RESUMEN

Pediatric chronic kidney disease (CKD) is characterized by many co-morbidities, including impaired growth and development, CKD-mineral and bone disorder, anemia, dysregulated iron metabolism, and cardiovascular disease. In pediatric CKD cohorts, higher circulating concentrations of fibroblast growth factor 23 (FGF23) are associated with some of these adverse clinical outcomes, including CKD progression and left ventricular hypertrophy. It is hypothesized that lowering FGF23 levels will reduce the risk of these events and improve clinical outcomes. Reducing FGF23 levels in CKD may be accomplished by targeting two key stimuli of FGF23 production-dietary phosphate absorption and iron deficiency. Ferric citrate is approved for use as an enteral phosphate binder and iron replacement product in adults with CKD. Clinical trials in adult CKD cohorts have also demonstrated that ferric citrate decreases circulating FGF23 concentrations. This review outlines the possible deleterious effects of excess FGF23 in CKD, summarizes data from the adult CKD clinical trials of ferric citrate, and presents the Ferric Citrate and Chronic Kidney Disease in Children (FIT4KiD) study, a randomized, placebo-controlled trial to evaluate the effects of ferric citrate on FGF23 in pediatric patients with CKD stages 3-4 (ClinicalTrials.gov Identifier NCT04741646).

Asunto(s)

Insuficiencia Renal Crónica , Niño , Compuestos Férricos , Factores de Crecimiento de Fibroblastos/metabolismo , Humanos , Hierro/uso terapéutico , Minerales , Fosfatos , Ensayos Clínicos Controlados Aleatorios como Asunto , Insuficiencia Renal Crónica/complicaciones

RESUMEN

BACKGROUND: This is a case report of an asymptomatic SARS-CoV-2 infection associated with new-onset nephrotic syndrome in a pediatric patient. This is the third case of new-onset nephrotic syndrome in children associated with SARS-CoV-2 infection, but is the first case report describing a new-onset nephrotic syndrome presentation in a patient who had asymptomatic COVID-19 infection. CASE PRESENTATION: This is a case of a previously healthy 5 year old female who presented with new-onset nephrotic syndrome in the setting of an asymptomatic COVID-19 infection. She presented with progressive edema, and laboratory findings were significant for proteinuria and hypercholesterolemia. She was treated with albumin, diuretics, and corticosteroid therapy, and achieved clinical remission of her nephrotic syndrome within 3 weeks of treatment. Though she was at risk of hypercoagulability due to her COVID-19 infection and nephrotic syndrome, she was not treated with anticoagulation, and did not develop any thrombotic events. CONCLUSIONS: Our case report indicates that SARS-CoV-2 infection could be a trigger for nephrotic syndrome, even in the absence of overt COVID-19 symptoms.

Asunto(s)

Infecciones Asintomáticas , COVID-19 , Síndrome Nefrótico , Manejo de Atención al Paciente/métodos , Inducción de Remisión/métodos , COVID-19/complicaciones , COVID-19/diagnóstico , COVID-19/fisiopatología , Preescolar , Edema/diagnóstico , Edema/etiología , Femenino , Humanos , Hipercolesterolemia/diagnóstico , Hipercolesterolemia/etiología , Síndrome Nefrótico/sangre , Síndrome Nefrótico/etiología , Síndrome Nefrótico/terapia , Síndrome Nefrótico/orina , Proteinuria/diagnóstico , Proteinuria/etiología , SARS-CoV-2/aislamiento & purificación , Resultado del Tratamiento

RESUMEN

BACKGROUND: Limited data exist about causes of chronic kidney disease (CKD) and impact on health-related quality of life (HRQoL) in African children. We evaluated types of kidney disease in Ugandan children 0-18 years and compared HRQoL in children with CKD or with benign or resolving kidney disease (non-CKD) to assess predictors of HRQoL. METHODS: Demographic, socioeconomic, and clinical data were obtained for this cross-sectional study. Pediatric Quality of Life Core Scale™ (PedsQL) was used to survey 4 domains and overall HRQoL. CKD and non-CKD scores were compared using unpaired t test. HRQoL predictors were evaluated using linear and logistic regression analyses. RESULTS: One hundred forty-nine children (71 CKD, 78 non-CKD; median age 9 years; male 63%) had the following primary diseases: nephrotic syndrome (56%), congenital anomalies of the urinary tract (CAKUT) (19%), glomerulonephritis (17%), and other (8%). CAKUT was the predominant etiology (39%) for CKD; 63% had advanced stages 3b-5. Overall HRQoL scores were significantly lower for CKD (57 vs. 86 by child report, p < 0.001; 63 vs. 86 by parent proxy report, p < 0.001). Predictors of lower HRQoL were advanced CKD stages 3b-5, primary caregiver non-parent, vitamin D deficiency, and anemia. CONCLUSION: Like other parts of the world, CAKUT was the main cause of CKD. Most CKD children presented at late CKD stages 3b-5. Compared with non-CKD, HRQoL in CKD was much lower; only two-thirds attended school. Vitamin D deficiency and anemia were potentially modifiable predictors of low HRQoL. Interventions with vitamin D, iron, and erythropoietin-stimulating agents might lead to improved HRQoL.

Asunto(s)

Insuficiencia Renal Crónica , Anemia , Niño , Estudios Transversales , Femenino , Humanos , Masculino , Calidad de Vida , Insuficiencia Renal Crónica/epidemiología , Uganda/epidemiología , Anomalías Urogenitales , Reflujo Vesicoureteral , Deficiencia de Vitamina D

RESUMEN

BACKGROUND: End-stage renal disease (ESRD) although rare among infants presents many management challenges. We sought to evaluate factors associated with PD catheter failure among infants initiated on chronic PD. METHODS: A retrospective chart review of all children under two years of age who had PD catheters placed for initiation of chronic PD from 2002 to 2015. Data was extracted for catheter related events occurring within 12 months of catheter placement. Cox and Poisson regression models were used to delineate factors associated catheter complications. RESULTS: Twenty-five infants with median age 18 days had PD catheters placed for chronic dialysis. Common complications included leakage around the exit site (31%), blockage (26%), migration or malposition (23%), catheter-related infections (18%), and other complications (2%). Predictors of initial PD catheter failure were age less than one month at catheter placement (hazard ratio (HR) 7.77, 95% CI, 1.70-35.39, p = 0.008), use of catheter within three days of placement (HR 5.67, 95% CI, 1.39-23.10, p = 0.015) and presence of a hernia (HR 8.64, 95% CI, 1.19-62.36, p = 0.033). In an adjusted Poisson regression model, PD catheter use within three days of placement was the only predictor of any catheter complication over the12 months of follow up. CONCLUSIONS: Use of PD catheters within three days of placement was associated with catheter failure. We recommend that when possible, catheters should be allowed to heal for at least three days prior to use to reduce risk of complications and improve catheter survival.

Asunto(s)

Catéteres de Permanencia/efectos adversos , Fallo Renal Crónico/terapia , Diálisis Peritoneal/efectos adversos , Diálisis Peritoneal/instrumentación , Infecciones Relacionadas con Catéteres/diagnóstico , Infecciones Relacionadas con Catéteres/epidemiología , Infecciones Relacionadas con Catéteres/prevención & control , Catéteres de Permanencia/tendencias , Femenino , Migración de Cuerpo Extraño/diagnóstico , Migración de Cuerpo Extraño/epidemiología , Migración de Cuerpo Extraño/prevención & control , Humanos , Lactante , Recién Nacido , Fallo Renal Crónico/diagnóstico , Fallo Renal Crónico/epidemiología , Masculino , Diálisis Peritoneal/tendencias , Estudios Retrospectivos , Resultado del Tratamiento

RESUMEN

FHL2, a member of the four and one half LIM domain protein family, is a critical transcriptional modulator. Here, we identify FHL2 as a critical regulator of hematopoietic stem cells (HSCs) that is essential for maintaining HSC self-renewal under regenerative stress. We find that Fhl2 loss has limited effects on hematopoiesis under homeostatic conditions. In contrast, Fhl2-null chimeric mice reconstituted with Fhl2-null bone marrow cells developed abnormal hematopoiesis with significantly reduced numbers of HSCs, hematopoietic progenitor cells (HPCs), red blood cells and platelets as well as hemoglobin levels. In addition, HSCs displayed a significantly reduced self-renewal capacity and were skewed toward myeloid lineage differentiation. We find that Fhl2 loss reduces both HSC quiescence and survival in response to regenerative stress, probably as a consequence of Fhl2-loss-mediated downregulation of cyclin-dependent kinase-inhibitors, including p21(Cip) and p27(Kip1). Interestingly, FHL2 is regulated under the control of a tissue-specific promoter in hematopoietic cells and it is downregulated by DNA hypermethylation in the leukemia cell line and primary leukemia cells. Furthermore, we find that downregulation of FHL2 frequently occurs in myelodysplastic syndrome and acute myeloid leukemia patients, raising a possibility that FHL2 downregulation has a role in the pathogenesis of myeloid malignancies.

Asunto(s)

Trasplante de Médula Ósea , Regulación de la Expresión Génica , Proteínas con Homeodominio LIM/genética , Leucemia Mieloide Aguda/genética , Proteínas Musculares/genética , Síndromes Mielodisplásicos/genética , Factores de Transcripción/genética , Animales , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/patología , Proliferación Celular , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Metilación de ADN , Hematopoyesis , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/patología , Humanos , Proteínas con Homeodominio LIM/deficiencia , Proteínas con Homeodominio LIM/metabolismo , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Ratones , Ratones Noqueados , Proteínas Musculares/deficiencia , Proteínas Musculares/metabolismo , Síndromes Mielodisplásicos/metabolismo , Síndromes Mielodisplásicos/patología , Regiones Promotoras Genéticas , Transducción de Señal , Estrés Fisiológico , Factores de Transcripción/deficiencia , Factores de Transcripción/metabolismo , Trasplante Isogénico , Irradiación Corporal Total

RESUMEN

BACKGROUND: We investigated prevalence of acute kidney injury (AKI) at hospitalization and its association with in-hospital mortality among Ugandan children hospitalized with common acute infections, and predictors of mortality among AKI children. METHODS: We enrolled 2,055 children hospitalized with primary diagnoses of acute gastroenteritis, malaria, or pneumonia. Serum creatinine, albumin, electrolytes, hemoglobin, and urine protein were obtained on admission. Participants were assessed for AKI based on serum creatinine levels. Demographic and clinical data were obtained using a primary care provider survey and medical chart review. Logistic regression was used to determine predictors of in-hospital mortality. RESULTS: A total of 278 (13.5%) of children had AKI on admission; for 76.2%, AKI was stage 2 (98/278) or stage 3 (114/278) defined as serum creatinine >2- or 3-fold above normal upper limit for age, respectively. AKI prevalence was particularly high in gastroenteritis (28.6%) and underweight children (20.7%). Twenty-five percent of children with AKI died during hospitalization, compared to 9.9% with no AKI (adjusted odds ratio (aOR) 3.5 (95% CI, 2.2-5.5)). In-hospital mortality risk did not differ by AKI stage. Predictors of in-hospital mortality among AKI children included primary diagnosis of pneumonia, aOR 4.5 (95% CI, 1.8-11.2); proteinuria, aOR = 2.1 (95% CI, 1.0-4.9) and positive human immunodeficiency virus (HIV) status, aOR 5.0 (95% CI, 2.0-12.9). CONCLUSIONS: Among children hospitalized with gastroenteritis, malaria, or pneumonia, AKI at admission was common and associated with high in-hospital mortality.

Asunto(s)

Lesión Renal Aguda/mortalidad , Infecciones/complicaciones , Infecciones/mortalidad , Adolescente , Factores de Edad , Niño , Preescolar , Creatinina/sangre , Femenino , Gastroenteritis/complicaciones , Gastroenteritis/mortalidad , Infecciones por VIH/microbiología , Mortalidad Hospitalaria , Humanos , Lactante , Recién Nacido , Pruebas de Función Renal , Modelos Logísticos , Malaria/complicaciones , Malaria/mortalidad , Masculino , Oportunidad Relativa , Neumonía/complicaciones , Neumonía/mortalidad , Prevalencia , Proteinuria/mortalidad , Riesgo , Factores Sexuales , Delgadez/mortalidad , Uganda/epidemiología

Asunto(s)

Mieloma Múltiple/etnología , Mieloma Múltiple/terapia , Trasplante de Células Madre/métodos , Adulto , Negro o Afroamericano , Anciano , Anciano de 80 o más Años , Terapia Combinada , Humanos , Persona de Mediana Edad

RESUMEN

BACKGROUND: Human immunodeficiency virus (HIV)-1 infection increases the burden of malaria by increasing susceptibility to infection and decreasing the response to malarial treatment. HIV-1 has also been found to suppress the immune system and predispose to severe forms of malaria in adults. There is still a paucity of data on the association between HIV-1 infection and cerebral malaria in children. The aim of this study was to determine whether HIV-1 infection is a risk factor for cerebral malaria in children. METHOD: We conducted an unmatched case-control study, in which 100 children with cerebral malaria were compared with 132 with uncomplicated malaria and 120 with no malaria. In stratified analyses we estimated odds ratios (ORs) and 95% confidence intervals (CIs) adjusted for age. RESULTS: HIV-1 infection was present in 9% of children with cerebral malaria compared to 2.3% in uncomplicated malaria (age-adjusted odds ratio (aOR) 5.94 (95% confidence interval (CI) 1.36-25.94, p = 0.012); and 2.5% in children with no malaria (aOR 3.85 (95% CI0.99-14.93, p = 0.037). The age-adjusted odds of being HIV-positive among children with cerebral malaria compared to the control groups (children with uncomplicated malaria and no malaria) was 4.98 (95% CI 1.54-16.07), p-value = 0.003. CONCLUSIONS: HIV-1 infection is associated with clinical presentation of cerebral malaria in children. Clinicians should ensure that children diagnosed with HIV infection are initiated on cotrimoxazole prophylaxis as soon as the diagnosis is made and caretakers counselled on the importance of adherence to the cotrimoxazole towards reducing the risk of acquiring P.falciparum malaria and associated complications such as cerebral malaria. Other malaria preventive measures such as use of insecticide-treated mosquito nets should also be emphasized during counselling sessions.

Asunto(s)

Infecciones por VIH/epidemiología , VIH-1 , Malaria Cerebral/epidemiología , Parasitemia/epidemiología , Anemia/epidemiología , Antimaláricos/uso terapéutico , Recuento de Linfocito CD4 , Estudios de Casos y Controles , Niño , Preescolar , Susceptibilidad a Enfermedades , Femenino , Infecciones por VIH/diagnóstico , Seropositividad para VIH , Humanos , Huésped Inmunocomprometido , Lactante , Malaria Cerebral/tratamiento farmacológico , Malaria Cerebral/parasitología , Masculino , Parasitemia/tratamiento farmacológico , Factores de Riesgo , Uganda/epidemiología

RESUMEN

Primed antidonor alloreactive T cells are detrimental to transplant outcome, but factors that impact the strength of this immune response prior to transplantation are unknown. We tested peripheral blood mononuclear cells from dialysis patients, against panels of allogeneic, primary B-cell lines in a newly standardized IFNγ ELISPOT panel of reactive T cell (PRT) assay. Results were correlated with known alloantibody-sensitizing events and other clinical parameters. As 25-OH-vitamin D deficiency is associated with enhanced cellular immunity, is common in dialysis patients and is correctable, we assessed the relationship between serum 25-OH-vitamin D and the PRT. Using independent test and validation cohorts we found that low serum levels of 25-OH-vitamin D (<26 ng/mL) correlated with high-PRT values (in the upper 50th percentile, OR 0.02, p = 0.01) independent of age, sex, race, previous transplant, transfusion, pregnancy, time on dialysis, panel of reactive antibody, iPTH, and treatment with 1,25-OH-vitamin D. The data provide a potential mechanism for the possible relationship between vitamin D deficiency and poor posttransplant outcome, and support studies to test the impact of 25-OH-vitamin D repletion on alloimmunity and allograft injury in kidney transplant candidates.

Asunto(s)

Diálisis Renal , Linfocitos T/inmunología , Deficiencia de Vitamina D/complicaciones , Adulto , Calcifediol/sangre , Femenino , Humanos , Trasplante de Riñón/inmunología , Masculino , Persona de Mediana Edad , Deficiencia de Vitamina D/inmunología

Asunto(s)

Trasplante de Células Madre Hematopoyéticas , Subtipo H1N1 del Virus de la Influenza A/inmunología , Gripe Humana/inmunología , Gripe Humana/virología , Adulto , Femenino , Neoplasias Hematológicas/inmunología , Neoplasias Hematológicas/cirugía , Neoplasias Hematológicas/virología , Humanos , Gripe Humana/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Adulto Joven

RESUMEN

A pretransplant test dose of i.v. BU was previously used in pediatric patients undergoing a reduced-intensity allogeneic hematopoietic SCT (HSCT). Here, we used a BU test dose in 23 adult patients who were not pancytopenic and underwent a myeloablative allogeneic HSCT prepared with fludarabine and i.v. BU (FluBU). Pharmacokinetics (PK) of BU were calculated after a test dose (0.8 mg/kg) was performed 2 weeks before transplant. Targeted BU area under the curve (AUC) range was 4800-5200 microM min. The mean BU dose calculated after the test dose was 3.5+/-0.5 mg/kg. To validate the test dose, PK studies were repeated in 17 patients after the first dose of BU during the conditioning regimen. An AUC below the therapeutic value of 4000 microM min was observed in 23% of the patients receiving a wt-based dose and in 0% of patients whose dose was calculated on the basis of the test dose (P=0.03). In patients who had a test dose, a significant correlation (P<0.0001) between the first and subsequent doses of BU during the conditioning regimen was observed. Our findings may allow more centers to pursue transplant strategies with targeted BU by overcoming the time limitation for PK studies during the conditioning regimen.

Asunto(s)

Busulfano/farmacocinética , Trasplante de Células Madre Hematopoyéticas/métodos , Acondicionamiento Pretrasplante , Vidarabina/análogos & derivados , Adolescente , Adulto , Área Bajo la Curva , Busulfano/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Acondicionamiento Pretrasplante/métodos , Vidarabina/uso terapéutico

RESUMEN

In this study, we utilized a conditioning regimen with fludarabine and myeloablative dose i.v. BU (12.8 mg/kg) (FluBU) in 36 adult patients (median age: 44 years, range: 18-61) with myeloid or lymphoid malignancies at standard risk (n=10) or high risk of relapse (n=26), who received an allogeneic hematopoietic SCT (HSCT) from HLA-matched related (n=16) or unrelated (n=20) donors. The source of hematopoietic stem cells was peripheral blood in 28 and marrow in 8 cases. Rabbit-antithymocyte globulin at 7 mg/kg was utilized in 21 patients. Acute GVHD grade II-IV was observed in 19% of the patients (grade III-IV in 14% of patients) and chronic GVHD in 11 of 30 evaluable patients (37%). At median follow-up of 737 days (range: 152-1,737) for alive patients, overall survival rates in standard- and high-risk patients were 80 and 35%, respectively, and event-free survival rates were 70 and 31%, respectively. TRM was 10% in standard-risk and 19% in high-risk patients. Post transplant relapse was observed in 20% standard-risk and in 46% high-risk patients. FluBU conditioning regimen is associated with a limited hematologic and extrahematologic toxicity and with an antitumor activity comparable to other standard myeloablative regimens.

Asunto(s)

Trasplante de Médula Ósea/métodos , Busulfano/administración & dosificación , Trasplante de Células Madre Hematopoyéticas/métodos , Agonistas Mieloablativos/administración & dosificación , Acondicionamiento Pretrasplante/métodos , Vidarabina/análogos & derivados , Adolescente , Adulto , Supervivencia sin Enfermedad , Quimioterapia Combinada , Femenino , Humanos , Infusiones Intravenosas , Leucemia/terapia , Linfoma no Hodgkin/terapia , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/terapia , Estudios Prospectivos , Trasplante Homólogo , Vidarabina/uso terapéutico

RESUMEN

Fludarabine was utilized in the conditioning regimen of 30 adult patients undergoing an allogeneic hematopoietic stem cell transplant. In 18 patients it was combined with full-dose busulfan (FluBu) as a myeloablative regimen and in 12 cases with melphalan (FluMel) as a reduced intensity conditioning (RIC) regimen. Patients in the FluBu group were younger than in the FluMel group (P=0.03). Of 30 patients, 24 received peripheral blood stem cells (PBSC) whereas six patients in the FluBu group received bone marrow cells. The hematological toxicity of each regimen was evaluated by analyzing the kinetics of the neutropenia induced by preparative regimens and the time to recovery of the absolute neutrophils count (ANC) and platelets post transplantation. In PBSC transplants, the median day of severe neutropenia (<500 ANC/microl) occurred on day +6 after the FluBu regimen and on day +3 after FluMel (P=ns), whereas both groups had a duration of severe neutropenia of 9 days and a comparable time for ANC and platelet engraftment. Extra-hematological toxicities were also comparable in the two groups. These findings suggest that the hematological and extra-hematological toxicities induced by fludarabine/full-dose i.v. busulfan are similar to those induced by a standard RIC regimen such as fludarabine/melphalan.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Agonistas Mieloablativos/farmacología , Acondicionamiento Pretrasplante/métodos , Adulto , Busulfano/administración & dosificación , Femenino , Supervivencia de Injerto/fisiología , Neoplasias Hematológicas/terapia , Humanos , Masculino , Melfalán/administración & dosificación , Persona de Mediana Edad , Neutropenia/inducido químicamente , Neutropenia/terapia , Análisis de Supervivencia , Trasplante Homólogo/métodos , Resultado del Tratamiento , Vidarabina/administración & dosificación , Vidarabina/análogos & derivados

RESUMEN

Multiple myeloma (MM) has a double incidence in African-American (AA) than in non-AA patients and previous studies have shown a higher mortality in the former patient population. Here, we retrospectively analyzed the results of autologous stem cell transplantation (ASCT) in 38 AA and 32 non-AA consecutive patients. The two groups were comparable at diagnosis for age, stage of the disease, cytogenetic abnormalities, beta(2) microglobulin and albumin blood levels, and plasma cell marrow infiltration. The rates of complete and partial response observed in AA and non-AA patients after induction chemotherapy (9 and 42 vs 13 and 33%) and at 2 months (31 and 25 vs 30 and 20%) following ASCT were similar. At 6 months after ASCT, a greater relapse rate was observed in non-AA patients (P=0.009). At a median follow-up of 26 months, AA patients had a greater event-free survival (P=0.02) than non-AA patients, whereas overall survival was comparable in the two groups. The initial finding that AA patients with MM, compared to non-AA patients, had more prolonged responses and comparable survival after ASCT suggests that intensified chemotherapy is equally effective in patients of various ethnicities.

Asunto(s)

Mieloma Múltiple/terapia , Trasplante de Células Madre , Adulto , Negro o Afroamericano , Anciano , Médula Ósea/patología , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/sangre , Mieloma Múltiple/etnología , Mieloma Múltiple/mortalidad , Mieloma Múltiple/patología , Recurrencia , Inducción de Remisión , Estudios Retrospectivos , Albúmina Sérica/análisis , Factores de Tiempo , Trasplante Autólogo , Microglobulina beta-2/sangre

Asunto(s)

Conservación de la Sangre , Transfusión de Sangre Autóloga , Eritropoyetina/farmacología , Trasplante de Células Madre Hematopoyéticas , Testigos de Jehová , Acondicionamiento Pretrasplante , Adulto , Conservación de la Sangre/métodos , Transfusión de Sangre Autóloga/psicología , Femenino , Humanos , Testigos de Jehová/psicología , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Proteínas Recombinantes , Trasplante Homólogo

RESUMEN

A total of 31 consecutive patients with hematologic malignancies who were considered poor candidates for TBI underwent allogeneic stem cell transplantation after conditioning with fludarabine and melphalan. A total of 25 matched sibling recipients received fludarabine 25 mg/m(2) x 5 days and melphalan 70 mg/m(2) x 2 days. For unrelated and haploidentical donor recipients, fludarabine was increased to 30 mg/m(2) and ATG 30 mg/kg x 4 days was added. Graft-versus-host disease prophylaxis consisted of tacrolimus and mini methotrexate. All patients engrafted. Regimen-related toxicity was considerable and included mainly renal, hepatic and mucosal toxicity. There were seven regimen-related-deaths including two VOD, two pulmonary, one renal, one cardiac and one mucosal toxicity. One case of fatal pulmonary toxicity death could be attributed to pre-existing pulmonary damage. Progression-free survival at 12 months was 44% (90% CI: 30-58%) for recipients of HLA-identical sibling transplants and 33% (90% CI: 21-45%) for all patients. In conclusion, the fludarabine-melphalan regimen leads to consistent engraftment. The regimen-related toxicity is considerable and cannot be explained solely by patient selection. Cardiac toxicity is emerging as a unique toxicity of this regimen. Despite toxicity, fludarabine-melphalan has considerable activity and leads to durable remission in a proportion of patients.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/toxicidad , Neoplasias Hematológicas/terapia , Acondicionamiento Pretrasplante/efectos adversos , Vidarabina/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Supervivencia sin Enfermedad , Supervivencia de Injerto , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/prevención & control , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/mortalidad , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Melfalán/administración & dosificación , Melfalán/toxicidad , Hermanos , Acondicionamiento Pretrasplante/métodos , Acondicionamiento Pretrasplante/mortalidad , Trasplante Homólogo , Vidarabina/administración & dosificación , Vidarabina/toxicidad

RESUMEN

Fludarabine, thiotepa and total body irradiation (TBI) has been used as conditioning in haplo-identical transplantation. We studied this conditioning regimen in adults undergoing matched sibling transplantation and alternative donor transplantation. A total of 30 consecutive patients underwent matched related, haplo-identical related or matched unrelated donor transplantation with fludarabine, thiotepa and TBI conditioning. All but four had advanced hematologic malignancies. For haplo-identical transplant, ATG was added to the regimen. All patients received peripheral blood stem cells; these were T-cell depleted for 2-antigen or 3-antigen mismatched related transplantation. Additional graft-versus-host disease prophylaxis consisted of tacrolimus and mini-methotrexate. One recipient of haplo-identical transplant failed to engraft; all other evaluable patients had prompt engraftment. Four patients died of regimen-related toxicity. In all, 14 additional patients died of regimen-related causes including four from failure to thrive with persistent thrombocytopenia and four from delayed pulmonary toxicity. Six patients relapsed. Progression-free survival at 12 months was 47% (90% CI: 25-69%) for recipients of HLA-identical sibling transplants and 30% (90% CI: 14-46%) for all patients. Five of six long-term survivors have extensive chronic GVHD. As a result of the delayed complications and a relatively high recurrence rate, we abandoned this regimen.

Asunto(s)

Antineoplásicos Alquilantes/toxicidad , Neoplasias Hematológicas/terapia , Trasplante de Células Madre de Sangre Periférica/métodos , Acondicionamiento Pretrasplante/métodos , Vidarabina/análogos & derivados , Irradiación Corporal Total/efectos adversos , Adolescente , Adulto , Antineoplásicos Alquilantes/administración & dosificación , Niño , Terapia Combinada , Supervivencia de Injerto , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/inmunología , Haplotipos , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/mortalidad , Histocompatibilidad , Humanos , Persona de Mediana Edad , Trasplante de Células Madre de Sangre Periférica/efectos adversos , Trasplante de Células Madre de Sangre Periférica/mortalidad , Análisis de Supervivencia , Tiotepa/administración & dosificación , Tiotepa/toxicidad , Acondicionamiento Pretrasplante/efectos adversos , Acondicionamiento Pretrasplante/mortalidad , Trasplante Homólogo/inmunología , Insuficiencia del Tratamiento , Resultado del Tratamiento , Vidarabina/administración & dosificación , Vidarabina/toxicidad , Irradiación Corporal Total/métodos

RESUMEN

To establish the incidence of CMV viremia after allogeneic blood stem cell transplantation, we studied 51 consecutive allogeneic peripheral blood stem cell (PBSC) transplant recipients. A total of 12 recipients were at moderate risk for CMV disease and 39 were at high risk. Conditioning regimens varied, but GvHD prophylaxis consisted of tacrolimus and mini-methotrexate in all patients. All patients received prophylactic ganciclovir from admission until day -2 and prophylactic acyclovir from day -1 until day 180 after transplantation. CMV viremia was treated with ganciclovir. Using a PCR-based technique, the cumulative incidence of CMV viremia was 31+/-14% by day 100 and 35+/-14% by day 150. Donor type, CMV risk group, underlying disorder, conditioning regimen, GvHD, and steroid use were not associated with the risk for CMV viremia. No cases of CMV disease occurred. We hypothesize that the low rate of CMV viremia and the absence of CMV disease in this cohort of PBSCT transplant recipients, which contrasts with other reports, may be related to the prophylactic use of high-dose acyclovir and possibly to pretransplant use of ganciclovir.

Asunto(s)

Aciclovir/uso terapéutico , Infecciones por Citomegalovirus/prevención & control , Ganciclovir/uso terapéutico , Trasplante de Células Madre de Sangre Periférica/efectos adversos , Premedicación , Aciclovir/administración & dosificación , Adolescente , Adulto , Antivirales/administración & dosificación , Antivirales/uso terapéutico , Infecciones por Citomegalovirus/tratamiento farmacológico , Femenino , Ganciclovir/administración & dosificación , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Trasplante de Células Madre de Sangre Periférica/métodos , Reacción en Cadena de la Polimerasa , Factores de Riesgo , Trasplante Homólogo , Viremia/diagnóstico , Viremia/tratamiento farmacológico , Viremia/prevención & control

RESUMEN

Severe regimen-related toxicity often complicates second transplant procedures performed in patients with hematological malignancies that have relapsed after an initial hematopoietic stem cell (HSC) transplant. Therefore, we studied the safety and efficacy of a reduced-intensity fludarabine and melphalan based conditioning regimen in 11 patients who had relapsed following an autologous (n = 7) or allogeneic (n = 4) HSC transplant. All patients received allogeneic peripheral blood HSC from either an HLA-identical (n = 7) or an HLA-mismatched (n = 4) relative. Diagnoses included AML (n = 9), ALL (n = 1), or Hodgkin's disease (n = 1). Only one patient was in complete remission at the time of second transplant. The median interval between first transplant and relapse was 163 days (range 58-1885). Recipients of HLA-mismatched transplants received antithymocyte globulin in addition to fludarabine and melphalan as part of the conditioning regimen. All 11 patients received acute GVHD prophylaxis consisting of tacrolimus and methotrexate. Ten of 11 patients achieved hematopoietic engraftment with a median time to absolute neutrophil count >0.5 x 10(9)/l and to platelet count of >20 x 10(9)/l of 14 and 19 days, respectively. All engrafting patients achieved 100% donor chimerism on initial analysis, except for one with persistent leukemia at day +19. Two patients experienced grade 3 regimen-related toxicity, manifesting as acute renal failure. Acute GVHD grades 2-4 occurred in two recipients and chronic GVHD in four. The 100-day mortality from all causes was 36%. Ten of 11 patients (91%) died a median of 140 days (range 9-996) after the second transplant. The causes of death included relapse (n = 5), sepsis (n = 4), and idiopathic pneumonia syndrome (n = 1). One patient with AML survives in remission at 880 days post-transplant. We conclude that fludarabine- and melphalan-based conditioning promotes full donor chimerism, even following HLA-mismatched transplants. However, the regimen may be more beneficial when applied to patients undergoing allogeneic HSC transplantation earlier in their disease course.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Acondicionamiento Pretrasplante/métodos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidad , Causas de Muerte , Femenino , Supervivencia de Injerto/inmunología , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/mortalidad , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Masculino , Melfalán/administración & dosificación , Persona de Mediana Edad , Recurrencia , Terapia Recuperativa , Tasa de Supervivencia , Quimera por Trasplante , Acondicionamiento Pretrasplante/mortalidad , Acondicionamiento Pretrasplante/normas , Resultado del Tratamiento , Vidarabina/administración & dosificación , Vidarabina/análogos & derivados

RESUMEN

PURPOSE: To evaluate whether administration of interleukin-2 (IL-2) with granulocyte colony-stimulating factor (G-CSF) improves mobilization of immune effector cells into the stem-cell graft of patients undergoing high-dose chemotherapy and autografting. PATIENTS AND METHODS: We performed a trial of stem-cell mobilization with IL-2 and G-CSF in advanced breast cancer patients receiving high-dose chemotherapy with cyclophosphamide, thiotepa, and carboplatin and stem cells followed by IL-2. The trial defined immune, hematologic, and clinical effects of IL-2 in this setting. RESULTS: Of 32 patients enrolled, nine received G-CSF alone for mobilization. Twenty-one of 23 patients mobilized with IL-2 plus G-CSF had stem cells collected with more mononuclear cells than those receiving G-CSF (19.3 v 10.4 x 10(8)/kg; P =.006), but fewer CD34(+) progenitor cells (6.9 v 22.0 x 10(6)/kg; P =.049). The IL-2 plus G-CSF-mobilized patients had greater numbers of activated T (CD3(+)/CD25(+)) cells (P =.009), natural killer (NK; CD56(+)) cells (P =.007), and activated NK (CD56 bright(+)) cells (P: =.039) than those patients mobilized with G-CSF. NK (P =.042) and lymphokine-activated killer (LAK) (P =.016) activity was increased in those mobilized with IL-2 + G-CSF, whereas G-CSF-mobilized patients had a decline in cytolytic activity. In the third week posttransplantation, immune reconstitution was superior in those mobilized with IL-2 plus G-CSF based on greater numbers of activated T cells (P =.003), activated NK cells (P =.04), and greater LAK activity (P =.003). The 16 of 21 IL-2 + G-CSF-mobilized patients with adequate numbers of stem cells (> 1.5 x 10(6) CD34(+) cells/kg) collected engrafted rapidly posttransplantation. CONCLUSION: The results demonstrate that G-CSF + IL-2 can enhance the number and function of antitumor effector cells in a mobilized autograft without impairing the hematologic engraftment, provided that CD34 cell counts are more than 1.5 x 10(6) cells/kg. Mobilization of CD34(+) stem cells does seem to be adversely affected. In those mobilized with IL-2 and G-CSF, post-stem-cell immune reconstitution of antitumor immune effector cells was enhanced.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/terapia , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Movilización de Célula Madre Hematopoyética/métodos , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/inmunología , Interleucina-2/administración & dosificación , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/inmunología , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Citotoxicidad Inmunológica/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Supervivencia de Injerto/efectos de los fármacos , Supervivencia de Injerto/inmunología , Movilización de Célula Madre Hematopoyética/efectos adversos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Células Madre Hematopoyéticas/efectos de los fármacos , Humanos , Infusiones Intraóseas , Interleucina-2/efectos adversos , Persona de Mediana Edad , Proyectos Piloto , Tiotepa/administración & dosificación , Tiotepa/efectos adversos