RESUMEN
Failure of second-generation tyrosine kinase inhibitors (2GTKI) is a challenging situation in patients with chronic myeloid leukemia (CML). Asciminib, recently approved by the US Federal Drug Administration, has demonstrated in clinical trials a good efficacy and safety profile after failure of 2GTKI. However, no study has specifically addressed response rates to asciminib in ponatinib pretreated patients (PPT). Here, we present data on responses to asciminib from 52 patients in clinical practice, 20 of them (38%) with prior ponatinib exposure. We analyzed retrospectively responses and toxicities under asciminib and compared results between PPT and non-PPT patients.After a median follow-up of 30 months, 34 patients (65%) switched to asciminib due to intolerance and 18 (35%) due to resistance to prior TKIs. Forty-six patients (88%) had received at least 3 prior TKIs. Regarding responses, complete cytogenetic response was achieved or maintained in 74% and 53% for non-PPT and PPT patients, respectively. Deeper responses such as major molecular response and molecular response 4.5 were achieved in 65% and 19% in non-PPT versus 32% and 11% in PPT, respectively. Two patients (4%) harbored the T315I mutation, both PPT.In terms of toxicities, non-PPT displayed 22% grade 3-4 TEAE versus 20% in PPT. Four patients (20% of PPT) suffered from cross-intolerance with asciminib as they did under ponatinib.Our data supports asciminib as a promising alternative in resistant and intolerant non-PPT patients, as well as in intolerant PPT patients; the resistant PPT subset remains as a challenging group in need of further therapeutic options.
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Antineoplásicos , Leucemia Mielógena Crónica BCR-ABL Positiva , Piridazinas , Antineoplásicos/efectos adversos , Resistencia a Antineoplásicos , Proteínas de Fusión bcr-abl/genética , Humanos , Imidazoles , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Niacinamida/análogos & derivados , Inhibidores de Proteínas Quinasas/efectos adversos , Pirazoles , Piridazinas/efectos adversos , Estudios RetrospectivosRESUMEN
BACKGROUND: Several commercial and academic autologous chimeric antigen receptor T-cell (CAR-T) products targeting CD19 have been approved in Europe for relapsed/refractory B-cell acute lymphoblastic leukemia, high-grade B-cell lymphoma and mantle cell lymphoma. Products for other diseases such as multiple myeloma and follicular lymphoma are likely to be approved by the European Medicines Agency in the near future. DESIGN: The European Society for Blood and Marrow Transplantation (EBMT)-Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association collaborated to draft best practice recommendations based on the current literature to support health care professionals in delivering consistent, high-quality care in this rapidly moving field. RESULTS: Thirty-six CAR-T experts (medical, nursing, pharmacy/laboratory) assembled to draft recommendations to cover all aspects of CAR-T patient care and supply chain management, from patient selection to long-term follow-up, post-authorisation safety surveillance and regulatory issues. CONCLUSIONS: We provide practical, clinically relevant recommendations on the use of these high-cost, logistically complex therapies for haematologists/oncologists, nurses and other stakeholders including pharmacists and health sector administrators involved in the delivery of CAR-T in the clinic.
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Hematología , Receptores Quiméricos de Antígenos , Acreditación , Adulto , Médula Ósea , Humanos , Inmunoterapia Adoptiva , Receptores de Antígenos de Linfocitos TAsunto(s)
Benzoatos/administración & dosificación , Trasplante de Células Madre Hematopoyéticas , Hidrazinas/administración & dosificación , Pirazoles/administración & dosificación , Trombocitopenia/tratamiento farmacológico , Adulto , Anciano , Aloinjertos , Benzoatos/efectos adversos , Femenino , Humanos , Hidrazinas/efectos adversos , Masculino , Persona de Mediana Edad , Pirazoles/efectos adversos , Estudios Retrospectivos , Trombocitopenia/sangre , Trombocitopenia/etiologíaAsunto(s)
Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Inmunosupresores/uso terapéutico , Acondicionamiento Pretrasplante/métodos , Adolescente , Adulto , Anciano , Femenino , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/mortalidad , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Sirolimus/uso terapéutico , Análisis de Supervivencia , Tacrolimus/uso terapéutico , Trasplante HomólogoRESUMEN
The impact of donor age in patients with acute myeloid leukemia and myelodysplastic syndrome who underwent allogeneic hematopoietic stem cell transplant (HSCT) remains unclear. In the current study, we evaluate 179 consecutive patients who received an HSCT, from January 2000 to January 2013, in our Institution. Most of the HSCT (91%) were HLA-matched. Patient and donor median age were 51 years (18-69) and 47 years (12-75) respectively, and 81 donors (45%) were older than 50 years. The median follow-up was 38 months (range 1-138), Kaplan-Meier estimated 3-year overall survival (OS) was 63% and disease free survival (DFS) was 56%. Interestingly, patients who received an HSCT from a donor older age (>50 y) showed a poorer OS (51% vs 73%; p=0.01), as well as a higher TRM (20% vs 8%; p=0.038) and higher relapse rate (28% vs 39%; p=0.03). In a stratified subanalysis, 3-year estimated OS was significantly lower among patients undergoing an HSCT from >50 years sibling donors compared to those receiving an HSCT from <50 years unrelated donor (54% vs 72%; p<0.001). In summary, we can conclude that receiving an HSCT from a donor over 50 years old is associated with poorer outcome in patients diagnosed with MDS and AML, and this information may be incorporated into the complex process of donor selection.
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Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicos/terapia , Donante no Emparentado/estadística & datos numéricos , Adolescente , Adulto , Factores de Edad , Anciano , Niño , Femenino , Trasplante de Células Madre Hematopoyéticas/mortalidad , Trasplante de Células Madre Hematopoyéticas/estadística & datos numéricos , Humanos , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/mortalidad , Análisis de Supervivencia , Trasplante Homólogo , Resultado del Tratamiento , Adulto JovenRESUMEN
Hypomethylating agents are able to prolong the overall survival of some patients diagnosed with acute myeloid leukemia. The aim of this study was to evaluate the clinical use of azacitidine as front-line therapy in unfit acute myeloid leukemia (AML) patients and to develop a clinical prediction model to identify which patients may benefit more from the drug. One hundred and ten untreated unfit AML patients received front-line azacitidine therapy in Spain, and response and survival were evaluated in them following European LeukemiaNet (ELN) guidelines. A clinical prediction rule was obtained from this population that was validated and refined in 261 patients treated in France, Austria and Italy. ELN response was achieved in 21.0% of the 371 patients (CI95% 17.0-25.5) and did not depend on bone marrow blast cell percentage. Median overall survival was 9.6 months (CI95% 8.5-10.8) and 40.6% of the patients were alive at 1 year (CI95% 35.5-45.7). European ALMA score (E-ALMA), based on performance status, white blood cell counts at azacitidine onset and cytogenetics, discriminated three risk groups with different survival and response rates. Azacitidine seems a reasonable therapeutic option for most unfit AML patients, i.e. those displaying a favorable or intermediate E-ALMA score.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Azacitidina/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Inducción de Remisión , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del Tratamiento , Estudios de Validación como AsuntoRESUMEN
Transplantation-associated thrombotic microangiopathy (TA-TMA) is a feared complication of allogeneic hematopoietic SCT (HSCT) owing to its high mortality rate. The use of calcineurin inhibitors or sirolimus (SIR) for GVHD prophylaxis has been suggested as a potential risk factor. However, the impact of tacrolimus (TAC) and SIR combinations on the increased risk of TA-TMA is currently not well defined. We retrospectively analyzed the incidence of TA-TMA in 102 allogeneic HSCT recipients who consecutively received TAC plus SIR (TAC/SIR) (n=68) or plus MTX (TAC/MTX)±ATG (n=34) for GVHD prophylaxis. No significant differences were observed in the incidence of TA-TMA between patients receiving TAC/SIR vs TAC/MTX±ATG (7.4% vs 8.8%, P=0.8). Only grade III-IV acute GVHD, previous HSCT and serum levels of TAC >25 ng/mL were associated with a greater risk of TA-TMA. Patients developing TA-TMA have significantly poorer survival (P<0.001); however, TA-TMA ceased to be an independent prognostic factor when it was included in a multivariate model. In conclusion, the combination of TAC/SIR does not appear to pose a higher risk of TA-TMA. By contrast, we identified three different risk groups for developing TA-TMA.
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Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Metotrexato/administración & dosificación , Sirolimus/administración & dosificación , Tacrolimus/administración & dosificación , Microangiopatías Trombóticas/etiología , Adulto , Anciano , Quimioterapia Combinada , Femenino , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/epidemiología , Trasplante de Células Madre Hematopoyéticas/estadística & datos numéricos , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/sangre , Incidencia , Masculino , Metotrexato/sangre , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Sirolimus/sangre , Tacrolimus/sangre , Microangiopatías Trombóticas/epidemiología , Trasplante Homólogo , Adulto JovenRESUMEN
Hematopoietic stem cell transplantation (HSCT) using umbilical cord blood (UCB) progenitors is increasingly being used. One of the problems that may arise after UCB transplantation is an impaired engraftment. Either intrabone (IB) injection of hematopoietic progenitors or mesenchymal stem cell (MSC) coadministration has been proposed among the strategies to improve engraftment. In the current study, we have assessed the effects of both approaches. Thus, NOD/SCID recipients were transplanted with human UCB CD34+ cells administered either intravenously (IV) or IB, receiving or not bone marrow (BM)-derived MSCs also IV or IB (in the right femur). Human HSC engraftment was measured 3 and 6 weeks after transplantation. Injected MSCs were tracked weekly by bioluminescence. Also, lodgment within the BM niche was assessed at the latter time point by immuno-fluorescence. Our study shows regarding HSC engraftment that the number of BM human CD45+ cells detected 3 weeks after transplantation was significantly higher in mice cotransplanted with human MSCs. Moreover, these mice had a higher myeloid (CD13+) engraftment and a faster B-cell (CD19+) chimerism. At the late time point evaluated (6 weeks), human engraftment was higher in the group in which both strategies were employed (IB injection of HSC and MSC coadministration). When assessing human MSC administration route, we were able to track MSCs only in the injected femurs, whereas they lost their signal in the contralateral bones. These human MSCs were mainly located around blood vessels in the subendosteal region. In summary, our study shows that MSC coadministration can enhance HSC engraftment in our xenogenic transplantation model, as well as IB administration of the CD34+ cells does. The combination of both strategies seems to be synergistic. Interestingly, MSCs were detected only where they were IB injected contributing to the vascular niche.
Asunto(s)
Sangre Fetal/citología , Trasplante de Células Madre Hematopoyéticas , Trasplante de Células Madre Mesenquimatosas , Adulto , Animales , Antígenos CD34/metabolismo , Linfocitos B/inmunología , Linfocitos B/metabolismo , Células de la Médula Ósea/citología , Células de la Médula Ósea/metabolismo , Huesos/fisiología , Quimerismo , Femenino , Supervivencia de Injerto/inmunología , Células HEK293 , Células Madre Hematopoyéticas/citología , Humanos , Antígenos Comunes de Leucocito/metabolismo , Masculino , Células Madre Mesenquimatosas/citología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Persona de Mediana Edad , Trasplante HeterólogoRESUMEN
PURPOSE: The aim of this study was to optimise the yield of metaphases in mesenchymal stromal cells (MSC) in vitro cultures and to study the karyotype of MSC expanded in good manufacturing practice (GMP) conditions for clinical use. BACKGROUND: MSC are being increasingly used in clinical trials for a number of diseases. Biosafety demonstration in all cases is mandatory. Unfortunately, current standard karyotyping methods fail to obtain enough number of evaluable metaphases. METHODS AND MATERIALS: In the present work, to optimise the yield of metaphases in MSC expanded in vitro, we have tested several conditions by modifying colcemid concentration (we have tested 0.01, 0.05 and 0.1 µg mL(-1) ) and exposure time (during 5, 15 and 24 h). We further applied these optimised conditions to 61 MSC expansions in GMP conditions for clinical use. RESULTS: Our results show that the highest number of metaphases was obtained when MSC were incubated with 0.05 µg mL(-1) of colcemid overnight (15 h), compared to the remaining experimental conditions. In most cases (59/61 cases) enough number of metaphases was obtained. And what is more relevant, only in one case a karyotypic abnormality was found (trisomy of chromosome 10), and cells were subsequently discarded for clinical use. CONCLUSION: We describe here an optimal method to obtain enough number of metaphases for karyotype analysis of in vitro expanded MSCs, what is essential for their clinical use in cell therapy programmes.
Asunto(s)
Cariotipificación/métodos , Células Madre Mesenquimatosas/citología , Metafase , Células Cultivadas , Femenino , Humanos , MasculinoAsunto(s)
Crioprotectores/efectos adversos , Dimetilsulfóxido/efectos adversos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Accidente Cerebrovascular/etiología , Criopreservación , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Masculino , Persona de Mediana EdadRESUMEN
It is an open question whether in multiple myeloma (MM) bone marrow stromal cells contain genomic alterations, which may contribute to the pathogenesis of the disease. We conducted an array-based comparative genomic hybridization (array-CGH) analysis to compare the extent of unbalanced genomic alterations in mesenchymal stem cells from 21 myeloma patients (MM-MSCs) and 12 normal donors (ND-MSCs) after in vitro culture expansion. Whereas ND-MSCs were devoid of genomic imbalances, several non-recurrent chromosomal gains and losses (>1 Mb size) were detected in MM-MSCs. Using real-time reverse transcription PCR, we found correlative deregulated expression for five genes encoded in regions for which genomic imbalances were detected using array-CGH. In addition, only MM-MSCs showed a specific pattern of 'hot-spot' regions with discrete (<1 Mb) genomic alterations, some of which were confirmed using fluorescence in situ hybridization (FISH). Within MM-MSC samples, unsupervised cluster analysis did not correlate with particular clinicobiological features of MM patients. We also explored whether cytogenetic abnormalities present in myelomatous plasma cells (PCs) were shared by matching MSCs from the same patients using FISH. All MM-MSCs were cytogenetically normal for the tested genomic alterations. Therefore we cannot support a common progenitor for myeloma PCs and MSCs.
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Hibridación Genómica Comparativa , Células Madre Mesenquimatosas/química , Mieloma Múltiple/genética , Adulto , Anciano , Anciano de 80 o más Años , Médula Ósea/patología , Células de la Médula Ósea/química , Linaje de la Célula , Células Cultivadas/química , Análisis por Conglomerados , Femenino , Dosificación de Gen , Regulación Neoplásica de la Expresión Génica , Humanos , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Mieloma Múltiple/patología , Células Madre Neoplásicas/química , Análisis de Secuencia por Matrices de Oligonucleótidos , Células Plasmáticas/química , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Tumorales Cultivadas/químicaRESUMEN
The presence of cytogenetic aberrations on mesenchymal stem cells (MSC) from myelodysplastic syndrome (MDS) patients is controversial. The aim of the study is to characterize bone marrow (BM) derived MSC from patients with MDS using: kinetic studies, immunophenotyping, fluorescent in situ hybridization (FISH) and genetic changes by array-based comparative genomic hybridization (array-CGH). In all 36 cases of untreated MDS were studied. MDS-MSC achieved confluence at a significantly slower rate than donor-MSC, and the antigenic expression of CD105 and CD104 was lower. Array-CGH studies showed DNA genomic changes that were proved not to be somatic. These results were confirmed by FISH. To confirm that genomic changes were also present in freshly obtained MSCs they were enriched by sorting BM cells with the following phenotype: CD45(-)/CD73(++)/CD34(-)/CD271(++). They also showed genomic changes that were confirmed by FISH. To analyze the relationship of these aberrations with clinical-biological data an unsupervised hierarchical cluster analysis was performed, two clusters were identified: the first one included the 5q- syndrome patients, whereas the other incorporated other MDS. Our results show, for the first time that MSC from MDS display genomic aberrations, assessed by array-CGH and FISH, some of them specially linked to a particular MDS subtype, the 5q- syndrome.
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Deleción Cromosómica , Cromosomas Humanos Par 5 , Células Madre Mesenquimatosas/patología , Síndromes Mielodisplásicos/patología , Adulto , Anciano , Anciano de 80 o más Años , Células de la Médula Ósea/patología , Examen de la Médula Ósea , Aberraciones Cromosómicas , Hibridación Genómica Comparativa , Femenino , Humanos , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/genéticaRESUMEN
Damage to the stem cell progenitors caused by the chemotherapy received in patients diagnosed with non-Hodgkin's lymphoma (NHL) may be an important factor limiting progenitor cell mobilization. The aim of the present analysis was to evaluate the effect of the chemotherapy on the different progenitor cell subpopulations obtained in the leukapheresis. For this purpose, a combination of immunophenotype and functional assays has been performed in 26 mobilized peripheral blood (PB) samples from NHL patients and 36 healthy donors. The different progenitor subpopulations analyzed by flow cytometry significantly correlated with the corresponding populations assessed by functional assays in both healthy donors and NHL patients (p<0.05, r>0.5). The number of committed CFU-GM was similar in both groups (p=0.246), but we found significant decrease in the number of BFU-E and more immature progenitors in PB from NHL patients as compared to donors (p<0.05). Moreover, the number of total CFU was significantly lower in NHL patients (p=0.007). Accordingly, CD34+ cells (p=0.018) and CD34+ subpopulations was decreased in NHL patients. Nevertheless, CD90 and CD34 intensity was significantly higher within CD34+ cells from NHL patients as compared to donors. However, although numerically reduced non-committed CD34+ cells are more immature in chemotherapy mobilized NHL patients. In summary, our results show that all NHL hematopoietic progenitors, analyzed by both immunophenotypical and functional approaches, are impaired in leukapheresis products.
Asunto(s)
Antígenos CD34/biosíntesis , Células Madre Hematopoyéticas/inmunología , Leucaféresis/métodos , Linfoma no Hodgkin/sangre , Antígenos Thy-1/biosíntesis , Antígenos CD34/análisis , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Donantes de Sangre , Células Cultivadas , Ensayo de Unidades Formadoras de Colonias , Femenino , Citometría de Flujo , Factor Estimulante de Colonias de Granulocitos/farmacología , Movilización de Célula Madre Hematopoyética , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/efectos de los fármacos , Humanos , Inmunofenotipificación , Linfoma no Hodgkin/diagnóstico , Linfoma no Hodgkin/terapia , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Antígenos Thy-1/análisisRESUMEN
BACKGROUND: The aim of this study was to identify circulating endothelial progenitor cells (EPC) with colony-forming capacity and compare them with the monocytic-macrophage lineage. METHODS: Forty-two healthy donors were analyzed. EPC were cultured with VEGF and b-FGF. Sequential studies were performed on days +7 (colonies) +21 and +35. Monocytic cells were cultured using the same conditions as EPC until day +21 or alternatively by adding IGF. RESULTS: The number of EPC colonies was higher in BM than in mobilized or steady-state PB. Using EPC medium, monocytic cells formed cord-like structures but no colonies. However, colonies grew when IGF was added to the medium. By immunocytochemistry, colonies showed CD45, CD31 and lysozyme but no vWF. Colonies were CD4+, CD13+dim, CD14+, CD15++, CD16-/+dim, CD31+dim, CD33+dim, CD45+, CD105-/+dim, lysozyme+ and VE-cadherin+, and constantly negative for CD34, CD133 and KDR, when flow cytometry was used. The immunophenotype of pre-cultured and cultured monocytes was similar to that described for EPC. DISCUSSION: Our results suggest that the so-called 'EPC' obtained at 7 days of culture belong to the monocyte-macrophage lineage, as they share immunophenotypic and molecular features.
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Células Endoteliales/citología , Monocitos/citología , Células Madre/citología , Adulto , Antígenos CD/análisis , Biomarcadores/análisis , Células Cultivadas , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Femenino , Factor 2 de Crecimiento de Fibroblastos/farmacología , Citometría de Flujo , Expresión Génica/efectos de los fármacos , Humanos , Inmunohistoquímica , Masculino , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Madre/efectos de los fármacos , Células Madre/metabolismo , Factores de Tiempo , Factor A de Crecimiento Endotelial Vascular/farmacología , Factor de von Willebrand/análisis , Factor de von Willebrand/genéticaRESUMEN
We present a patient with critical limb ischemia who was successfully treated with the injection of autologous peripheral blood (PB) CD133+ purified stem cells (SC) into the gastrocnemius muscle. No serious adverse events related to G-CSF administration, mononuclear cells harvest or CD133+ SC administration was observed. After 17 months of follow-up, our patient has experienced limb salvage, symptomatic relief and functional improvement. Moreover, we have observed the appearance of flow in the right posterior tibial artery that was absent before the procedure. To our knowledge, this is the first case of critical limb ischemia treated with PB CD133+ SC.
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Antígenos CD/metabolismo , Células Endoteliales/trasplante , Extremidades/irrigación sanguínea , Glicoproteínas/metabolismo , Isquemia/cirugía , Péptidos/metabolismo , Trasplante de Células Madre/métodos , Antígeno AC133 , Anciano , Células Endoteliales/metabolismo , Estudios de Seguimiento , Humanos , Masculino , Resultado del TratamientoRESUMEN
Acute graft-versus-host disease (aGVHD) remains one of the most severe complications after allogeneic transplantation; in particular, the presence of gut involvement has been related to increased mortality and poorer response. The use of systemic steroids remains the standard for first-line treatment despite its severe secondary effects. Beclomethasone dipropionate (BDP) is a topically active corticosteroid with low absorption, thereby avoiding many of the deleterious side effects associated with systemic steroids. In the present study we analyzed the efficacy of BDP in a series of 26 patients who were diagnosed with grade 1 and 2 gastrointestinal aGVHD. Twenty patients (77%) responded to BDP treatment, 17 (65.5%) reached complete remission (CR), and 3 (11.5%) showed partial response. Among those patients who reached CR, 5 relapsed, although 1 of them reached second CR after a second course of BDP; therefore, 13 (50%) of the 26 patients did not require systemic steroids to treat gastrointestinal aGVHD. CR rates in those showing gastrointestinal symptoms were 68% for patients with persistent nausea, 50% for those with vomiting, and 54% for those with diarrhea (P=.2). No patient included in the study developed any symptom related to adrenal axis suppression. Thirteen patients (50%) developed >or=1 infectious episode during the first 100 days after transplantation. Transplant-related mortality was 0% at 100 days, and overall transplant-related mortality was 30%, with only 2 patients dying due to infectious complications. Therefore, our study shows that monotherapy with oral BDP is an effective initial therapeutic approach for mild to moderate intestinal GVHD, which avoids complications related to systemic steroids.
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Antiinflamatorios/administración & dosificación , Beclometasona/administración & dosificación , Enfermedades Gastrointestinales/tratamiento farmacológico , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Neoplasias Hematológicas/terapia , Administración Oral , Adolescente , Adulto , Anciano , Antiinflamatorios/efectos adversos , Beclometasona/efectos adversos , Supervivencia sin Enfermedad , Femenino , Enfermedades Gastrointestinales/etiología , Enfermedades Gastrointestinales/mortalidad , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/mortalidad , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Factores de TiempoRESUMEN
Traditional models of hematopoiesis have been hierarchical in nature. Over the past 10 years, we have developed data indicating that hematopoiesis is regulated in a continuum with deterministic and stochastic components. We have shown that the most primitive stem cells, as represented by lineage negative rhodamine(low) Hoechst(low) murine marrow cells are continuously or intermittently cycling as determined by in vivo BrdU labeling. When marrow stem cells are induced to transit cell cycle by in vitro exposure to cytokines, either IL-3, IL-6, IL-11, and steel factor or thrombopoietin, FLT3 ligand, and steel factor, they progress through cycle in a highly synchronized fashion. We have determined that when the stem cells progress through a cytokine stimulated cell cycle the homing, engraftment, adhesion protein, global gene expression, and hematopoietic differentiation phenotypes all change in a reversible fashion. This has led to the continuum model, in which, with cycle transit, chromatin is continually changing altering open transcription areas and providing a continually changing landscape of transcriptional opportunity. More recently, we have extended the changing differentiation profiles to differentiation into lung cells and found that non-hematopoietic differentiation also shows cycle related reversibly modulation. These observations all together support a continuum model of stem cell regulation in which the phenotype of the marrow stem cells is continually and reversibly changing over time.
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Células de la Médula Ósea/fisiología , Células Madre/citología , Células Madre/fisiología , Animales , Ciclo Celular/fisiología , Diferenciación Celular/fisiología , Humanos , Fenotipo , Procesos EstocásticosRESUMEN
While in bone marrow allogeneic transplantation the infusion of high doses of progenitor stem cells has a favourable impact on outcome, due to a faster hematopoietic and immune recovery, in the peripheral blood allo-setting the infusion of a high number of CD34 cells increases the risk of extensive chronic graft vs. host disease (cGVHD). This higher incidence of extensive cGVHD has an adverse impact on outcome due to a higher transplant related mortality, specially among patients receiving T-cell depleted allogeneic transplantation with myeloablative conditioning. By contrast, patients undergoing reduced intensity conditioning regimen may benefit from increasing higher CD34 + cell doses, especially those categorized as high risk according to disease status at transplant. Thus, the source of progenitors cells, type of conditioning and GVHD prophylaxis, among other factors, may influence the effect of the progenitor cell dose on outcome after allogeneic transplant.