysabri) (anti-VLA4) is a novel agent for treatment of relapsing multiple sclerosis (MS) [Polman C.H., O'Connor P.W., Havrdova E. et al., 2006. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med. 354, 899-910.]. Controlled trials have shown considerable efficacy in preventing relapses, in excess of that seen for other EMEA-approved disease modulating drugs. While well-tolerated and generally safe, three cases of progressive multifocal leukoencephalopathy (PML) occurred in the context of 3 clinical trials encompassing some 3300 patients using this drug in multiple sclerosis and Crohn's disease. Immune compromised patients, such as those receiving immunosuppressive medications, are at a higher risk of developing PML. Natalizumab was recently approved for the treatment of relapsing forms of MS. This includes patients who had an inadequate response to other therapies and some of these patients will have already received immunosuppressants. These agents have the potential to cause prolonged effects on the immune system, even after dosing has been discontinued. Determining that these patients are not immunocompromised will be an important safety issue to consider prior to the initiation of natalizumab therapy. This short report summarizes interdisciplinary practical recommendations from specialists in neuroimmunology, rheumatology, transplantation medicine and clinical immunology.
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Anticuerpos Monoclonales/uso terapéutico , Factores Inmunológicos/uso terapéutico , Esclerosis Múltiple/terapia , Guías de Práctica Clínica como Asunto , Anticuerpos Monoclonales Humanizados , Humanos , NatalizumabRESUMEN
Melphalan-based autologous stem cell transplant (Mel-ASCT) is a standard therapy for multiple myeloma, but is associated with severe oral mucositis (OM). To identify predictors for severe OM, we studied 381 consecutive newly diagnosed myeloma patients who received Mel-ASCT. Melphalan was given at 200 mg/m2 body surface area (BSA), reduced to 140 mg/m2 for serum creatinine >3 mg/dl. Potential covariates included demographics, pre-transplant serum albumin and renal and liver function tests, and mg/kg melphalan dose received. The BSA dosing resulted in a wide range of melphalan doses given (2.4-6.2 mg/kg). OM developed in 75% of patients and was severe in 21%. Predictors of severe OM in multiple logistic regression analyses were high serum creatinine (odds ratio (OR)=1.581; 95% confidence interval (CI): 1.080-2.313; P=0.018) and high mg/kg melphalan (OR=1.595; 95% CI: 1.065-2.389; P=0.023). An OM prediction model was developed based on these variables. We concluded that BSA dosing of melphalan results in wide variations in the mg/kg dose, and that patients with renal dysfunction who are scheduled to receive a high mg/kg melphalan dose have the greatest risk for severe OM following Mel-ASCT. Pharmacogenomic and pharmacokinetic studies are needed to better understand interpatient variability of melphalan exposure and toxicity.
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Melfalán/efectos adversos , Mieloma Múltiple/tratamiento farmacológico , Agonistas Mieloablativos/efectos adversos , Estomatitis/inducido químicamente , Acondicionamiento Pretrasplante/efectos adversos , Adulto , Anciano , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Femenino , Glucosa Oxidasa/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Incidencia , Enfermedades Renales/complicaciones , Lactoperoxidasa/uso terapéutico , Masculino , Melfalán/administración & dosificación , Persona de Mediana Edad , Modelos Teóricos , Muramidasa/uso terapéutico , Agonistas Mieloablativos/administración & dosificación , Valor Predictivo de las Pruebas , Análisis de Regresión , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Estomatitis/epidemiología , Estomatitis/etiología , Acondicionamiento Pretrasplante/métodos , Trasplante Autólogo/efectos adversosRESUMEN
We evaluated the risk factors for infection of 367 consecutive myeloma patients who underwent high-dose melphalan and autologous stem cell transplantation (ASCT). Examination of bone marrow iron stores (BMIS) prior to ASCT was used to evaluate body iron stores. Other variables included age, sex, active smoking, myeloma remission status, severity of mucositis and duration of severe neutropenia post-ASCT (<100 absolute neutrophils counts (ANC)/microl). Median age was 56 years; 61% of patients were males. 140 episodes of severe infections occurred in 116 patients, including bacteremia (73), pneumonia (40), severe colitis (25) and bacteremia with septic shock (two). The infection incidence per 1,000 days at risk was 45.2. Pre-ASCT risk factors for severe infection by univariate analysis were increased BMIS (OR=2.686; 95% CI 1.707-4.226; P<0.0001), smoking (OR=1.565; 95% CI 1.005-2.437; P=0.0474) and male gender (OR=1.624; 95% CI 1.019-2.589; P=0.0414). Increased BMIS (OR=2.716; 95% CI 1.720-4.287; P<0.0001) and smoking (OR=1.714; 95% CI 1.081-2.718; P=0.022) remained significant by multivariate analysis. Duration of ANC <100 micro/l (OR=1.129; 95% CI 1.039-1.226; P=0.0069 and OR=1.127; 95% CI 1.038-1.224; P=0.0045 by both univariate and multivariate analysis, respectively) was the only post-ASCT risk factor for infection. Increased pre-transplant BMIS and smoking are significant predictors of severe infection after myeloablative chemotherapy followed by ASCT in myeloma patients.
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Infecciones/epidemiología , Sobrecarga de Hierro/complicaciones , Mieloma Múltiple/terapia , Trasplante de Células Madre/efectos adversos , Talidomida/uso terapéutico , Análisis de Varianza , Inhibidores de la Angiogénesis/uso terapéutico , Femenino , Humanos , Sobrecarga de Hierro/etiología , Masculino , Persona de Mediana Edad , Mieloma Múltiple/tratamiento farmacológico , Análisis MultivarianteRESUMEN
To identify a correlation between metaphase cytogenetics and relapse after reduced intensity conditioning (RIC) allotransplant for patients with multiple myeloma, data on 60 patients (median age 52) who received grafts from a sibling (n = 49) or unrelated donor (n = 11) were analyzed. Fifty-three patients (88%) showed chromosomal abnormalities (CA) before the allotransplant, including 42 with abnormalities involving 13q (CA13). Twenty-two patients (41%) relapsed post-allotransplant at a median of 165 days. Of these, 11 patients showed abnormal cytogenetics at the time of post-allotransplant relapse at a median of 167 days. Of 54 patients who developed graft-versus-host disease, relapse occurred in 19 of 48 patients (43%) with CA present before RCI allotransplant, versus 1 of 6 without CA (17%) (P = 0.06). Loss of CA before RIC allotransplant and disease status > PR after RIC allotransplant were significantly associated with a lower risk of post-allotransplant relapse with cytogenetic abnormalities; 5.2 vs 36%, and 18 vs 53%, (both P < 0.05), respectively. The current data suggests that myeloma associated with persistent clonal cytogenetic abnormalities is an entity which most likely escapes the effects of a graft versus myeloma activity, maybe because of acquisition of resistance to immunologic manipulations.
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Aberraciones Cromosómicas , Mieloma Múltiple/genética , Mieloma Múltiple/terapia , Acondicionamiento Pretrasplante/métodos , Escape del Tumor/genética , Adulto , Anciano , Células Clonales/patología , Femenino , Efecto Injerto vs Tumor/genética , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Masculino , Metafase , Persona de Mediana Edad , Mieloma Múltiple/patología , Recurrencia , Análisis de Supervivencia , Trasplante HomólogoRESUMEN
The duration of neutropenia (absolute neutrophil count (ANC) < or = 100/microl) identifies cancer patients at risk for infection. A test that precedes ANC > or = 100/microl would be of clinical value. The immature reticulocyte fraction (IRF) reflects erythroid engraftment and hence a recovering marrow. We evaluated the IRF as predictor of marrow recovery among 90 myeloma patients undergoing their first and second (75 patients) melphalan-based autologous stem cell transplantation (Mel-ASCT). The time to IRF doubling (IRF-D) preceded ANC > or = 100/microl in 99% of patients after the first Mel-ASCT by (mean+/-s.d.) 4.23+/-1.96 days and in 97% of the patients after the second Mel-ASCT by 4.11+/-1.95 days. We validated these findings in a group of 117 myeloma patients and 99 patients with various disorders undergoing ASCT with different conditioning regimens. We also compared the time to hypophosphatemia and to absolute monocyte count > or = 100/microl to the time to ANC > or = 100/microl. These markers were reached prior to this ANC end point in 55 and 25% of patients but were almost always preceded by IRF-D. We conclude that the IRF-D is a simple, inexpensive and widely available test that can predict marrow recovery several days before ANC> or = 100/microl.
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Trasplante de Células Madre Hematopoyéticas , Mieloma Múltiple/terapia , Neutropenia/terapia , Neutrófilos/patología , Recuento de Reticulocitos/métodos , Estudios de Cohortes , Humanos , Cinética , Mieloma Múltiple/diagnóstico , Valor Predictivo de las Pruebas , Recuperación de la Función , Estudios Retrospectivos , Trasplante AutólogoRESUMEN
Over the last decade, hematopoietic stem cells transplantation (HSCT) has been increasingly used in the treatment of severe progressive autoimmune diseases. We report a retrospective survey of 183 multiple sclerosis (MS) patients, recorded in the database of the European Blood and Marrow Transplantation Group (EBMT). Transplant data were available from 178 patients who received an autologous graft. Overall, transplant related mortality (TRM) was 5.3% and was restricted to the period 1995-2000, with no further TRM reported since then. Busulphan-based regimens were significantly associated with TRM. Clinical status at the time of transplant and transplant techniques showed some correlations with toxicity. No toxic deaths were reported among the 53 patients treated with the BEAM (carmustine, etoposide, cytosine-arabinoside, melphalan)/antithymocyte globulin (ATG) regimen without graft manipulation, irrespective of their clinical condition at the time of the transplant. Improvement or stabilization of neurological conditions occurred in 63% of patients at a median follow-up of 41.7 months, and was not associated with the intensity of the conditioning regimen. In this large series, HSCT was shown as a promising procedure to slow down progression in a subset of patients affected by severe, progressive MS; the safety and feasibility of the procedure can be significantly improved by appropriate patient selection and choice of transplant regimen.
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Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/mortalidad , Esclerosis Múltiple Crónica Progresiva/mortalidad , Esclerosis Múltiple Crónica Progresiva/terapia , Adolescente , Adulto , Bases de Datos Factuales , Evaluación de la Discapacidad , Progresión de la Enfermedad , Europa (Continente) , Femenino , Estudios de Seguimiento , Movilización de Célula Madre Hematopoyética/efectos adversos , Movilización de Célula Madre Hematopoyética/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Crónica Progresiva/fisiopatología , Sistema de Registros , Estudios Retrospectivos , Análisis de Supervivencia , Trasplante AutólogoRESUMEN
Although high-dose therapy and autologous stem cell transplant (ASCT) is superior to conventional chemotherapy for treatment of myeloma, most patients relapse and the time to relapse depends upon the initial prognostic factors. The administration of non-cross-resistant chemotherapies during the post-transplant period may delay or prevent relapse. We prospectively studied the role of consolidation chemotherapy (CC) after single autologous peripheral blood stem cell transplant (auto-PBSCT) in 103 mostly newly diagnosed myeloma patients (67 patients were < or =6 months from the initial treatment). Patients received conditioning with BCNU, melphalan+/-gemcitabine and auto-PBSCT followed by two cycles of the DCEP+/-G regimen (dexamethasone, cyclophosphamide, etoposide, cisplatin+/-gemcitabine) at 3 and 9 months post-transplant and alternating with two cycles of DPP regimen (dexamethasone, cisplatin, paclitaxel) at 6 and 12 months post-transplant. With a median follow-up of 61.2 months, the median event-free survival (EFS) and overall survival (OS) are 26 and 54.1 months, respectively. The 5-year EFS and OS are 23.1 and 42.5%, respectively. Overall, 51 (49.5%) patients finished all CC, suggesting that a major limitation of this approach is an inability to deliver all planned treatments. In order to improve results following autotransplantation, novel agents or immunologic approaches should be studied in the post-transplant setting.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Mieloma Múltiple/terapia , Trasplante de Células Madre de Sangre Periférica , Acondicionamiento Pretrasplante , Adulto , Anciano , Cisplatino , Terapia Combinada/métodos , Ciclofosfamida , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Dexametasona , Supervivencia sin Enfermedad , Etopósido , Femenino , Estudios de Seguimiento , Humanos , Inmunosupresores/administración & dosificación , Masculino , Melfalán/administración & dosificación , Persona de Mediana Edad , Mieloma Múltiple/mortalidad , Agonistas Mieloablativos/administración & dosificación , Estudios Prospectivos , Trasplante Autólogo , GemcitabinaRESUMEN
Bone marrow (BM) stem cell reserves and function and stromal cell hematopoiesis supporting capacity were evaluated in 15 patients with multiple sclerosis (MS) and 61 normal controls using flow cytometry, clonogenic assays, long-term BM cultures (LTBMCs) and enzyme-linked immunosorbent assays. MS patients displayed normal CD34+ cell numbers but a low frequency of colony-forming cells (CFCs) in both BM mononuclear and purified CD34+ cell fractions, compared to controls. Patients had increased proportions of activated BM CD3+/HLA-DR+ and CD3+/CD38+ T cells that correlated inversely with CFC numbers. Patient BM CD3+ T cells inhibited colony formation by normal CD34+ cells and patient CFC numbers increased significantly following immunomagnetic removal of T cells from BMMCs, suggesting that activated T cells may be involved in the defective clonogenic potential of hematopoietic progenitors. Patient BM stromal cells displayed normal hematopoiesis supporting capacity indicated by the CFC number in the nonadherent cell fraction of LTBMCs recharged with normal CD34+ cells. Culture supernatants displayed normal stromal derived factor-1 and stem cell factor/kit ligand but increased flt-3 ligand levels. These findings provide support for the use of autologous stem cell transplantation in MS patients. The low clonogenic potential of BM hematopoietic progenitors probably reflects the presence of activated T cells rather than an intrinsic defect.
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Células de la Médula Ósea/citología , Células Madre Hematopoyéticas/citología , Esclerosis Múltiple/terapia , Trasplante de Células Madre/métodos , Células del Estroma/citología , ADP-Ribosil Ciclasa 1/biosíntesis , Adulto , Antígenos CD34/biosíntesis , Enfermedades Autoinmunes/terapia , Células de la Médula Ósea/metabolismo , Complejo CD3/biosíntesis , Células Cultivadas , Citocinas/metabolismo , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Antígenos HLA-DR/biosíntesis , Sistema Hematopoyético/inmunología , Humanos , Separación Inmunomagnética , Leucocitos Mononucleares/metabolismo , Linfocitos/citología , Masculino , Persona de Mediana Edad , Modelos Estadísticos , Células Madre/citología , Linfocitos T/citología , Factores de TiempoRESUMEN
PURPOSE: Correctly identifying infection in cancer patients can be challenging. Limited data suggest that positron emission tomography (PET) using fluorine-18 fluorodeoxyglucose (FDG) may be useful for diagnosing infection. To determine the role of FDG-PET in the diagnosis of infection in patients with multiple myeloma (MM). PATIENTS AND METHODS: The medical records of 248 patients who had FDG-PET performed for MM staging or infection work-up revealing increased uptake at extramedullary sites and/or bones and joints that would be atypical for MM between October 2001 and May 2004 were reviewed to identify infections and evaluate FDG-PET contribution to patient outcome. RESULTS: One hundred sixty-five infections were identified in 143 adults with MM. Infections involved the respiratory tract [99; pneumonia (93), sinusitis (six)], bone, joint and soft tissues [26; discitis (10), osteomyelitis (nine), septic arthritis (one), cellulitis (six)], vascular system [18; septic thrombophlebitis (nine), infection of implantable catheter (eight), septic emboli (one)], gastrointestinal tract [12; colitis (seven), abdominal abscess (three), and diverticulitis and esophagitis (one each)], and dentition [periodontal abscess (10)]. Infections were caused by bacteria, mycobacteria, fungi, and viruses. FDG-PET detected infection even in patients with severe neutropenia and lymphopenia (30 episodes). The FDG-PET findings identified infections not detectable by other methods (46 episodes), determined extent of infection (32 episodes), and led to modification of work-up and therapy (55 episodes). Twenty silent, but clinically relevant, infections were detected among patients undergoing staging FDG-PET. CONCLUSION: In patients with MM, FDG-PET is a useful tool for diagnosing and managing infections even in the setting of severe immunosuppression.
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Fluorodesoxiglucosa F18 , Artropatías/diagnóstico por imagen , Mieloma Múltiple/diagnóstico por imagen , Radiofármacos , Infecciones de los Tejidos Blandos/diagnóstico por imagen , Tomografía Computarizada de Emisión , Adulto , Anciano , Antibacterianos/uso terapéutico , Femenino , Humanos , Artropatías/microbiología , Masculino , Registros Médicos , Persona de Mediana Edad , Mieloma Múltiple/microbiología , Estudios Retrospectivos , Infecciones de los Tejidos Blandos/microbiología , Factores de TiempoRESUMEN
Malignant pleural effusion (MPE) in multiple myeloma (MM) is rare. Approximately 80 cases have been reported. To delineate optimal treatment and prognostic variables in these patients, we reviewed 11 MM patients with MPE. MPE developed at median of 12 months from diagnosis of MM. All the patients had high-risk disease based on complex karyotypic abnormalities including deletions of chromosome-13 (n=9), elevated beta-2 microglobulin (B2M) (n=9), high C-reactive protein (CRP) (n=8), high plasma cell labeling index (n=5) or high LDH (n=5). A significant increase in B2M, LDH, and CRP was observed at the onset of MPE. The initial diagnosis of MPE was based on positive cytology (n=9), pleural fluid cIg/DNA (n=9) or pleural fluid cytogenetics (n=4). Pleural tissue infiltration was found on pleural biopsy and autopsy in one patient each. Systemic chemotherapy comprising dexamethasone, cyclophosphamide, etoposide and cisplatin (DCEP) (n=7) and pleurodesis (n=7) were effective in resolving MPE but survival was short. High dose chemotherapy with peripheral blood stem cell support for MPE in six patients conferred no clear survival advantage. These patients died at median of four months from onset of MPE. Patients with bone marrow complex karyotypic abnormalities including deletion-13 (n=9) had a shorter (median--18 months) overall survival compared to patients with normal cytogenetics (median--38 months). MPE in patients with MM is often associated with high-risk disease including deletion 13 chromosomal abnormality and heralds a poor prognosis despite aggressive local and systemic treatment.
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Proteína C-Reactiva/metabolismo , L-Lactato Deshidrogenasa/metabolismo , Mieloma Múltiple/complicaciones , Mieloma Múltiple/diagnóstico , Derrame Pleural Maligno/complicaciones , Derrame Pleural Maligno/diagnóstico , Microglobulina beta-2/metabolismo , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Diagnóstico Diferencial , Femenino , Estudios de Seguimiento , Humanos , Cariotipificación , Masculino , Persona de Mediana Edad , Mieloma Múltiple/tratamiento farmacológico , Derrame Pleural Maligno/tratamiento farmacológico , Valor Predictivo de las Pruebas , Pronóstico , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
The value of serum C-reactive protein (CRP) levels as a predictor of complications in neutropenic patients needs to be further defined. We sought to identify an association between severe complications and daily CRP levels measured in 104 multiple myeloma patients during the 3 week period following high-dose melphalan and autologous transplant. Significantly higher mean CRP levels and CRP velocity of increase were observed among patients with severe complications. A cut-off point of 100 mg/l (CRP levels) and 15 mg/l/day (CRP velocity) identified patients likely to suffer severe complications with 86 and 75% sensitivity, respectively. Prospective validation of this model is currently underway.
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Proteína C-Reactiva/metabolismo , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Mieloma Múltiple/complicaciones , Proteína C-Reactiva/análisis , Esquema de Medicación , Quimioterapia Combinada , Humanos , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/terapia , Estudios Prospectivos , Análisis de Regresión , Estudios Retrospectivos , Factores de Riesgo , Sensibilidad y EspecificidadRESUMEN
Experimental data and early phase I/II studies suggest that high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (HSCT) can arrest progression of severe autoimmune diseases. We have evaluated the toxicity and disease response in 473 patients with severe autoimmune disease treated with autologous HSCT between 1995 and 2003, from 110 centers participating in the European Group for Blood and Marrow Transplantation (EBMT) autoimmune disease working party database. Survival, transplant-related mortality, treatment response and disease progression were assessed. In all, 420 patients (89%; 86+/-4% at 3 years, median follow-up 20 months) were alive, 53 (11%) had died from transplant-related mortality (N=31; 7+/-3% at 3 years) or disease progression (N=22; 9+/-4% at 3 years). Of 370 patients, 299 evaluable for response (81%) showed a treatment response, which was sustained in 213 (71% of responders). Response was associated with disease (P<0.001), was better in patients who received cyclophosphamide during mobilization (relative risk (RR)3.28 (1.57-6.83)) and was worse with increasing age (>40 years, RR0.29 (0.11-0.82)). Disease progression was associated with disease (P<0.001) and conditioning intensity (high intensity, RR1; intermediate intensity, RR1.81 (0.96-3.42)); low intensity, RR2.34 (1.074-5.11)). These data from the collective EBMT experience support the hypothesis that autologous HSCT can alter disease progression in severe autoimmune disease.
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Enfermedades Autoinmunes/terapia , Trasplante de Médula Ósea , Trasplante de Células Madre de Sangre Periférica , Enfermedades Autoinmunes/mortalidad , Trasplante de Médula Ósea/métodos , Trasplante de Médula Ósea/mortalidad , Ciclofosfamida/administración & dosificación , Femenino , Supervivencia de Injerto , Movilización de Célula Madre Hematopoyética/métodos , Humanos , Inmunosupresores/administración & dosificación , Masculino , Trasplante de Células Madre de Sangre Periférica/métodos , Trasplante de Células Madre de Sangre Periférica/mortalidad , Acondicionamiento Pretrasplante , Trasplante AutólogoRESUMEN
Two novel chromosomal translocations were identified in 2 patients with chronic lymphocytic leukemia (CLL). Case 1: 60 year-old male, stage Rai 0/Binet A, with mutated immunoglobulin heavy (IgH) and lambda (Iglambda) light chain genes; karyotype: 46, XY, t(9;12)(q12;p11) [3]/ 46, XY [22]. Case 2: 56 year-old male, stage Rai 2/Binet B, with mutated IgH and unmutated Iglambda genes; karyotype: 46, XY, add(10)(q26), t(13;18)(q14;q21) [8]/ 46, XY [27]. Although both translocations are novel, the involved breakpoints (especially 13q14 and 18q21) have been reported to participate in various aberrations in CLL patients. Aberrations affecting bands 9q12 and 12p11, as in case 1, are generally rare.
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Cromosomas Humanos/genética , Leucemia Linfocítica Crónica de Células B/genética , Translocación Genética/genética , Humanos , Cariotipificación , Masculino , Persona de Mediana EdadRESUMEN
High-dose treatment (HDT) with autologous stem cell transplant(s) (ASCT) improved survival, when compared to standard treatment, in multiple myeloma patients. Although the superiority of HDT is clearly recognized by the medical community, what is less appreciated is the disproportionate benefit enjoyed (as a result of this approach) by various patient subgroups. As the clinical heterogeneity of myeloma can be currently traced to its underlying genetic features, prognostically different patient groups can be identified largely based on the presence of adverse cytogenetic abnormalities and high serum levels of lactate dehydrogenase at baseline (high-risk features). While HDT applied to high-risk patients leads to modest survival gains, the same treatment, as the backbone of a comprehensive approach, can be curative in a minority of low-risk patients. A third group of low-risk patients will enjoy rather prolonged (10-year) survival, interrupted, however, by responsive relapses. In a manner analogous to follicular lymphoma, this latter group may transform to a more aggressive disease, characterized by the new acquisition of adverse cytogenetic abnormalities. Improving the complete response rate in these patients, by integrating newer therapeutic agents, may increase their cure rate. Currently non-myeloablative, allogeneic transplants (and possibly proteasome inhibitors) are the most promising approaches for high-risk patients.
Asunto(s)
Mieloma Múltiple/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Humanos , Mieloma Múltiple/mortalidad , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Autologous haematopoietic stem cell transplantation is now a feasible and effective treatment for selected patients with severe autoimmune diseases. Worldwide, over 650 patients have been transplanted in the context of phase I and II clinical trials. The results are encouraging enough to begin randomised phase III trials. However, as predicted, significant transplant-related morbidity and mortality have been observed. This is primarily due to complications related to either the stage of the disease at transplant or due to infections. The number of deaths related to cardiac toxicity is low. However, caution is required when cyclophosphamide or anthracyclines such as mitoxantrone are used in patients with a possible underlying heart damage, for example, systemic sclerosis patients. In November 2002, a meeting was held in Florence, bringing together a number of experts in various fields, including rheumatology, cardiology, neurology, pharmacology and transplantation medicine. The object of the meeting was to analyse existing data, both published or available, in the European Group for Blood and Marrow Transplantation autoimmune disease database, and to propose a safe approach to such patients. A full cardiological assessment before and during the transplant emerged as the major recommendation.