RESUMEN
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 , Humanos , Tirosina Quinasa 3 Similar a fms/genética , Anciano , Masculino , Femenino , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/diagnóstico , Proteínas Nucleares/genética , Estudios Retrospectivos , Persona de Mediana Edad , Anciano de 80 o más Años , Pronóstico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Vidarabina/análogos & derivados , Vidarabina/uso terapéutico , Vidarabina/administración & dosificación , Adulto , Tasa de SupervivenciaRESUMEN
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
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 , Humanos , Femenino , Enfermedad Injerto contra Huésped/diagnóstico , Estudios Transversales , Estudios Retrospectivos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Persona de Mediana Edad , Adulto , Enfermedades de los Genitales Femeninos/etiología , Enfermedad Crónica , Disfunciones Sexuales Fisiológicas/etiología , Disfunciones Sexuales Fisiológicas/epidemiología , Ginecología , Dispareunia/etiología , Dispareunia/epidemiología , Prevalencia , Síndrome de Bronquiolitis Obliterante , GinecólogosRESUMEN
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
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
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/genéticaAsunto(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
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
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 TAsunto(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 HomólogoAsunto(s)
Corazón/fisiopatología , Leucemia/terapia , Trasplante de Células Madre , Adolescente , Adulto , Anciano , Presión Sanguínea , Diástole , Ecocardiografía , Femenino , Humanos , Leucemia/diagnóstico , Masculino , Persona de Mediana Edad , Periodo Preoperatorio , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Sístole , Factores de Tiempo , Trasplante Homólogo , Resultado del Tratamiento , Función Ventricular Izquierda , Adulto JovenRESUMEN
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 GenéticaAsunto(s)
Biomarcadores de Tumor/genética , Médula Ósea/patología , Células Dendríticas/patología , Neoplasias Hematológicas/diagnóstico , Reacción del Ácido Peryódico de Schiff , Vacuolas/patología , Anciano , Antígenos CD/genética , Protocolos de Quimioterapia Combinada Antineoplásica , Médula Ósea/metabolismo , Ciclofosfamida , Células Dendríticas/metabolismo , Doxorrubicina , Rayos gamma , Expresión Génica , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patología , Neoplasias Hematológicas/terapia , Humanos , Masculino , Cuidados Paliativos , Prednisona , Vacuolas/metabolismo , VincristinaRESUMEN
Large studies, mostly based on series of patients receiving CSA/tacrolimus (TKR) plus MTX as immunoprophylaxis, have demonstrated a deleterious effect on survival of the presence of a single mismatch out of eight loci after allogeneic hematopoietic SCT (alloHSCT). We retrospectively analyzed a series of 159 adult patients who received sirolimus(SRL)/TKR prophylaxis after alloHSCT. We compared overall outcomes according to HLA compatibility in A, B, C and DRB1 loci at the allele level: 7/8 (n=20) vs 8/8 (n=139). Donor type was unrelated in 95% vs 70% among 7/8 vs 8/8 pairs, respectively (P=0.01). No significant differences were observed in 3-year OS (68 vs 62%), 3-year EFS (53 vs 49%) and 1-year non-relapse mortality (9 vs 13%). Cumulative incidence of grades II-IV acute GVHD (aGVHD) was significantly higher in 7/8 alloHSCT (68% vs 42%, P<0.001) but no significant differences were found for III-IV aGVHD (4.5% vs 11%), overall (35% vs 53%) and extensive (20% vs 35%) chronic GHVD in 7/8 vs 8/8 subgroups, respectively. In summary, the present study indicates favorable outcomes after alloHSCT using the combination of SRL/TKR combination as GVHD prophylaxis with OS in the range of 55-70%, and non-significant differences in overall outcomes, irrespective of the presence of any mismatches at obligatory loci.
Asunto(s)
Enfermedad Injerto contra Huésped , Antígenos HLA , Inmunosupresores/administración & dosificación , Sirolimus/administración & dosificación , Trasplante de Células Madre , Tacrolimus/administración & dosificación , Acondicionamiento Pretrasplante , Adolescente , Adulto , Anciano , Aloinjertos , Supervivencia sin Enfermedad , Femenino , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/prevención & control , Neoplasias Hematológicas/mortalidad , Neoplasias Hematológicas/terapia , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Tasa de SupervivenciaRESUMEN
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.
Asunto(s)
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
Frequency of additional chromosomal abnormalities in chronic myeloid leukemia (CML) is estimated to be 7% in chronic phase and increases to 40-70% in advanced disease. Progression of CML from chronic phase to accelerated phase or blast crisis is often associated with secondary chromosomal aberrations. We report an exceptional case of CML as debut in lymphoblastic blast crisis and a subsequent progression in myeloblastic blast crisis with rare cytogenetic abnormalities.
RESUMEN
The role of hemopoietic stem cell transplantation (HSCT) is not well established in certain types of lymphoma, such as those with a high relapse risk or relapsing after initial therapy. New chemotherapeutic schemes and immunotherapy have improved survival of these patients. Nevertheless, there is not enough evidence regarding whether transplantation is the best therapeutic approach. Moreover, published data on long-term follow-up of high-risk lymphoma patients treated with HSCT are scarce. We analyzed 177 consecutive patients diagnosed with a high risk of relapse or with relapsed lymphoma who underwent HSCT after induction with standard chemotherapy in a tertiary academic center from 1989 to 2013. The median age was 40 years. Diagnoses were Hodgkin disease (n = 56), diffuse large B-cell lymphoma (n = 44), follicular lymphoma (n = 29), mantle cell lymphoma (n = 15), T-cell lymphoma (n = 18), and others (n = 15). Patients received either an autologous graft (n = 154) in first complete remission (1CR; n = 59) or more advanced stages (AS; n = 95), or an allogeneic graft (n = 23) in 1CR (n = 4) or AS (n = 19). In the autologous group, overall survival (OS) at 5 years was 57% and 75% in the periods 1989-2001 and 2002-2013, respectively (P = .05). Patients receiving an allogeneic graft presented an OS of 25% and 43% in the 2 periods. With a mean follow-up of 5 years (95% confidence interval 3.5-6.6), for patients receiving a transplant in 1CR, OS at 5 years was 80%, and for those receiving a transplant in AS it was 59% (P = .003). Nonrelapse mortality (NRM) at 5 years was 3.1% in the autologous group and 27.9% in the allogeneic group (P < .001). The main cause of NRM was infection (44%) in the whole cohort. All this leads to the conclusion that transplantation, as a therapeutic strategy, has shown a high long-term OS in this subgroup of patients with such a poor prognosis. OS improved over the years and reaching 1CR was a good prognostic feature. Infections were the main cause of NRM.