RESUMEN
BACKGROUND: Several studies have described a potential anti-tumour effect of cannabinoids (CNB). CNB receptor 2 (CB2) is mostly present in hematopoietic stem cells (HSC). The present study evaluates the anti-leukaemic effect of CNB. METHODS: Cell lines and primary cells from acute myeloid leukaemia (AML) patients were used and the effect of the CNB derivative WIN-55 was evaluated in vitro, ex vivo and in vivo. RESULTS: We demonstrate a potent antileukemic effect of WIN-55 which is abolished with CB antagonists. WIN-treated mice, xenografted with AML cells, had better survival as compared to vehicle or cytarabine. DNA damage-related genes were affected upon exposure to WIN. Co-incubation with the PARP inhibitor Olaparib prevented WIN-induced cell death, suggesting PARP-mediated apoptosis which was further confirmed with the translocation of AIF to the nucleus observed in WIN-treated cells. Nicotinamide prevented WIN-related apoptosis, indicating NAD+ depletion. Finally, WIN altered glycolytic enzymes levels as well as the activity of G6PDH. These effects are reversed through PARP1 inhibition. CONCLUSIONS: WIN-55 exerts an antileukemic effect through Parthanatos, leading to translocation of AIF to the nucleus and depletion of NAD+, which are reversed through PARP1 inhibition. It also induces metabolic disruptions. These effects are not observed in normal HSC.
Asunto(s)
Leucemia Mieloide Aguda , Parthanatos , Humanos , Animales , Ratones , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Parthanatos/efectos de los fármacos , Línea Celular Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto , Apoptosis/efectos de los fármacos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Piperazinas/farmacología , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Cannabinoides/farmacología , Ftalazinas/farmacología , Poli(ADP-Ribosa) Polimerasas/metabolismo , Daño del ADN/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Antineoplásicos/farmacologíaRESUMEN
FLT3-ITD and NPM1 mutations are key to defining the genetic risk profile of acute myeloid leukemia (AML). We aimed to assess the prognostic features of the FLT3-ITD and NPM1 mutations in old and/or unfit individuals with AML treated with non-intensive therapies in the era before azacitidine-venetoclax approbation. The results of various non-intensive regimens were also compared. We conducted a retrospective analysis that included patients treated with different non-intensive regimens, between 2007 and 2020 from PETHEMA AML registry. We compiled 707 patients with a median age of 74 years and median follow-up time of 37.7 months. FLT3-ITD patients (N = 98) showed a non-significant difference in overall survival (OS) compared to FLT3-ITD negative-patients (N = 608) (P = 0.17, median OS was 5 vs 7.3 months respectively). NPM1-mutated patients (N = 144) also showed a non-significant difference with NPM1 wild type (N = 519) patients (P = 0.25, median OS 7.2 vs 6.8 respectively). In the Cox regression analysis neither NPM1 nor FLT3-ITD nor age were significant prognostic variables for OS prediction. Abnormal karyotype and a high leukocyte count showed a statistically significant deleterious effect. Azacitidine also showed better survival compared to FLUGA (low dose cytarabine plus fludarabine). NPM1 and FLT3-ITD seem to lack prognostic value in older/unfit AML patients treated with non-intensive regimens other than azacitidine-venetoclax combination.
Asunto(s)
Leucemia Mieloide Aguda , Mutación , Proteínas Nucleares , Nucleofosmina , Tirosina Quinasa 3 Similar a fms , Anciano , Femenino , Humanos , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Tirosina Quinasa 3 Similar a fms/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/diagnóstico , Proteínas Nucleares/genética , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Vidarabina/análogos & derivados , Vidarabina/uso terapéutico , Vidarabina/administración & dosificaciónRESUMEN
OBJECTIVE: Menopause and chronic graft-versus-host disease (cGvHD) are the leading causes of morbidity after allogeneic hematopoietic stem cell transplantation (alloHSCT). Genitalia are one of the target organs of cGvHD causing sexual dysfunction and local symptoms, which may impair women's quality of life. The aim of this study is to describe the prevalence and clinical characteristics of genital cGvHD. METHODS: A retrospective cross-sectional observational study was performed including 85 women with alloHSCT. All women were diagnosed and counseled by a trained gynecologist. Health-related quality of life was assessed by the Cervantes Short-Form Scale and sexual function was evaluated by the Female Sexual Function Index. RESULTS: Seventeen women (20%) included in the study were diagnosed with genital cGvHD. The main complaints were vulvovaginal dryness (42.2%) and dyspareunia (29.4%), the presence of erythema/erythematous plaques (52.9%) being the most frequent sign. Median time from transplant to diagnosis of genital cGvHD was 17 months among those with mild involvement, 25 months for moderate and 42 months for severe forms. Mortality was 29.4% in patients who developed cGvHD with genital involvement versus 8.8% among those without (p = 0.012). CONCLUSION: Early gynecological evaluation might allow to identify patients with mild forms of genital cGvHD, potentially enabling better management and improved outcomes.
Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Calidad de Vida , Adulto , Femenino , Humanos , Persona de Mediana Edad , Enfermedad Crónica , Estudios Transversales , Dispareunia/etiología , Dispareunia/epidemiología , Enfermedades de los Genitales Femeninos/etiología , Enfermedad Injerto contra Huésped/diagnóstico , Ginecólogos , Ginecología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Prevalencia , Estudios Retrospectivos , Disfunciones Sexuales Fisiológicas/etiología , Disfunciones Sexuales Fisiológicas/epidemiologíaRESUMEN
The substance P/neurokinin-1 receptor system has been implicated in tumor cell proliferation. Neurokinin-1 receptor has been identified in different solid tumors but not frequently in hematopoietic malignant cells. We investigated the presence of the Neurokinin-1 receptor in acute myeloid leukemia cell lines (KG-1 and HL-60), demonstrating that acute myeloid leukemia cell lines overexpress the truncated Neurokinin-1 receptor isoform compared with lymphocytes from healthy donors. Using the MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) method, we demonstrated that substance P induced cell proliferation in both acute myeloid leukemia cell lines. We also observed that four different Neurokinin-1 receptor antagonists (L-733,060, L-732,138, CP 96-345 and aprepitant) elicited inhibition of acute myeloid leukemia cell growth lines in a concentration-dependent manner, while growth inhibition was only marginal in lymphocytes; the specific antitumor action of Neurokinin-1 receptor antagonists occurs via the Neurokinin-1 receptor, and leukemia cell death is due to apoptosis. Finally, administration of high doses of daily intraperitoneal fosaprepitant to NOD scid gamma mice previously xenografted with the HL60 cell line increased the median survival from 4 days (control group) to 7 days (treated group) (p = 0.059). Taken together, these findings suggest that Neurokinin-1 receptor antagonists suppress leukemic cell growth and may be considered to be potential antitumor drugs for the treatment of human acute myeloid leukemia.
Asunto(s)
Leucemia Mieloide Aguda/tratamiento farmacológico , Antagonistas del Receptor de Neuroquinina-1/farmacología , Receptores de Neuroquinina-1/química , Animales , Apoptosis , Proliferación Celular , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Receptores de Neuroquinina-1/metabolismo , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Ring 21 is an unstable structural abnormality of chromosome 21 that can lead to RUNX1 gene amplification. We present a unique case with a carrier patient of a constitutional ring chromosome 21 (partial monosomy and trisomy 21) with dysmorphic features and congenital malformations phenotype, who developed acute myeloid leukaemia with myelodysplasia-related changes and two ring 21 chromosomes with RUNX1 amplification. The patient's constitutional ring 21 chromosome showed alterations in tumour suppressor genes, and oncogenes, but not in RUNX1. RUNX1 gene expression at acute myeloid leukaemia diagnosis, showed no upregulation, so other genes may also be the genetic amplification targets in this patient. Copyright © 2016 John Wiley & Sons, Ltd.
Asunto(s)
Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicos/genética , Preescolar , Cromosomas Humanos Par 21/genética , Femenino , Amplificación de Genes , Humanos , Cromosomas en AnilloRESUMEN
The exchange of information during interactions of T cells with dendritic cells, B cells or other T cells regulates the course of T, B and DC-cell activation and their differentiation into effector cells. The tumor necrosis factor superfamily member LIGHT (homologous to lymphotoxin, exhibits inducible expression and competes with HSV glycoprotein D for binding to herpesvirus entry mediator, a receptor expressed on T lymphocytes) is transiently expressed upon T cell activation and modulates CD8 T cell-mediated alloreactive responses upon herpes virus entry mediator (HVEM) and lymphotoxin ß receptor (LTßR) engagement. LIGHT-deficient mice, or WT mice treated with LIGHT-targeting decoy receptors HVEM-Ig, LTßR-Ig or sDcR3-Ig, exhibit prolonged graft survival compared to untreated controls, suggesting that LIGHT modulates the course and severity of graft rejection. Therefore, targeting the interaction of LIGHT with HVEM and/or LTßR using recombinant soluble decoy receptors or monoclonal antibodies represent an innovative therapeutic strategy for the prevention and treatment of allograft rejection and for the promotion of donor-specific tolerance.
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Anticuerpos Monoclonales/farmacología , Rechazo de Injerto/inmunología , Enfermedad Injerto contra Huésped/inmunología , Receptor beta de Linfotoxina/antagonistas & inhibidores , Trasplante de Órganos , Miembro 14 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/antagonistas & inhibidores , Animales , Humanos , Receptor beta de Linfotoxina/inmunología , Receptor beta de Linfotoxina/metabolismo , Ratones , Unión Proteica , Trasplante Homólogo , Miembro 14 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/inmunologíaAsunto(s)
Sustitución de Aminoácidos , Trasplante de Células Madre Hematopoyéticas , Leucemia de Mastocitos/genética , Leucemia Mielomonocítica Crónica/genética , Mutación Missense , Proteínas de Neoplasias/genética , Neoplasias Primarias Secundarias/genética , Mutación Puntual , Proteínas Proto-Oncogénicas c-kit/genética , Aloinjertos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Combinada , Progresión de la Enfermedad , Estudios de Asociación Genética , Humanos , Cadenas kappa de Inmunoglobulina/sangre , Leucemia de Mastocitos/tratamiento farmacológico , Leucemia de Mastocitos/patología , Leucemia de Mastocitos/terapia , Leucemia Mielomonocítica Crónica/tratamiento farmacológico , Leucemia Mielomonocítica Crónica/patología , Leucemia Mielomonocítica Crónica/terapia , Masculino , Persona de Mediana Edad , Gammopatía Monoclonal de Relevancia Indeterminada/sangre , Gammopatía Monoclonal de Relevancia Indeterminada/genética , Neoplasias Primarias Secundarias/tratamiento farmacológico , Neoplasias Primarias Secundarias/patología , Neoplasias Primarias Secundarias/terapia , Paraproteínas/análisis , Inducción de RemisiónRESUMEN
At this time, allogeneic transplantation should be offered only within the context of clinical trials. The likelihood of achieving prolonged complete remission with standard therapy with new drugs and autografting renders allogeneic transplantation unadvisable as first-line treatment in most patients. In this situation, the procedure must be reserved only for young patients with very poor prognostic factors or with progression of the disease offer receiving first-line treatment. After the first relapse, it should be applied to patients with an adverse cytogenetics and early relapse (< 18 months) after optimized treatment that includes new drugs and autologous transplantation. In any case, the patient should undergo transplantation with minimal disease. For the remaining patients, this procedure should not be considered the last therapeutic resort, since in this context there is a very low probability of success. On the other hand, conducting the procedure does not imply that the patient will not benefit a posteriori from other treatments, should they become necessary. Caution must be used when interpreting the available data from comparative studies. We have an obligation to continue exploring and improving this strategy which, to date, constitutes the most effective therapeutic tool available to us.
Asunto(s)
Mieloma Múltiple/cirugía , Trasplante de Células Madre , Trasplante Homólogo , Medicina Basada en la Evidencia , Humanos , Selección de Paciente , Guías de Práctica Clínica como Asunto , Pronóstico , Recurrencia , Medición de Riesgo , Factores de Riesgo , Terapia Recuperativa , Trasplante de Células Madre/efectos adversos , Factores de Tiempo , Trasplante Homólogo/efectos adversos , Resultado del TratamientoRESUMEN
The NIH classification intends to standardize the diagnostic criteria for chronic CVHD and to establish prognosis groups that will help to identify patient risk and thus decide on the most appropriate treatment. This study assesses the predictive value of this classification and analyzes new prognostic factors in a series of 820 patients receiving allogeneic grafts at three sites: Hospital Universitario de Salamanca, Hospital de la Santa Creu i Sant Pau, in Barcelona, and Karolinska Institutet, in Stockholm. In the univariate analysis, the classification limited/extensive, the NIH class, and the type of onset have a significant influence on overall survival and transplant-related mortality. Additionally, the overlap syndrome is associated with a shorter survival in the multivariate analysis, only the NIH class-with on HR of 2.89 (95% Cl: 1.75-4.76; p < 0.007) for mild and moderate versus severe disease-has a significant influence on survival. Excluding the NIH class, the type of onset is Identified as an independent factor for survival. Therefore, the NIH class and the type of onset are confirmed as the most significant variables. This is important in order to identify patients with a higher risk of death after transplantation, and shorter survival. On the other hand, it is a very laborious classification; for this reason it is necessary to establish the degree of involvement of lungs, skin, digestive tract, and liver, and to identify the number of organs, because these factors significantly affect survival.
Asunto(s)
Enfermedad Injerto contra Huésped/clasificación , Trasplante de Órganos/efectos adversos , Terminología como Asunto , Enfermedad Crónica , Enfermedad Injerto contra Huésped/diagnóstico , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/terapia , Humanos , Análisis Multivariante , Trasplante de Órganos/mortalidad , Medición de Riesgo , Factores de Riesgo , Índice de Severidad de la Enfermedad , España , Análisis de Supervivencia , Tasa de Supervivencia , Suecia , Factores de Tiempo , Trasplante Homólogo , Resultado del TratamientoRESUMEN
This multicenter phase I trial was designed to evaluate the safety and efficacy of bortezomib (Bz) as part of both the conditioning regimen and the graft-versus-host disease (GvHD) prophylaxis. Patients received fludarabine, melphalan and Bz (days -9 and -2). GVHD prophylaxis consisted of Bz (days +1, +4, and +7), sirolimus (Siro) from day -5 and tacrolimus (Tk) from -3 (except the first five patients that did not receive Tk). Twenty-five patients with poor prognostic multiple myeloma were included. Eleven out of the 19 patients had high-risk features. Out of the 21 patients evaluable at day +100, 14 were in CR (67%) and 7 (33%) in PR. Cumulative incidence (CI) of nonrelapse mortality at 1 year was 24%. CI of grades 2-4 and 3-4 acute GvHD was 35% and 10%, respectively; CI of chronic GvHD was 35% and 55% at 1 and 2 years, respectively. Overall and event free survival at 2 years were 64% and 31%, respectively. Bz as part of the conditioning regimen and in the combination with Siro/tacrolimus for GvHD prophylaxis is safe and effective allowing an optimal disease control early after transplant and reducing the risk of GvHD.
Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Mieloma Múltiple , Bortezomib/uso terapéutico , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Mieloma Múltiple/terapia , Tacrolimus , Acondicionamiento PretrasplanteRESUMEN
Natural killer (NK) cells are a population of innate type I lymphoid cells essential for early anti-viral responses and are known to modulate the course of humoral and cellular-mediated T cell responses. We assessed the role of NK cells in allogeneic CD8 T cell-mediated responses in an immunocompetent mouse model across an MHC class I histocompatibility barrier to determine its impact in therapeutic clinical interventions with polyclonal or monoclonal antibodies (mAbs) targeting lymphoid cells in transplantation. The administration of an NK cell depleting antibody to either CD8 T cell replete or CD8 T cell-depleted naïve C57BL/6 immunocompetent mice accelerated graft rejection. This accelerated rejection response was associated with an in vivo increased cytotoxic activity of CD8 T cells against bm1 allogeneic hematopoietic cells and bm1 skin allografts. These findings show that NK cells were implicated in the control host anti-donor cytotoxic responses, likely by competing for common cell growth factors in both CD8 T cell replete and CD8 T cell-depleted mice, the latter reconstituting in response to lymphopenia. Our data calls for precaution in solid organ transplantation under tolerogenic protocols involving extensive depletion of lymphocytes. These pharmacological biologics with depleting properties over NK cells may accelerate graft rejection and promote aggressive CD8 T cell cytotoxic alloresponses refractory to current immunosuppression.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Rechazo de Injerto/inmunología , Células Asesinas Naturales/inmunología , Trasplante de Piel , Animales , Presentación de Antígeno , Células Cultivadas , Citotoxicidad Inmunológica , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Isoantígenos/inmunología , Depleción Linfocítica , Ratones , Ratones Endogámicos C57BL , Mutación/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
HLA-matched related or unrelated donors are not universally available. Consequently, patients can be offered hematopoietic stem cell transplantation (HSCT) from alternative donors, including mismatched unrelated donors (MMURD), known to cause a higher incidence of acute GVHD (aGVHD) and chronic GVHD. In vivo T-cell-depletion strategies, such as antithymocyte globulin (ATG) therapy, significantly decrease the risk of GVHD. We performed a multicenter, retrospective study comparing tacrolimus (TAC) and sirolimus (SIR) with or without ATG in 104 patients (TAC-SIR=45, TAC-SIR-ATG=59) who underwent MMURD HSCT. Use of ATG was associated with a lower incidence, albeit not statistically significant, of grades 2-4 aGVHD (46% vs 64%, P=0.09), no difference in grades 3-4 aGVHD (10% vs 15%, P=0.43), a trend for a lower incidence of moderate/severe chronic GVHD (16% vs 37%, P=0.09) and more frequent Epstein-Barr virus reactivation (54% vs 18%, P=0.0002). There were no statistically significant differences in 3-year overall survival (OS) (TAC-SIR-ATG=40% (95% confidence interval (CI)=24-56%) vs TAC-SIR=54% (95% CI=37-70%), P=0.43) or 3-year cumulative incidence of relapse/progression (TAC-SIR-ATG=40% (95% CI=28-58%) vs TAC-SIR=22% (95% CI=13-39%), P=0.92). An intermediate Center for International Blood & Marrow Transplant Research disease risk resulted in a significantly lower non-relapse mortality and better OS at 3 years. Our study suggests that addition of ATG to TAC-SIR in MMURD HSCT does not affect OS when compared with TAC-SIR alone.
Asunto(s)
Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/prevención & control , Sirolimus/administración & dosificación , Trasplante de Células Madre , Tacrolimus/administración & dosificación , Donante no Emparentado , Enfermedad Aguda , Adolescente , Adulto , Anciano , Aloinjertos , Enfermedad Crónica , Supervivencia sin Enfermedad , Femenino , Antígenos HLA , Humanos , Depleción Linfocítica , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de Supervivencia , Linfocitos TRESUMEN
Dendritic cells (DC) play a key role in initiating immune reactions after allogeneic stem cell transplantation. The two main peripheral blood DC populations are myeloid (DC1) and lymphoplasmacytoid (DC2). A new subset of myeloid DC, expressing CD16, has been identified. We analyzed the number and CD86 expression of DC subsets in peripheral blood of 18 healthy donors, before and after granulocyte colony-stimulating factor (G-CSF) and in the inoculum of allogeneic peripheral blood transplants (allo-PBT; n=100) and allogeneic bone marrow transplants (allo-BMT; n=22). Granulocyte colony-stimulating factor administration increased the median number of DC1 (P=0.0007), of DC2 (P<0.0001) and of DC CD16+ (P=0.0001). Granulocyte colony-stimulating factor administration was also associated with a significant decrease of CD86 expression on DC1 (P=0.0003) and with a trend for an increase on DC CD16+ (P=0.07). Recipients of allo-PBT received similar quantities of DC1 and higher doses of DC2 and DC CD16+ than recipients of allo-BMT (P=0.5; P=0.0001; P<0.0001, respectively). Granulocyte colony-stimulating factor modifies the number of DC in peripheral blood and the expression of the costimulatory molecule CD86. This resulted in a different composition of DC2 and especially of DC CD16+ in the harvests, which might explain some of the differences observed in allogeneic reactions after allo-PBT with respect to allo-BMT.
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Antígeno B7-2/genética , Trasplante de Médula Ósea/inmunología , Células Dendríticas/inmunología , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Anticuerpos Monoclonales , Antígenos CD/sangre , Antígenos CD/genética , Trasplante de Médula Ósea/patología , Células Dendríticas/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/inmunología , Humanos , Inmunofenotipificación , Activación de Linfocitos , Subgrupos Linfocitarios/inmunología , Receptores de IgG/sangre , Donantes de Tejidos , Trasplante Homólogo/inmunologíaRESUMEN
In this retrospective study, we evaluated donor lymphocyte infusions given for relapsed (n=48) or persistent (n=15) myeloma following non-myeloablative allogeneic stem cell transplantation (Allo-SCT). Twenty-four of 63 patients (38.1%) responded: 12 patients (19.0%) with a partial response (PR) and 12 patients (19.0%) with a complete response (CR). Overall survival after donor lymphocyte infusions (DLI) was 23.6 months (1.0-50.7+). Median overall survival for non-responding patients was 23.6 months and has not been reached for the patients responding to DLI. In responders, progression-free survival after DLI was 27.8 months (1.2-46.2+). Patients with a PR had a median progression-free survival of 7.0 months, whereas patients with a CR to DLI had a median progression-free survival of 27.8 months. Major toxicities were acute graft-versus-host disease (GVHD) (38.1%) and chronic GVHD (42.9%). Seven patients (11.1%) died from treatment-related mortality. The only significant prognostic factors for response to DLI were the occurrence of acute and chronic GVHD. There was a trend towards significance for time between transplantation and DLI, and response. Donor lymphocyte infusion following non-myeloablative Allo-SCT is a valuable strategy for relapsed or persistent disease.
Asunto(s)
Transfusión de Linfocitos , Mieloma Múltiple/terapia , Trasplante de Células Madre , Enfermedad Aguda , Adulto , Anciano , Enfermedad Crónica , Supervivencia sin Enfermedad , Femenino , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/complicaciones , Mieloma Múltiple/mortalidad , Recurrencia , Inducción de Remisión , Trasplante de Células Madre/mortalidad , Trasplante Homólogo , Resultado del TratamientoRESUMEN
IMPORTANCE: Functional methionine synthase reductase deficiency, also known as cobalamin E disorder, is a rare autosomal recessive inherited disease that results in an impaired remethylation of homocysteine to methionine. It presents with macrocytic anemia, hyperhomocysteinemia, and hypomethioninemia, and may also be accompanied with neurological impairment. CLINICAL PRESENTATION: We describe two new cases of unrelated girls with megaloblastic anemia misclassified at first as congenital dyserythropoietic anemia with development of neurologic dysfunction in one of them. INTERVENTION: The posterior finding of biochemical features (hyperhomocysteinemia and hypomethioninemia) focused the diagnosis on the inborn errors of intracellular vitamin B12. Subsequent molecular analysis of the methionine synthase reductase (MTRR) gene revealed compound heterozygosity for a transition c.1361C > T (p.Ser454Leu) and another, not yet described in literature, c.1677-1G > A (p.Glu560fs) in one patient, and a single homozygosis mutation, c.1361C > T (p.Ser545Leu) in the other one. These mutations confirmed the diagnosis of cobalamin E deficiency. CONCLUSION: Treatment with hydroxocobalamin in combination with betaine appears to be useful for hematological improvement and prevention of brain disabilities in CblE-affected patients. Our study widens the clinical, molecular, metabolic, and cytological knowledge of deficiency MTRR enzyme.
Asunto(s)
Sustitución de Aminoácidos , Anemia Macrocítica , Betaína/administración & dosificación , Ferredoxina-NADP Reductasa , Hidroxocobalamina/administración & dosificación , Errores Innatos del Metabolismo , Adulto , Anemia Macrocítica/tratamiento farmacológico , Anemia Macrocítica/enzimología , Anemia Macrocítica/genética , Niño , Femenino , Ferredoxina-NADP Reductasa/deficiencia , Ferredoxina-NADP Reductasa/genética , Humanos , Hiperhomocisteinemia/tratamiento farmacológico , Hiperhomocisteinemia/enzimología , Hiperhomocisteinemia/genética , Errores Innatos del Metabolismo/tratamiento farmacológico , Errores Innatos del Metabolismo/enzimología , Errores Innatos del Metabolismo/genética , Mutación MissenseRESUMEN
INTRODUCTION: Chromosomal rearrangements involving NUP98 gene have been associated with human leukemias such as de novo AML, therapy-related AML (t-AML), myelodysplastic syndrome (MDS), and chronic myeloid leukemia (CML). Genetic fusion NUP98-HOXA9, caused by t(7;11)(p15;p15), is a recurrent cytogenetic alteration in de novo acute myeloid leukemia (AML) usually found in young Asian patients and its description in therapy-related myeloid neoplasms (t-MN) is rare. Only one Asian case with molecular demonstration of the NUP98-HOXA9 fusion has been reported in therapy-related leukemia. NUP98-HOXA9 leukemogenic mechanism is derived from the transcription factor activity of the chimeric protein, which enhances the expression of genes related to cellular differentiation arrest and proliferation. PATIENTS AND METHODS: We studied a Caucasian woman with a therapy-related acute myeloid leukemia after Ewing's sarcoma. Molecular demonstration of the genetic fusion NUP98-HOXA9 was performed by RT-PCR, and gene expression was analyzed by real-time PCR, including four AML patients with MLL rearrangements for comparative analysis. Cytologic and flow cytometric analysis was also carried out. RESULTS: After cytologic and flow cytometric analysis diagnostics was therapy-related myeloid neoplasm (t-MN). The major component of blasts in the acute leukemia was with neutrophilic differentiation, but 13% erythroid lineage blasts were also found. Cytogenetic and FISH analysis revealed t(7;11)(p15;p15) and NUP98-HOXA9 fusion gene was demonstrated. Gene expression analysis showed upregulation of EVI1 and MEIS1 in the index patient, both of them previously related to a worst outcome. CONCLUSION: In this work, we include a detailed molecular, clinical, cytological, and cytometric study of the second t-AML bearing NUP98-HOXA9 genetic fusion.
Asunto(s)
Proteínas de Unión al ADN/genética , Expresión Génica , Proteínas de Homeodominio/genética , Leucemia Mieloide Aguda/etiología , Células Mieloides/metabolismo , Proteínas de Neoplasias/genética , Neoplasias Primarias Secundarias , Proteínas de Complejo Poro Nuclear/genética , Proteínas de Fusión Oncogénica/genética , Proto-Oncogenes/genética , Factores de Transcripción/genética , Tirosina Quinasa 3 Similar a fms/genética , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Manejo de la Enfermedad , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunofenotipificación , Hibridación Fluorescente in Situ , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Proteína del Locus del Complejo MDS1 y EV11 , Proteína 1 del Sitio de Integración Viral Ecotrópica Mieloide , Translocación GenéticaRESUMEN
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.