RESUMEN
Since we reported the first successful case of allogeneic hematopoietic SCT (allo-HSCT), we have performed allo-HSCT for 29 patients with chronic active EBV infection (CAEBV), using either myeloablative conditioning (MAC) allo-HSCT (MAST) or reduced-intensity conditioning (RIC) allo-HSCT (RIST). In this retrospective analysis we compared the outcomes after MAST and RIST to identify the optimal conditioning for patients with CAEBV. Of 29 patients, 11 underwent allo-HSCT with MAC, consisting of TBI (12 Gy), etoposide (900 mg/m²) and CY (120 mg/kg) or melphalan (210 mg/m²), and the remaining 18 patients received allo-HSCT after RIC, consisting of fludarabine (â¼ 180 mg/m²) and melphalan (140 mg/m²) or CY (120 mg/kg), with/without antithymocyte globulin and low-dose irradiation. Donor sources were 8 related BM, 2 related peripheral blood, 5 CD34 selected cells from HLA-haploidentical donors, 8 unrelated BM and 8 unrelated cord blood. The 3-year-EFS rate was 54.5 ± 15.0% for MAST group and 85.0 ± 8.0% for RIST group, and the 3-year OS rate was 54.5 ± 15.0% for MAST group and 95.0 ± 4.9% for RIST group (P = 0.016). Allo-HSCT after RIC seems to be a promising approach for the treatment of CAEBV.
Asunto(s)
Infecciones por Virus de Epstein-Barr/terapia , Trasplante de Células Madre Hematopoyéticas , Acondicionamiento Pretrasplante/métodos , Adolescente , Adulto , Antígenos CD/metabolismo , Antivirales/uso terapéutico , Niño , Preescolar , Enfermedad Crónica , Infecciones por Virus de Epstein-Barr/tratamiento farmacológico , Infecciones por Virus de Epstein-Barr/virología , Femenino , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/mortalidad , Herpesvirus Humano 4/aislamiento & purificación , Humanos , Lactante , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/virología , Masculino , Estudios Retrospectivos , Análisis de Supervivencia , Trasplante Homólogo , Carga Viral , Adulto JovenAsunto(s)
Proteínas de Unión al ADN/genética , Leucemia Mielomonocítica Aguda/genética , Proteínas de Fusión Oncogénica/genética , Proto-Oncogenes , Factores de Transcripción , Secuencia de Aminoácidos , Secuencia de Bases , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 12/genética , Proteínas de Unión al ADN/metabolismo , Reordenamiento Génico , N-Metiltransferasa de Histona-Lisina , Humanos , Lactante , Masculino , Proteína Quinasa 8 Activada por Mitógenos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Datos de Secuencia Molecular , Proteína de la Leucemia Mieloide-Linfoide , Proteínas Nucleares , Estructura Terciaria de Proteína , Translocación GenéticaRESUMEN
Human herpesvirus 6 (HHV-6) infection and disease are serious complications of allogeneic hematopoietic stem cell transplantation (allo-SCT). Ganciclovir (GCV) is effective against HHV-6 in vitro but the antiviral susceptibility of HHV-6 has not been well characterized in vivo. We retrospectively compared the HHV-6 reactivation rate in pediatric allo-SCT recipients with and without GCV prophylaxis. The HHV-6 reactivation rate at 3 weeks after allo-SCT in patients without prophylactic GCV administration was significantly higher than that in those receiving prophylactic GCV (11/28 vs 0/13, P < 0.01). Five of 36 patients without prophylactic GCV showed clinical manifestations including skin rash, interstitial pneumonitis, persistent thrombocytopenia, enterocolitis and thrombotic microangiopathy, respectively. HHV-6-associated symptoms were observed in one of the 13 patients receiving prophylactic GCV. This patient showed fever, diarrhea and graft rejection concomitantly with a sudden increase of HHV-6 DNA copy number. Patients who received GCV for treatment of HHV-6 infection showed an improvement in symptoms and/or decrease of HHV-6 copy number. Thus, GCV is effective for treating HHV-6 disease after allo-SCT in vivo.
Asunto(s)
Antivirales/uso terapéutico , Ganciclovir/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Herpesvirus Humano 6/efectos de los fármacos , Infecciones por Roseolovirus/prevención & control , Niño , ADN Viral/sangre , Evaluación de Medicamentos , Femenino , Herpes Zóster/prevención & control , Herpesvirus Humano 6/crecimiento & desarrollo , Herpesvirus Humano 6/aislamiento & purificación , Humanos , Masculino , Reacción en Cadena de la Polimerasa , Estudios Retrospectivos , Infecciones por Roseolovirus/tratamiento farmacológico , Infecciones por Roseolovirus/epidemiología , Infecciones por Roseolovirus/mortalidad , Trasplante Homólogo , Viremia/tratamiento farmacológico , Activación Viral/efectos de los fármacosRESUMEN
Unrelated cord blood transplantation (CBT) has been worldwide for bone marrow reconstitution. CBT is associated with a high frequency of engraftment failure and rejection due to a small dose of graft cells. In cases of engraftment failure or rejection following unrelated CBT, retransplantation from the original donors is impossible. We report a successful transplantation with CD34+ blood cells selected from a 2-loci HLA-mismatched mother to a child with acute monocytic leukemia after engraftment failure of the primary CBT. Selected CD34+ blood cell transplantation is a useful approach for retransplantation in the setting of engraftment failure.
Asunto(s)
Antígenos CD34 , Células Sanguíneas/trasplante , Trasplante de Células Madre Hematopoyéticas , Adulto , Antígenos CD34/análisis , Células Sanguíneas/citología , Células Sanguíneas/inmunología , Supervivencia sin Enfermedad , Femenino , Sangre Fetal/citología , Supervivencia de Injerto , Histocompatibilidad , Prueba de Histocompatibilidad , Humanos , Recién Nacido , Leucemia Monocítica Aguda/terapia , MasculinoRESUMEN
We report three pediatric patients with ganciclovir-resistant cytomegalovirus (CMV) retinitis who were successfully treated with foscarnet. The patients were recipients of hematopoietic stem cell transplantation (SCT) from HLA-mismatched donors. Because these patients had developed or experienced progressive CMV retinitis during ganciclovir therapy, they received foscarnet therapy at 60 mg/kg every 8 h. Their retinitis resolved promptly after initiating foscarnet therapy, suggesting foscarnet's effectiveness in treating ganciclovir-resistant CMV infection. The amount of CMV mRNA was quantitatively measured using an NASBA technique, which amplified the beta2.7 transcripts specific for CMV replication. This technique was useful for monitoring disease activity in a more rapid and sensitive manner than the PCR assay for CMV DNA.
Asunto(s)
Antivirales/administración & dosificación , Retinitis por Citomegalovirus/terapia , Farmacorresistencia Viral , Foscarnet/administración & dosificación , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Adolescente , Niño , Citomegalovirus/genética , Retinitis por Citomegalovirus/diagnóstico , Retinitis por Citomegalovirus/etiología , Femenino , Ganciclovir/administración & dosificación , Humanos , Lactante , Técnicas de Amplificación de Ácido Nucleico , ARN Viral/sangreRESUMEN
To assess the involvement of vascular endothelial cell activation and damage in stem cell transplantation (SCT)-related complications, such as acute and chronic GVHD and thrombotic microangiopathy (TMA), we investigated the changes in serum levels of soluble forms of vascular cell adhesion molecule-1 (sVCAM-1) and E-selectin (sE-selectin) in SCT. The soluble form of intercellular adhesion molecule-1 (sICAM-1) was also analyzed. In patients with acute GVHD (grades II-IV), serum levels of sE-selectin and sICAM-1 increased around onset of GVHD (day 30). While the increase of sE-selectin levels was transient, sICAM-1 levels remained high until day 60. In patients with extensive chronic GVHD, sVCAM-1 as well as sE-selectin levels significantly increased. The appearance of clinical symptoms was preceded by elevations of sVCAM-1 and sE-selectin levels on day 60, and sICAM-1 levels on days 30 and 60. For the analysis of TMA, to exclude the influence of GVHD, serum levels were measured in auto-SCT patients. Around the onset of TMA, sVCAM-1 and sE-selectin levels significantly increased in patients with TMA without an increase of sICAM-1 levels. These findings support the notion that activation and injury of endothelium are commonly involved in the pathogenesis of acute and chronic GVHD and TMA.
Asunto(s)
Moléculas de Adhesión Celular/sangre , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Adolescente , Biomarcadores/sangre , Niño , Preescolar , Selectina E/sangre , Endotelio Vascular/lesiones , Endotelio Vascular/metabolismo , Enfermedad Injerto contra Huésped/sangre , Enfermedad Injerto contra Huésped/etiología , Humanos , Lactante , Molécula 1 de Adhesión Intercelular/sangre , Leucemia/complicaciones , Leucemia/terapia , Solubilidad , Trombosis/sangre , Trombosis/etiología , Factores de Tiempo , Trasplante Autólogo/efectos adversos , Trasplante Homólogo/efectos adversos , Molécula 1 de Adhesión Celular Vascular/sangreRESUMEN
The rae28 gene (rae28) is a murine homologue of the Drosophila polyhomeotic gene, which is a member of the Polycomb-group genes. In this study, we examined the role of rae28 in lymphocyte development. Because homozygous rae28-deficient (rae28-/-) mice died in the perinatal period, we examined lymphocyte development by generating chimeric mice reconstituted with green fluorescence protein-labeled mutant fetal liver cells as well as in in vitro culture systems. We further examined RAE28 expression by reverse transcriptase polymerase chain reaction assay in human leukemic cells with B-lineage acute lymphoblastic leukemia (ALL). Severe B-cell maturation arrest was observed in rae28-/- between pro- and pre-B lymphocyte stages. B-cell development was also delayed in heterozygous neonates. Furthermore, interleukin-7-dependent colony-forming ability was impaired not only in homozygous lymphocytes but also in heterozygotes. Its human homologue, RAE28, is located on chromosome 12p13, which frequently is associated with chromosomal abnormalities and loss of heterozygosity in patients with hematologic malignancies. To determine whether a link exists between RAE28 and leukemia, we examined RAE28 expression in leukemic cells from pediatric patients with B-lineage ALL. RAE28 expression was not detected in four B-cell precursor ALL cases of a total of 43 examined, although RAE28 is normally expressed constitutively during the process of B-cell maturation as assessed in isolated cell populations. rae28 plays an important role in the early B-cell developmental stage in a gene dosage-dependent manner. Furthermore, the human RAE28 locus may provide a candidate gene causing the molecular pathogenesis of childhood B-cell precursor ALL.
Asunto(s)
Linfocitos B/citología , Proteínas Portadoras , Hematopoyesis/genética , Proteínas de Homeodominio/genética , Síndromes de Inmunodeficiencia/genética , Proteínas de Neoplasias/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Animales , Linfoma de Burkitt/patología , Diferenciación Celular/genética , Trasplante de Células , Niño , Preescolar , Quimera , Cromosomas Humanos Par 12/genética , Técnicas de Cocultivo , Cruzamientos Genéticos , Femenino , Eliminación de Gen , Regulación Leucémica de la Expresión Génica , Genes Reporteros , Genotipo , Proteínas Fluorescentes Verdes , Células Madre Hematopoyéticas/efectos de los fármacos , Proteínas de Homeodominio/fisiología , Humanos , Interleucina-7/farmacología , Hígado/citología , Hígado/embriología , Proteínas Luminiscentes/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Proteínas de Neoplasias/fisiología , Complejo Represivo Polycomb 1 , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , ARN Mensajero/biosíntesis , ARN Neoplásico/biosíntesis , Proteínas Recombinantes de Fusión/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Linfocitos T/citología , Timo/anomalías , Timo/embriología , Células Tumorales Cultivadas/efectos de los fármacosRESUMEN
We report a 5-year-old boy with juvenile myelomonocytic leukemia (JMML) which relapsed after an allogeneic bone marrow transplant who was successfully treated with interferon-alpha (IFN-alpha). One year after starting the therapy, he remains clinically well and in complete remission while continuing treatment with IFN-alpha and bestatin. Although the precise mechanism by which remission was induced is uncertain, a GVL effect combined with a direct antileukemia effect of IFN-alpha may be responsible. Further assessment of the role of IFN-alpha in relapsed JMLL patients is warranted.
Asunto(s)
Antineoplásicos/uso terapéutico , Trasplante de Médula Ósea , Interferón-alfa/uso terapéutico , Leucemia Mielomonocítica Crónica/terapia , Preescolar , Terapia Combinada , Efecto Injerto vs Leucemia , Humanos , Leucemia Mielomonocítica Crónica/tratamiento farmacológico , MasculinoRESUMEN
We analyzed the expression pattern of adhesion molecules including beta 1-integrins (CD49c, CD49d, CD49e, CD49f), beta 2-integrins (CD11a, CD11b, CD11c), CD44, and CD54 in 141 children with B-cell precursor acute lymphoblastic leukemia (pre-B ALL) and in 21 children with B-cell ALL/non-Hodgkin's lymphoma (B-ALL/NHL). The frequencies of CD11a, CD49f, and CD44 expression were significantly higher in CD34+ pre-B ALL than in CD34- pre-B ALL. Although CD49d, CD49e, and CD44 were less frequently expressed in B-ALL/NHL than in pre-B ALL, the expression of CD11a and CD54 were more frequent in B-ALL/NHL. In pre-B ALL, expression of CD11a positively correlated with that of CD11b (P < .05) and CD54 (P < .01), and CD49c positively correlated with CD49f (P < .01). Of the clinical parameters of patients with pre-B ALL, expression of CD11a was associated with a low leukocyte count (P < .05). The presence of CD54 on the cell surface was an independent factor indicating a poor prognosis. The estimated 5-year event-free survival was 42.3% for CD54+ (n = 31) compared with 70.3% for CD54- patients (n = 38) (P < .05). These findings demonstrated that expression of adhesion molecules is dependent on the phenotype of B-lineage cells and that the expression of some of these molecules has clinical significance.
Asunto(s)
Linfoma de Burkitt/metabolismo , Moléculas de Adhesión Celular/metabolismo , Linfoma de Células B/metabolismo , Antígenos CD/metabolismo , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/patología , Linfoma de Burkitt/diagnóstico , Linfoma de Burkitt/patología , Inmunofenotipificación , Integrinas/metabolismo , Linfoma de Células B/diagnóstico , Linfoma de Células B/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , PronósticoRESUMEN
The Polycomb group of (Pc-G) genes and trithorax group of genes are known to play a crucial role in the maintenance of the transcriptional repression state of Hox genes, probably through modification of the chromatin configuration. The rae28/mph1 gene is a mammalian homologue of the Drosophila polyhomeotic gene, which belongs to the Pc-G genes. As reported previously, we established mice deficient in the rae28/mph1 gene and showed that these homozygous animals displayed the developmental defects compatible with a human congenital disorder, CATCH22 syndrome. In this study we analyzed the structural organization of the human counterpart of the rae28/mph1 gene (RAE28/HPH1) and its processed pseudogene (psiPH), which are located on, respectively, human chromosome 12p13 and 12q13. The HPH1 gene consists of 15 exons spanning approximately 26 kb and its structural organization is well conserved between mouse and human. These genetic information of the RAE28/HPH1 gene may provide an important clue for further examination of its involvement in human congenital disorders related to CATCH22 syndrome.
Asunto(s)
Proteínas Portadoras , Cromosomas Humanos Par 12 , Proteínas de Drosophila , Proteínas de Homeodominio/genética , Animales , Secuencia de Bases , Mapeo Cromosómico , ADN Complementario , Proteínas de Unión al ADN/genética , Humanos , Ratones , Datos de Secuencia Molecular , Nucleoproteínas/genética , Complejo Represivo Polycomb 1 , Análisis de Secuencia de ADN , Homología de Secuencia de Ácido NucleicoRESUMEN
Morphophenotypic lineage switches occur in a small percentage of those with acute leukemia, and the underlying mechanisms are not clear. In this study, we attempted to induce a lineage switch in acute myelocytic leukemia (AML) with monosomy 7, whose lineage had switched from acute T-lymphocytic leukemia (T-ALL) during chemotherapy, in severe combined immunodeficient (SCID) mice. Although the transplanted myeloid cells were engrafted in SCID mice without cytokine administration, T-ALL developed in SCID mice treated with recombinant human granulocyte-macrophage colony-stimulating factor or recombinant human interleukin 3. Analysis of the nucleotide sequences of the rearranged T-cell receptor gamma-chain (TCR-gamma) gene revealed that this lineage switch resulted from the selection of the T-lineage subclone in SCID mice, which had expanded at onset. In addition, we found that the T-lineage and myeloid cells belonged to the distinct subclones, which were different in TCR-gamma gene rearrangements, but were derived from a common clone with an identical N-ras gene mutation for both subclones. In in vitro cultures, only the myeloid subclone grew; the T-lineage subclone failed to grow even in the presence of recombinant human granulocyte-macrophage colony-stimulating factor or recombinant human interleukin 3. These results suggested that the initial diagnostic T-lymphoid subclone, whose growth was dependent on these cytokines and the hematopoietic microenvironment, emerged from a bipotential T-lymphoid/myeloid leukemic stem cell, and further genetic event(s) induced the myeloid subclone, which grew independently of these cytokines and the microenvironment.
Asunto(s)
Linaje de la Célula , Cromosomas Humanos Par 7 , Leucemia Mieloide/patología , Leucemia-Linfoma de Células T del Adulto/patología , Monosomía , Enfermedad Aguda , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Secuencia de Bases , Preescolar , ADN de Neoplasias , Reordenamiento Génico de la Cadena gamma de los Receptores de Antígenos de los Linfocitos T , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Humanos , Interleucina-3/farmacología , Cariotipificación , Leucemia Mieloide/genética , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Leucemia-Linfoma de Células T del Adulto/genética , Masculino , Ratones , Ratones SCID , Datos de Secuencia Molecular , Trasplante de Neoplasias , Proteínas Recombinantes/farmacología , Células Tumorales CultivadasRESUMEN
Major dose-limiting factors of high-dose thiotepa (TEPA) and melphalan are life-threatening mucositis and neurotoxicity. To administer a maximum dose of these drugs safely and to obtain a maximum anti-cancer effect, a double-conditioning regimen with a single grafting, two cycles of administration of a combination of TEPA (300-600 mg/m2) plus melphalan (70-150 mg/m2) with a 1-week interval was attempted in 20 patients with pediatric advanced or chemotherapy-resistant solid tumors (seven rhabdomyosarcoma, four hepatoblastoma, three neuroblastoma and four other malignancy). Combinations of TEPA plus melphalan/busulfan (Bu) (8-10 mg/kg) and TEPA plus Bu were given to four and two patients with brain tumors, respectively. In an additional two patients, three cycles of drug administration were performed. According to the results of the dose-escalating study, the maximum tolerable doses of TEPA and melphalan for children aged 2 years old or older were 1000 mg/m2 and 280 mg/m2, respectively. Mucositis was dose-limiting. Renal toxicity was also dose-limiting in young children (<2 years old). There were two treatment-related deaths (7%) (fungal pneumonia and renal tubular acidosis). Among 13 patients who received high-dose chemotherapy during CR, 10 are alive with no evidence of disease (15-59 months, median: 35 months) and in 13 evaluable patients without CR, six are alive without regrowth of the disease (14-59 months, median: 39 months). Thus, these novel conditioning regimens allowed us to increase the dose intensity to nearly the maximum for each drug and seemed to reduce adverse effects compared to previously reported regimens with these drugs. With regard to the effect on outcome, the results of this study seem to be encouraging, but a further study on a larger number of patients is required.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias/terapia , Adolescente , Adulto , Agranulocitosis/inducido químicamente , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Busulfano/administración & dosificación , Busulfano/efectos adversos , Niño , Preescolar , Trasplante de Células Madre Hematopoyéticas , Humanos , Lactante , Melfalán/administración & dosificación , Melfalán/efectos adversos , Neoplasias/tratamiento farmacológico , Tiotepa/administración & dosificación , Tiotepa/efectos adversos , Trombocitopenia/inducido químicamente , Acondicionamiento PretrasplanteRESUMEN
We examined five children who underwent allogeneic peripheral stem cell transplantation (PSCT) using positively selected CD34+ cells from three or two loci-mismatched donors. CD34+ cells mobilized from peripheral blood were separated by immunomagnetic beads. CD34+ cells at 2.2-6.2 x 10(6)/kg were transplanted into three patients with refractory leukemia, a patient with relapsed medulloblastoma and a patient with Fanconi's anemia following a conditioning regimen which included irradiation, alkylating agents and antithymocyte globulin treatment. The number of infused CD3+ cells included in grafts was 2.3-22.7 x 10(4)/kg. Four patients achieved engraftment and hematopoietic reconstitution (> 5 x 10(8)/l of neutrophils on day 10 or 11). Graft rejection was observed in the patient with Fanconi's anemia, but a rapid engraftment was obtained after second PSCT. Although no prophylactic agents other than ATG (included in the conditioning regimen) were used, greater than grade I acute GVHD was not observed, but limited chronic GVHD was observed in two patients. The two patients with leukemia relapsed on days 103 and 210, respectively, and the patient with medulloblastoma died of disease on day 159. The patient with Fanconi's anemia died of fungal infection. CMV and HHV-6 diseases developed in four and two patients, respectively. Thus, although SCT using positively selected peripheral CD34+ cells may be an alternative approach for overcoming graft rejection and GVHD from HLA- mismatched donors, persistent immune deficiency attributing to extremely low numbers of T cells in grafts can potentially lead to reactivation of herpes viruses.