RESUMEN
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)
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
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
An adequate response of the innate immune system after allo-SCT is crucial for the clinical outcome of patients submitted to this procedure. EP300 is one of the key genes of the innate immune system (IIS). We evaluated the influence of gene variant A>G rs20551 in EP300 in donor and/or recipient on clinical results after HLA-identical sibling allo-SCT. Patients with AA gene variant had a lower relapse incidence (31 vs 48%, P=0.025; odds ratio (OR)=1.6, P=0.05), attained better disease-free survival (AA: 53% vs AG+GG: 24%, P=0.001; OR=1.8, P=0.01), and better OS (AA: 53% vs AG+GG: 34%, P=0.001; OR=1.9, P=0.007). This beneficial association was more evident when AA gene variant was present in both donor and patient. In healthy individuals, AA gene variant was associated with lower IL2 production after a mitogenic stimuli, higher CD4+ cell response after CMV infection, and higher expression of innate immune genes (IRF-3 and MIF), cell cycle genes (AURKB, CCNA2 and CCNB1), lymphocyte survival genes (NFAT5 and SLC38A2), and with a lower expression of P53 compared with recessive GG gene variant. These findings suggest a beneficial effect of the AA gene variant in rs20551 on clinical outcome after allo-SCT.
Asunto(s)
Proteína p300 Asociada a E1A/genética , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/cirugía , Trasplante de Células Madre Hematopoyéticas/métodos , Adolescente , Adulto , Anciano , Supervivencia sin Enfermedad , Proteína p300 Asociada a E1A/inmunología , Antígenos HLA/inmunología , Neoplasias Hematológicas/inmunología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Estudios Retrospectivos , Factores de Riesgo , Donantes de Tejidos , Resultado del Tratamiento , Adulto JovenRESUMEN
Prognosis of patients relapsing after stem cell transplantation (SCT) is poor if no further treatment is given. A second SCT is a limited option in these high-risk patients. We retrospectively analyzed the outcomes of second SCT in acute myeloid leukemia, myelodysplastic syndrome, and acute lymphoblastic leukemia after a first SCT. Twenty-five of 30 patients received second allogeneic SCT. Variables related to survival were disease status before second allogeneic SCT and time interval between transplants more than 1 year (P<.01 and P<.02 in multivariate analysis). Treatment-related mortality was 33% with no impact of the conditioning regimen on overall survival. Second allogeneic SCT in selected patients may be an option in this group with a poor outcome.