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1.
Bone Marrow Transplant ; 52(5): 717-725, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-28092349

RESUMEN

Improving haematopoietic cell transplantation outcomes by selection of an HLA-matched unrelated donor is best practice; however, donor selection by secondary characteristics is controversial. We studied 1271 recipients with haematological malignancies who underwent T-cell-depleted allografts and had complete data on HLA-matching status for six loci (HLA-A, -B, -C, -DRB1, -DQB1, -DPB1) and clinical outcome data. Five-year overall survival was 40.6%. HLA mismatching (at HLA-A, -B, -C, -DRB1, -DQB1) relative risk (RR) 1.22, 95% confidence interval (CI) 1.2-1.5, P=0.033 for 1 mismatch and RR 1.46, 95% CI 1.1-1.9, P=0.009 for >1 mismatch) and CMV mismatching (RR 1.37, 95% CI 1.2-1.6, P<0.001) were significantly associated with inferior survival. Donors aged <30 years showed a trend towards better survival. The multivariate model for mortality, combining CMV and HLA-match status, found an RR of 1.36 (95% CI 1.1-1.7, P=0.003) for HLA matched/CMV mismatched, an RR of 1.22 (95% CI 0.99-1.5, P=0.062) for HLA mismatched/CMV matched and an RR of 1.81 (95% CI 1.4-2.3, P=<0.001) for HLA/ CMV mismatched, compared with the HLA/CMV-matched recipients. These data suggest that HLA and CMV matching status should be considered when selecting unrelated donors and that CMV matching may abrogate the effect of an HLA mismatch.


Asunto(s)
Citomegalovirus/inmunología , Antígenos HLA/inmunología , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Donante no Emparentado/provisión & distribución , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Histocompatibilidad , Humanos , Depleción Linfocítica , Masculino , Persona de Mediana Edad , Factores de Riesgo , Pruebas Serológicas , Análisis de Supervivencia , Adulto Joven
3.
Bone Marrow Transplant ; 50(2): 244-7, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25387092

RESUMEN

Discrepancies exist between the care of unrelated donors (UDs) and related donors (RDs), particularly regarding medical suitability criteria, consenting procedures and donor follow-up. Changes to the most recent JACIE standards have addressed these issues. We studied 208 RDs who underwent PBSC or BM donation in a single centre during 2004-2013 to determine the impact of regulatory changes on donor care, and assessed the safety and efficacy of stem cell donation in donors not meeting UD medical suitability criteria. We observed significant improvements in donor consenting procedures (P=0.003) and donor follow-up (P=0.007) after stipulations in these areas were introduced. We saw a higher incidence of serious adverse events (SAEs) in RDs not meeting UD suitability criteria (P=0.018), and a higher incidence of SAEs in donors ⩾60 years (P=0.020). Haematopoietic progenitor cell donation is less safe in RDs who do not meet UD criteria for medical suitability. Although changes to JACIE standards have improved practice, development of specific medical suitability for RDs and guidelines around 'grey areas' where risks to a donor are unclear or theoretical, will be important in improving RD safety and standardising practice.


Asunto(s)
Médula Ósea , Selección de Donante/normas , Trasplante de Células Madre de Sangre Periférica , Donante no Emparentado , Anciano , Humanos , Persona de Mediana Edad
4.
Bone Marrow Transplant ; 49(5): 704-8, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24566709

RESUMEN

There are few prospective studies evaluating the role of extracorporeal photopheresis (ECP) in chronic GVHD (cGVHD) and only occasional reports of the effect of ECP on patients' quality of life (QoL). We report a single-centre prospective study of patients undergoing fortnightly ECP for moderate or severe cGVHD. Response was assessed after 6 months of treatment using NIH scoring criteria and reduction in immunosuppression. QoL assessments were undertaken at baseline and at 6 months using the chronic GVHD symptom scale (cGVHD SS) and dermatology life quality index (DLQI). An intention-to-treat analysis showed that 19/38 (50%) of patients had a complete or partial response. Twenty-seven out of 38 patients completed 6 months of ECP treatment and 70% (19/27) had a complete or partial response. Eighty per cent of patients who completed 6 months of ECP treatment had a reduction in immunosuppression dose. A subset of patients completed QoL questionnaires. Seventeen out of 18 patients (94%) showed an improvement in scores. The mean cGVHD SS and mean DLQI score were both significantly lower after 6 months of ECP (22 compared with 36, P=0.012 and 3.4 compared with 6.9, P=0.009, respectively). This study confirms that ECP can lead to objective clinical responses and, in addition, may lead to an improvement in QoL in cGVHD.


Asunto(s)
Enfermedad Injerto contra Huésped/terapia , Inmunoterapia/métodos , Fotoféresis/métodos , Calidad de Vida , Piel/inmunología , Adolescente , Adulto , Anciano , Enfermedad Crónica , Resistencia a Medicamentos/inmunología , Femenino , Enfermedad Injerto contra Huésped/inmunología , Humanos , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Esteroides/uso terapéutico , Encuestas y Cuestionarios , Tasa de Supervivencia , Resultado del Tratamiento , Adulto Joven
5.
Bone Marrow Transplant ; 49(5): 679-83, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24510069

RESUMEN

The presence of minimal residual disease (MRD) by multiparametric flow cytometry (MFC) has been associated with adverse outcomes in AML patients treated with chemotherapy alone, but its impact in the setting of allogeneic hematopoietic SCT (HSCT) is less clear. We studied 88 patients who underwent myeloablative (MA) or reduced-intensity conditioned allogeneic HSCT for AML in first or subsequent remission at our center. MRD status was determined using three-color MFC on pre-HSCT BM aspirates, and patients were stratified by MRD status into MRD-negative, low-level MRD-positive (<1%) or high-level MRD-positive groups (1-4.9%). Two-year survival estimates in these groups were 66.8%, 51% and 30%, respectively (P=0.012), and 2-year estimates of relapse were 7.6, 37 and 70% (P<0.001). Pre-HSCT MRD was related to disease characteristics including secondary AML (P=0.002) and primary induction failure (P=0.005), but, despite these strong correlations, MRD remained independently associated with poorer survival in multivariate analysis (hazard ratio, 1.92; P=0.014). Pre-HSCT MRD is associated with adverse clinical outcomes in AML patients undergoing reduced-intensity or MA HSCT in first or subsequent remission and should be integrated into transplant strategies for patients with AML.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/terapia , Neoplasia Residual/diagnóstico , Acondicionamiento Pretrasplante/métodos , Adolescente , Adulto , Anciano , Citometría de Flujo , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Leucemia Mieloide Aguda/mortalidad , Persona de Mediana Edad , Análisis Multivariante , Agonistas Mieloablativos/uso terapéutico , Neoplasia Residual/mortalidad , Valor Predictivo de las Pruebas , Pronóstico , Recurrencia , Estudios Retrospectivos , Análisis de Supervivencia , Trasplante Homólogo , Adulto Joven
6.
Bone Marrow Transplant ; 48(7): 982-7, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23318533

RESUMEN

Myeloablative allo-SCT decreases relapse incidence (RI) in ALL. Reduced intensity conditioning (RIC) may extend allo-SCT to older and less fit patients. Sixty-nine ALL patients reported to the BSBMT underwent fludarabine-based RIC allo-SCT, 38 from unrelated donors (UD). Forty-four patients received alemtuzumab. ALL was in CR in 64 patients (93%). This was a second or third SCT in 23 patients. Two-year OS and PFS were 36% and 32%, respectively. In multivariate analysis male recipients demonstrated better OS and PFS (hazard ratio (HR) = 0.42, P = 0.008 and HR = 0.45, P = 0.012, respectively). Two-year TRM was 29%: higher with younger age (HR = 0.97/year, P = 0.041), female recipient (HR = 2.55, P = 0.049) and increasing grade of acute GVHD (HR = 1.87, P = 0.001). Two-year RI was 38% and was lower in patients with acute and chronic GVHD (HR = 0.62 per increasing grade, P = 0.035 and HR = 0.52, P = 0.025, respectively). Long-term ALL-free survival is achievable following fludarabine-based RIC allo-SCT. The association between GVHD and decreased RI suggests the presence of a GVL effect.


Asunto(s)
Efecto Injerto vs Leucemia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Trasplante de Células Madre , Acondicionamiento Pretrasplante , Enfermedad Aguda , Adolescente , Adulto , Factores de Edad , Alemtuzumab , Aloinjertos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Antineoplásicos/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/terapia , Humanos , Masculino , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Factores Sexuales , Sociedades Médicas , Tasa de Supervivencia , Reino Unido , Vidarabina/administración & dosificación , Vidarabina/análogos & derivados
8.
Bone Marrow Transplant ; 47(6): 824-30, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21927038

RESUMEN

Extracorporeal photopheresis (ECP) has become a recognised treatment for steroid-refractory chronic GVHD (cGVHD), but the optimal frequency and duration of treatment are yet to be established. We report on 82 consecutive patients with mucocutaneous cGVHD who received a bimonthly regimen of ECP treatment for two consecutive days, which could be subsequently tapered to a monthly regimen depending on response. Patients were steroid-refractory, steroid-dependent or steroid-intolerant, and 29 (35%) had multiorgan involvement. The median duration of treatment was 330 days (42-987). The median number of ECP cycles was 15 (1.5-32). Response was assessed by clinical assessment and reduction in immunosuppression after 6 months. 69/82 (84%) had completed 6 months of ECP and 65/69 (94%) had ≥ 50% improvement in symptoms and signs of cGVHD. A total of 77% of patients who completed 6 months of ECP had a reduction in immunosuppression dose and 80% had decreased their steroid dose (27.5% stopped, 30% had ≥ 75% reduction, 17.5% had ≥ 50% reduction and 25% had <50% reduction). OS at 3 years from the start of ECP was 69%. This study reports the largest series of patients receiving bimonthly ECP treatment for cGVHD, and confirms that ECP allows successful reduction of immunosuppression.


Asunto(s)
Enfermedad Injerto contra Huésped/terapia , Fotoféresis/métodos , Enfermedades de la Piel/terapia , Adolescente , Adulto , Anciano , Enfermedad Crónica , Femenino , Neoplasias Hematológicas/terapia , Humanos , Masculino , Persona de Mediana Edad , Factores de Tiempo
9.
Bone Marrow Transplant ; 47(1): 88-94, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21358686

RESUMEN

The clinical course of 2009 H1N1 influenza in Allo-SCT patients is unknown. Data were collected in the UK from October 2009 to April 2010 on laboratory-confirmed cases of H1N1 influenza in Allo-SCT recipients. H1N1 infection was diagnosed in 60 patients, median age 42 years, at a median of 10 months post-SCT. Twenty-one patients (35%) developed pneumonia and nine (15%) required admission to intensive care units. Actuarial mortality was 7% at 28 days and 19% 4 months post-diagnosis of 2009 H1N1 influenza. Increasing age and pre-existing lung disease were risk factors for pneumonia (P=0.006 and 0.037, respectively); older age was a risk factor for death (P=0.012). Morbidity and mortality from 2009 H1N1 influenza in SCT patients exceeds that of immunocompetent patients, but parallels that in other critically ill hospitalised cohorts; the elderly and those with chronic pulmonary disease are at greatest risk.


Asunto(s)
Subtipo H1N1 del Virus de la Influenza A , Gripe Humana/mortalidad , Pandemias , Neumonía/mortalidad , Trasplante de Células Madre , Adolescente , Adulto , Factores de Edad , Anciano , Trasplante de Médula Ósea , Niño , Preescolar , Estudios de Cohortes , Cuidados Críticos , Supervivencia sin Enfermedad , Femenino , Humanos , Lactante , Gripe Humana/terapia , Masculino , Persona de Mediana Edad , Neumonía/terapia , Sociedades Médicas , Tasa de Supervivencia , Factores de Tiempo , Trasplante Homólogo , Reino Unido/epidemiología
10.
Clin Transplant ; 25(2): 222-7, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-20201951

RESUMEN

Mycophenolate mofetil (MMF) is used to treat acute and chronic graft versus host disease (GvHD). There is scant evidence in the literature about mycophenolic acid (MPA) trough level monitoring in GvHD. We therefore reviewed 32 patients treated with MMF for acute (n = 19) or chronic GvHD (n = 13). Twelve (63%) of 19 patients with acute GvHD and nine (69%) of 13 with chronic GvHD showed a good response. In all 21 patients who responded to MMF, their mean total MPA levels were therapeutic (1-3.5 mg/L), whereas five of 11 patients who did not respond had sub-therapeutic mean MPA levels (p = 0.002). Sixteen (66%) of 24 steroid refractory or dependent patients responded to MMF. Associations between the mean total MPA level for each patient and the corresponding mean serum albumin concentration showed therapeutic mean total MPA levels for all 23 patients with mean albumin ≥ 31 g/L but sub-therapeutic mean total MPA levels in five of nine patients with mean albumin <31 g/L (p = 0.0006). In conclusion, MMF is efficacious in steroid refractory and dependent acute or chronic GvHD with statistically significant correlation between therapeutic plasma total MPA trough levels and clinical response. Serum albumin levels should be taken into account when considering MMF dose adjustments.


Asunto(s)
Albúminas/análisis , Antibióticos Antineoplásicos/farmacocinética , Monitoreo de Drogas , Enfermedad Injerto contra Huésped/prevención & control , Ácido Micofenólico/farmacocinética , Enfermedad Aguda , Adolescente , Adulto , Antibióticos Antineoplásicos/sangre , Área Bajo la Curva , Enfermedad Crónica , Femenino , Supervivencia de Injerto , Trasplante de Células Madre Hematopoyéticas , Humanos , Masculino , Persona de Mediana Edad , Ácido Micofenólico/sangre , Distribución Tisular , Resultado del Tratamiento , Adulto Joven
11.
Bone Marrow Transplant ; 44(1): 51-6, 2009 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-19139735

RESUMEN

Empirical antifungal therapy is frequently used in allogeneic transplant patients who have persistent febrile neutropenia and can be associated with high cost, toxicity and breakthrough infections. There are limited reports of strategies for early diagnosis of invasive fungal infection (IFI) and, to our knowledge, no reports of treatment strategies based only on high-resolution computerized tomography (HRCT) scans. We used an early treatment strategy for IFI in 99 consecutive patients undergoing allogeneic transplantation. Patients received caspofungin if they had antibiotic-resistant neutropenic fever for more than 72 h and a positive HRCT scan. Fifty-three of 99 patients (54%) had antibiotic-resistant neutropenic fever at 72 h and would have received parenteral antifungal treatment if an empirical approach had been used. The HRCT-based strategy reduced the use of parenteral antifungal agents to 17/99 patients (17%), a 68% reduction. No subsequent diagnoses of IFI occurred within 100 days in patients with a negative HRCT. Only one patient died from IFI within 100 days. These data suggest that this non-empirical strategy may be feasible and that caspofungin may be effective in this setting. A randomized controlled trial is warranted to further assess these results.


Asunto(s)
Antifúngicos/administración & dosificación , Equinocandinas/administración & dosificación , Trasplante de Células Madre Hematopoyéticas , Micosis/diagnóstico por imagen , Micosis/tratamiento farmacológico , Micosis/mortalidad , Tomografía Computarizada por Rayos X/métodos , Adolescente , Adulto , Anciano , Caspofungina , Femenino , Neoplasias Hematológicas/diagnóstico por imagen , Neoplasias Hematológicas/mortalidad , Neoplasias Hematológicas/terapia , Humanos , Lipopéptidos , Masculino , Persona de Mediana Edad , Micosis/etiología , Factores de Tiempo , Trasplante Homólogo
12.
Bone Marrow Transplant ; 44(1): 7-12, 2009 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-19139741

RESUMEN

Allogeneic haematopoietic cell transplantation is an established curative treatment modality for patients with malignant and non-malignant haematological disorders. Since the first related umbilical cord blood transplant (UCBT) in 1988, the use of UCB as a stem cell source for transplantation has become a standard practice in many countries, with approximately 8000 such transplants having been performed worldwide to date.


Asunto(s)
Algoritmos , Trasplante de Células Madre de Sangre del Cordón Umbilical/normas , Selección de Donante/normas , Acondicionamiento Pretrasplante/normas , Enfermedades Hematológicas/terapia , Humanos , Guías de Práctica Clínica como Asunto , Trasplante Homólogo , Reino Unido
13.
Tissue Antigens ; 63(5): 401-11, 2004 May.
Artículo en Inglés | MEDLINE | ID: mdl-15104672

RESUMEN

Sustained myeloid engraftment is an important determinant of outcome in hematopoietic stem cell transplantation (HSCT). Human tumor necrosis factor (TNF)-alpha is encoded by a gene, TNFA, located in the class III region of the major histocompatibility complex on chromosome 6, flanked by the human leukocyte antigen (HLA) class I and II regions. A number of polymorphisms in the promoter region of the TNFA gene have been associated with increased production of TNF-alphain vivo. Additionally, raised TNF-alpha levels have been reported to have a detrimental effect on the outcome in HSCT, in particular on early complications such as acute graft vs host disease, failure to engraft, and transplant-related mortality. There is evidence of linkage disequilibrium (LD) between TNFA promoter polymorphisms and extended HLA haplotypes. We have genotyped 73 cell lines and 189 donor/recipient pairs (undergoing HSCT) for their TNFA polymorphism, all of which had been well characterized with respect to their HLA genes. We found evidence of strong LD between HLA genes and TNFA; however, there was also evidence for recombination events having taken place, as we found that a number of transplant pairs who were matched for their HLA haplotypes were not matched for their TNFA alleles. We analyzed early outcomes in the transplant recipients and found a significant delay in engraftment in those pairs where both donor and recipients possessed an AG allele (associated with higher TNF-alpha levels). Our results suggest a functional effect of TNFA polymorphisms on myeloid engraftment in unrelated HSCT.


Asunto(s)
Antígenos HLA/genética , Trasplante de Células Madre Hematopoyéticas , Desequilibrio de Ligamiento , Neutrófilos/patología , Regiones Promotoras Genéticas , Factor de Necrosis Tumoral alfa/genética , Adolescente , Adulto , Secuencia de Bases , Línea Celular Tumoral , Niño , Preescolar , Haplotipos , Humanos , Lactante , Recuento de Leucocitos , Persona de Mediana Edad , Datos de Secuencia Molecular , Polimorfismo Genético
14.
Br J Haematol ; 124(4): 499-503, 2004 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-14984501

RESUMEN

As part of its clinical governance programme the British Society for Blood and Marrow Transplantation (BSBMT) undertook an analysis of transplant outcome for adults undergoing human leucocyte antigen - identical sibling allogeneic transplantation for chronic myeloid leukaemia (CML) in first chronic phase (CP1) or autologous transplantation for Hodgkin's disease (HD). The study aimed to compare transplant-related mortality (TRM) and survival for patients reported to the BSBMT with patients transplanted in the rest of Europe, reported to the European Group for Blood and Marrow Transplantation (EBMT). The outcomes for 104 allogeneic transplants for CML in 24 UK/Irish centres were compared with 775 allografts in 145 other European centres. For HD, 241 autografts from 38 UK/Irish centres were compared with 1145 transplants in 239 other European centres. For both diseases, the cohorts were broadly matched with the exception of CML, where 85% of patients were transplanted <1 year from diagnosis in the UK/Ireland compared with 68% in the EBMT (P = 0.001). Cox regression analysis was undertaken using known delineated variables affecting transplant outcome in addition to the registry of origin. The adjusted survival curves for CML showed no significant differences between the two groups, with 3-year survival probabilities of 70.2% and 67.1% for the EBMT and BSBMT cohorts respectively. Likewise, the analysis for HD showed overlapping survival curves, with 3-year survival probabilities of 71.8% (EBMT) and 70.8% (BSBMT). TRM was not statistically different in either disease. This study demonstrates the potential for using national registries to benchmark transplant outcome against the EBMT registry.


Asunto(s)
Benchmarking/métodos , Trasplante de Células Madre Hematopoyéticas/mortalidad , Trasplante de Células Madre Hematopoyéticas/normas , Enfermedad de Hodgkin/terapia , Leucemia Mieloide de Fase Crónica/terapia , Sistema de Registros , Adolescente , Adulto , Anciano , Femenino , Trasplante de Células Madre Hematopoyéticas/métodos , Enfermedad de Hodgkin/mortalidad , Humanos , Irlanda/epidemiología , Leucemia Mieloide de Fase Crónica/mortalidad , Masculino , Auditoría Médica , Persona de Mediana Edad , Probabilidad , Análisis de Supervivencia , Trasplante Autólogo , Trasplante Homólogo , Resultado del Tratamiento , Reino Unido/epidemiología
15.
Bone Marrow Transplant ; 31(11): 1001-8, 2003 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-12774051

RESUMEN

The importance of matching for HLA-DPB1 in unrelated donor haematopoietic stem cell (HSC) transplantation is little understood. Most transplant centres do not, currently, prospectively match for DPB1, but emerging data show that DPB1 matching does play a role in determining outcome. We studied the impact of HLA-DPB1 matching on outcome in 143 recipients of T-cell depletion transplants, who matched with their respective unrelated donors (allelic level) at HLA-A, -B, -C, -DRB1 and -DQB1. Of those matched at DPB1, 47.2% (17/36) developed acute graft-versus-host disease (aGvHD) as compared to 66.3% (55/83) of those who were mismatched. This led to a 19.1% (95% CI 0.1-38.3%) increase in the chance of developing aGvHD in mismatched patients (P=0.049). Relapse of the original disease occurred in 51 recipients; 23 of 37 (62%) matched at both DPB1 alleles, 28 of 82 (34%) were mismatched at one or two DPB1 alleles. Thus, there was a significantly higher relapse rate (P=0.0011) in transplant recipients who matched at both DPB1 alleles. In conclusion, a donor/recipient DPB1 match was associated with a significantly lower incidence of aGvHD and a significantly higher incidence of disease relapse. This study provides further evidence for an immunogenic role of HLA-DPB1 in HSC transplants.


Asunto(s)
Enfermedad Injerto contra Huésped/epidemiología , Antígenos HLA-DP/inmunología , Trasplante de Células Madre Hematopoyéticas/métodos , Prueba de Histocompatibilidad/métodos , Enfermedad Aguda , Adolescente , Adulto , Niño , Preescolar , Infecciones por Citomegalovirus/epidemiología , Femenino , Enfermedad Injerto contra Huésped/mortalidad , Cadenas beta de HLA-DP , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Lactante , Leucemia/mortalidad , Leucemia/terapia , Depleción Linfocítica/métodos , Masculino , Persona de Mediana Edad , Paridad , Valor Predictivo de las Pruebas , Probabilidad , Recurrencia , Tasa de Supervivencia , Linfocitos T/inmunología , Factores de Tiempo
16.
Gene Ther ; 9(20): 1359-68, 2002 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-12365001

RESUMEN

The immune function of retrovirus-mediated gene modified (GM) T cells is critical for a beneficial effect to follow their adoptive transfer into patients. Recent clinical data show that GM T cells expanded with PHA have reduced function in vivo. However, little functional analysis of PHA stimulation is available. Our results show that expansion of T cells with PHA impairs their ability to respond (proliferation, cytotoxicity and IFN gamma and perforin expression) to allogeneic stimulation or viral antigens in vitro. Conversely, CD3/CD28-based protocols can preserve this immune function. Retroviral transduction did not alter the functional profile induced by polyclonal stimulation. We investigated the mechanisms leading to this functional effect, and identified differential effects of PHA and CD3/CD28 on the distribution of CCR7/CD45RA T cell functional subsets, which may explain the functional differences observed. While CD3/CD28 stimulation parallels the lineage differentiation pattern induced by antigens in physiological conditions, PHA induces a skewed distribution of the CCR7/CD45RA functional T cell subsets, with near disappearance of the subpopulations that display the effector phenotype. Overall, this study demonstrates a functional disadvantage for transduction protocols based on PHA, uncovers mechanisms that may explain this functional effect, and provides us with information to design and select transduction protocols with an improved functional outcome.


Asunto(s)
Antígenos CD28/inmunología , Complejo CD3/inmunología , Terapia Genética/métodos , Fitohemaglutininas/efectos adversos , Subgrupos de Linfocitos T/inmunología , Diferenciación Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Vectores Genéticos , Humanos , Antígenos Comunes de Leucocito/inmunología , Fitohemaglutininas/farmacología , Retroviridae/genética , Estimulación Química , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/efectos de los fármacos , Transducción Genética/métodos
17.
Br J Haematol ; 115(3): 622-9, 2001 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-11736947

RESUMEN

Acute leukaemias in relapse after allogeneic stem cell transplantation (SCT) respond poorly to donor leucocyte infusions (DLI) compared with chronic myeloid leukaemia (CML), at least in part because of faster disease kinetics. Fludarabine-containing 'non-myeloablative' chemotherapy followed by further allo SCT may offer more rapid and effective disease control. We report 14 patients with relapse after allo SCT for acute leukaemia [seven acute myeloid leukaemia (AML), five acute lymphoblastic leukaemia (ALL)] or refractory anaemia with excess blasts in transformation (RAEB-t, n = 2) treated with fludarabine, high-dose cytosine arabinoside (ara-C) and granulocyte colony-simulating factor (G-CSF) with (n = 10) or without (n = 2) idarubicin (FLAG +/- Ida) or DaunoXome (FLAG-X) (n = 2) and second allo SCT from the original donor. Donors were fully human leucocyte antigen (HLA) -matched in 13 cases with a single class A mismatch in one. Actuarial overall survival was 60% and disease-free survival was 26% at 58 months. Remissions after the second SCT were longer than those after the first bone marrow transplantation (BMT) in eight of the 13 assessable patients to date. Haematopoietic recovery was rapid. Transplants were well tolerated with no treatment-related deaths. The major complication was graft-versus-host disease (GvHD, acute >/= grade II-2 cases, chronic - eight cases, two limited, six extensive) although there have been no deaths attributable to this. FLAG +/- Ida and second allo SCT is a safe and useful approach and may be more effective than DLI in the treatment of acute leukaemias relapsing after conventional allo SCT.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Trasplante de Médula Ósea , Citarabina/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Idarrubicina/administración & dosificación , Leucemia/terapia , Acondicionamiento Pretrasplante/métodos , Vidarabina/análogos & derivados , Vidarabina/administración & dosificación , Enfermedad Aguda , Adulto , Anemia Refractaria con Exceso de Blastos/terapia , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Filgrastim , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Leucemia Mieloide/terapia , Masculino , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Proteínas Recombinantes , Recurrencia , Reoperación , Estudios Retrospectivos , Tasa de Supervivencia , Trasplante Homólogo
19.
Cytotherapy ; 3(3): 203-10, 2001.
Artículo en Inglés | MEDLINE | ID: mdl-12171727

RESUMEN

BACKGROUND: We report our updated experience of allogeneic transplantation in lympho-proliferative disorders using a reduced-intensity conditioning regimen combining BEAM (plus fludarabine in three cases) with pre-transplant CAMPATH. Post-transplant donor lymphocytes have been infused for persisting disease or relapse, and both chimerism and minimal residual disease have been monitored utilizing molecular techniques. METHODS: Thirty patients with median age 47.6 years underwent allogeneic transplantation for relapsed or high-risk lymphoproliferative disease using HLA-identical (sibling n = 25, unrelated n = 2) or one antigen mismatched sibling donors (n = 3). Twenty-one had NHL, three had HD and six had CLL/PLL. Stem-cell source was PBSC (n = 24), BM (n = 5) or both (n = 1) with a median CD34 dose of 4.5 x 10(6)/kg. GvHD prophylaxis was with CYA and MTX. RESULTS: Engraftment was prompt in the majority of patients, with a median of 15 days to both ANC > 0.5 and platelets > 20. There have been three transplant-related deaths secondary to viral pneumonitis or bacterial pneumonia. Seven patients developed Grade I-II acute GvHD post-transplant. Of 28 evaluable patients, 18 achieved a CR at assessment 2-3 months post-transplant and a further patient converted from PR to CR following DLI, to give an overall CR rate of 68%. Three patients had early progressive disease and six have relapsed from CR or progressed from PR (two of whom have achieved CR following DLI therapy). Overall survival is 67% and event-free survival 48% at 3 years. With a median follow-up of 1.3 years 57% of patients are currently alive and lymphoma-free. A molecular remission has been achieved in nine of 12 informative patients. DISCUSSION: These encouraging results show that this reduced-intensity conditioning regimen is effective, with a low-toxicity profile compared with conventional TBI-based conditioning, and certainly merits further evaluation in this setting.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carmustina/uso terapéutico , Citarabina/uso terapéutico , Etopósido/uso terapéutico , Terapia de Inmunosupresión/métodos , Trastornos Linfoproliferativos/terapia , Melfalán/uso terapéutico , Trasplante de Células Madre/métodos , Acondicionamiento Pretrasplante/métodos , Trasplante Homólogo/métodos , Adolescente , Adulto , Alemtuzumab , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/toxicidad , Anticuerpos Monoclonales Humanizados , Anticuerpos Antineoplásicos/efectos adversos , Anticuerpos Antineoplásicos/toxicidad , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidad , Donantes de Sangre , Carmustina/efectos adversos , Carmustina/toxicidad , Citarabina/efectos adversos , Citarabina/toxicidad , Progresión de la Enfermedad , Etopósido/efectos adversos , Etopósido/toxicidad , Femenino , Supervivencia de Injerto/efectos de los fármacos , Supervivencia de Injerto/inmunología , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Terapia de Inmunosupresión/tendencias , Transfusión de Linfocitos/métodos , Transfusión de Linfocitos/tendencias , Trastornos Linfoproliferativos/inmunología , Trastornos Linfoproliferativos/fisiopatología , Masculino , Melfalán/efectos adversos , Melfalán/toxicidad , Persona de Mediana Edad , Monitoreo Fisiológico , Prevención Secundaria , Trasplante de Células Madre/efectos adversos , Tasa de Supervivencia , Quimera por Trasplante/inmunología , Acondicionamiento Pretrasplante/tendencias , Trasplante Homólogo/efectos adversos , Resultado del Tratamiento
20.
Cytotherapy ; 2(6): 423-8, 2000.
Artículo en Inglés | MEDLINE | ID: mdl-12044222

RESUMEN

BACKGROUND: PBSC are increasingly being used as the source of stem cells in allogeneic transplantation. An increased incidence of chronic GvHD has been suggested following unmanipulated allogeneic PBSC transplantation (PBSCT), however, how this affects overall survival is not yet clear. Our aim was to study the impact of chronic GvHD on survival and relapse following allogeneic PBSCT. METHODS: We have analyzed data from 73 patients undergoing HLA-matched allogeneic PBSCT. GvHD prophylaxis was with CYA and MTX in 97% of patients. We have studied the incidence of chronic GvHD and its affect on relapse and survival in these patients. All patients were at least 100 days post-transplant at the time of analysis. RESULTS: Seventy-three patients were evaluable for analysis of chronic GvHD. The overall incidence of chronic GvHD was 55% (limited in 18% and extensive in 37%). Overall median survival was 991 days, with a 4 year survival rate of 48%. Twelve patients relapsed. Patients with chronic GvHD had a significantly lower incidence of disease relapse (p = 0.005) with a relapse probability of 8% at 3 years, compared with 40% in patients with no chronic GvHD. In addition, the extent of chronic GvHD had a marked effect on survival, patients with limited chronic GvHD had a 4 year survival rate of 83%, compared with 45% in patients with extensive chronic GvHD and 38% in patients with no chronic GvHD. This difference was primarily due to the low incidence of relapse and low mortality seen in patients with limited chronic GvHD. DISCUSSION: The presence and extent of chronic GvHD is an important predictor of outcome following allogeneic PBSCT, in that patients who developed either limited or extensive chronic GvHD had a low risk of disease relapse.


Asunto(s)
Enfermedad Injerto contra Huésped/complicaciones , Enfermedad Injerto contra Huésped/mortalidad , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/terapia , Trasplante de Células Madre/efectos adversos , Adolescente , Adulto , Causas de Muerte , Niño , Enfermedad Crónica , Femenino , Enfermedad Injerto contra Huésped/epidemiología , Neoplasias Hematológicas/mortalidad , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Recurrencia , Tasa de Supervivencia , Factores de Tiempo , Trasplante Homólogo
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