RESUMO
Umbilical cord blood is the preferred donor cell source for children with Inherited Metabolic disorders undergoing Hematopoietic Cell Transplant (HCT), and its use has been associated with improved "engrafted survival" and higher donor chimerism compared to other cell sources. However, as in other pediatric cord blood transplants for non-malignant disease, immune-mediated cytopenia and primary graft failure limit its use, and the latter remains the commonest cause of death following cord blood transplant for non-malignant disease. We have previously shown an association between immune-mediated cytopenia and graft failure in inherited metabolic diseases suggesting that both immune-mediated cytopenia and graft failure could be mediated by antibodies from the residual recipient B cells. Since rituximab is effective in depletion of B cells and management of refractory immune-mediated cytopenia following HCT, we have added rituximab to the conditioning regimen. We studied 57 patients in 2 centers who received myeloablative conditioning for cord blood transplant in Hurler syndrome, and report a significant improvement in event-free survival with reduced incidence of graft failure and without any evidence of immune-mediated cytopenia in those patients that had received rituximab.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Mucopolissacaridose I , Criança , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Rituximab/uso terapêutico , Condicionamento Pré-Transplante/efeitos adversosRESUMO
BACKGROUND: Ciprofloxacin is used as antimicrobial prophylaxis in pediatric acute lymphoblastic leukemia (ALL) to decrease infections with gram-negative bacteria. However, there are no clear guidelines concerning prophylactic dose. AIMS: To determine the pharmacokinetics and pharmacodynamics (PKPD) of ciprofloxacin prophylaxis in a pediatric ALL population. The effect of patient characteristics and antileukemic treatment on ciprofloxacin exposure, the area under the concentration time curve over minimal inhibitory concentration (AUC24/MIC) ratios, and emergence of resistance were studied. METHODS: A total of 615 samples from 129 children (0-18 years) with ALL were collected in a multicenter prospective study. A population pharmacokinetic model was developed. Microbiological cultures were collected prior to and during prophylaxis. An AUC24/MIC of ≥125 was defined as target ratio. RESULTS: A 1-compartment model with zero-order absorption and allometric scaling best described the data. No significant (P < .01) covariates remained after backward elimination and no effect of asparaginase or azoles were found. Ciprofloxacin AUC24 was 16.9 mg*h/L in the prednisone prophase versus 29.3 mg*h/L with concomitant chemotherapy. Overall, 100%, 81%, and 18% of patients at, respectively, MIC of 0.063, 0.125, and 0.25 mg/L achieved AUC24/MIC ≥ 125. In 13% of the patients, resistant bacteria were found during prophylactic treatment. CONCLUSION: Ciprofloxacin exposure shows an almost 2-fold change throughout the treatment of pediatric ALL. Depending on the appropriateness of 125 as target ratio, therapeutic drug monitoring or dose adjustments might be indicated for less susceptible bacteria starting from ≥ 0.125 mg/L to prevent the emergence of resistance and reach required targets for efficacy.
Assuntos
Ciprofloxacina , Leucemia-Linfoma Linfoblástico de Células Precursoras , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Área Sob a Curva , Criança , Ciprofloxacina/farmacologia , Ciprofloxacina/uso terapêutico , Farmacorresistência Bacteriana , Humanos , Testes de Sensibilidade Microbiana , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Estudos ProspectivosRESUMO
Fludarabine is the most frequently used agent in conditioning regimens for allogeneic hematopoietic cell transplantation (HCT). Body surface area-based dosing leads to highly variable fludarabine exposure. We studied the relation between fludarabine exposure and clinical outcomes. A retrospective, pharmacokinetic-pharmacodynamic analysis was conducted with data from patients undergoing HCT with fludarabine (160 mg/m2) as part of a myeloablative conditioning (busulfan targeted to an area under the plasma-concentration-time curve [AUC] of 90 mg*h/L) and rabbit antithymocyte globulin (6-10 mg/kg; from day -9/-12) between 2010 and 2016. Fludarabine exposure as AUC was calculated for each patient using a previously published population pharmacokinetic model and related to 2-year event-free survival (EFS) by means of (parametric) time-to-event models. Relapse, nonrelapse mortality (NRM), and graft failure were considered events. One hundred ninety-two patients were included (68 benign and 124 malignant disorders). The optimal fludarabine exposure was determined as an AUC of 20 mg*h/L. In the overexposed group, EFS was lower (hazard ratio [HR], 2.0; 95% confidence interval [CI], 1.1-3.5; P = .02), due to higher NRM (HR, 3.4; 95% CI, 1.6-6.9; P <001) associated with impaired immune reconstitution (HR, 0.43; 95% CI, 0.26-0.70; P <001). The risks of NRM and graft failure were increased in the underexposed group (HR, 3.3; 95% CI, 1.2-9.4; P = .02; HR, 4.8; 95% CI, 1.2-19; P = .02, respectively). No relationship with relapse was found. Fludarabine exposure is a strong predictor of survival after HCT, stressing the importance of optimum fludarabine dosing. Individualized dosing, based on weight and "renal function" or "therapeutic drug monitoring," to achieve optimal fludarabine exposure might improve survival.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Agonistas Mieloablativos/uso terapêutico , Condicionamento Pré-Transplante , Vidarabina/análogos & derivados , Adolescente , Adulto , Causas de Morte , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade , Agonistas Mieloablativos/administração & dosagem , Agonistas Mieloablativos/efeitos adversos , Agonistas Mieloablativos/farmacocinética , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Vidarabina/administração & dosagem , Vidarabina/efeitos adversos , Vidarabina/farmacocinética , Vidarabina/uso terapêutico , Adulto JovemRESUMO
Essentials A pediatric pharmacogenetic dosing algorithm for acenocoumarol has not yet been developed. We conducted a multicenter retrospective follow-up study in children in the Netherlands. Body surface area and indication explained 45.0% of the variability in dose requirement. Adding the genotypes of VKORC1, CYP2C9 and CYP2C18 to the algorithm increased this to 61.8%. SUMMARY: Background The large variability in dose requirement of vitamin K antagonists is well known. For warfarin, pediatric dosing algorithms have been developed to predict the correct dose for a patient; however, this is not the case for acenocoumarol. Objectives To develop dosing algorithms for pediatric patients receiving acenocoumarol with and without genetic information. Methods The Children Anticoagulation and Pharmacogenetics Study was designed as a multicenter retrospective follow-up study in Dutch anticoagulation clinics and children's hospitals. Pediatric patients who used acenocoumarol between 1995 and 2014 were selected for inclusion. Clinical information and saliva samples for genotyping of the genes encoding cytochrome P450 (CYP) 2C9, vitamin K epoxide reductase complex subunit 1 (VKORC1), CYP4F2, CYP2C18 and CYP3A4 were collected. Linear regression was used to analyze their association with the log mean stable dose. A stable period was defined as three or more consecutive International Normalized Ratio measurements within the therapeutic range over a period of ≥ 3 weeks. Results In total, 175 patients were included in the study, of whom 86 had a stable period and no missing clinical information (clinical cohort; median age 8.9 years, and 49% female). For 80 of these 86 patients, genetic information was also available (genetic cohort). The clinical algorithm, containing body surface area and indication, explained 45.0% of the variability in dose requirement of acenocoumarol. After addition of the VKORC1, CYP2C9, and CYP2C18 genotypes to the algorithm, this increased to 61.8%. Conclusions These findings show that clinical factors had the largest impact on the required dose of acenocoumarol in pediatric patients. Nevertheless, genetic factors, and especially VKORC1, also explained a significant part of the variability.
Assuntos
Acenocumarol/administração & dosagem , Anticoagulantes/administração & dosagem , Acenocumarol/análise , Acenocumarol/farmacocinética , Adolescente , Fatores Etários , Algoritmos , Anticoagulantes/análise , Anticoagulantes/farmacocinética , Variação Biológica Individual , Biotransformação/genética , Superfície Corporal , Criança , Pré-Escolar , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Estudos de Associação Genética , Humanos , Lactente , Masculino , Modelos Biológicos , Polimorfismo de Nucleotídeo Único , Guias de Prática Clínica como Assunto , Estudos Retrospectivos , Saliva/química , Trombofilia/tratamento farmacológico , Vitamina K/antagonistas & inibidoresRESUMO
Essentials The knowledge of quality and safety of acenocoumarol and phenprocoumon use in children is limited. We used data from a multicenter retrospective follow-up study in children in the Netherlands. The quality of anticoagulation control in the first month of use was low, but improved thereafter. No thromboembolic events occurred, however bleeding events occurred in 1-3 out of 10 patients. SUMMARY: Background The use of vitamin-K antagonists in pediatric patients is rare and information on the quality and safety of treatment with acenocoumarol and phenprocoumon is limited. Objectives To assess the quality, safety and effectiveness during the first year of acenocoumarol and phenprocoumon treatment in pediatric patients in the Netherlands. Methods The Children Anticoagulation and Pharmacogenetics Study (CAPS) was designed as a multicenter retrospective follow-up study. Patients who used acenocoumarol or phenprocoumon at an age of ≤ 18 years, were selected from four pediatric hospitals and one anticoagulation clinic in the Netherlands. The quality of treatment was assessed by calculating the percentage of time in therapeutic INR range (TTR) for the first month and for every 3 months of use during the first year of treatment. Effectiveness and safety were assessed by the number of thromboembolic and bleeding events. Results In total, 213 patients participated, of whom 187 (155 acenocoumarol; 32 phenprocoumon) were included in this analysis. The mean TTR was 47.0% and 51.4% in the first month of use for acenocoumarol and phenprocoumon, respectively. After the first 3 months the mean TTR for both VKAs was above 64%. In 14.6% (acenocoumarol) and 31.3% (phenprocoumon) of the patients a bleeding event occurred during the first year of treatment; no thromboembolic events were reported. Conclusions The quality of anticoagulation treatment was low during the first month of use and leaves room for improvement. After the first month it increased to an acceptable level. However, bleeding events occurred frequently during the first year.
Assuntos
Acenocumarol/administração & dosagem , Anticoagulantes/administração & dosagem , Coagulação Sanguínea/efeitos dos fármacos , Femprocumona/administração & dosagem , Tromboembolia/tratamento farmacológico , Acenocumarol/efeitos adversos , Administração Oral , Adolescente , Fatores Etários , Anticoagulantes/efeitos adversos , Criança , Pré-Escolar , Monitoramento de Medicamentos/métodos , Feminino , Fidelidade a Diretrizes/normas , Hemorragia/induzido quimicamente , Humanos , Lactente , Coeficiente Internacional Normatizado , Masculino , Países Baixos , Femprocumona/efeitos adversos , Guias de Prática Clínica como Assunto/normas , Padrões de Prática Médica/normas , Indicadores de Qualidade em Assistência à Saúde/normas , Estudos Retrospectivos , Tromboembolia/sangue , Tromboembolia/diagnóstico , Fatores de Tempo , Resultado do TratamentoRESUMO
This study was performed to estimate the cost-effectiveness of a combined physical exercise and psychosocial intervention for children with cancer compared with usual care. Sixty-eight children, aged 8-18 years old, during or within the first year post-cancer treatment were randomised to the intervention (n = 30) and control group (n = 38). Health outcomes included fitness, muscle strength and quality adjusted life years; all administered at baseline, 4- and 12-month follow-up. Costs were gathered by 1 monthly cost questionnaires over 12 months, supplemented by medication data obtained from pharmacies. Results showed no significant differences in costs and effects between the intervention and control group at 12-month follow-up. On average, societal costs were 299 higher in the intervention group than in the control group, but this difference was not significant. Cost-effectiveness acceptability curves indicated that the intervention needs large societal investments to reach reasonable probabilities of cost-effectiveness for quality of life and lower body muscle strength. Based on the results of this study, the intervention is not cost-effective in comparison with usual care.
Assuntos
Terapia por Exercício/métodos , Custos de Cuidados de Saúde , Força Muscular , Neoplasias/reabilitação , Aptidão Física , Psicoterapia/métodos , Qualidade de Vida , Anos de Vida Ajustados por Qualidade de Vida , Absenteísmo , Adolescente , Criança , Análise Custo-Benefício , Terapia por Exercício/economia , Feminino , Humanos , Masculino , Neoplasias/economia , Neoplasias/psicologia , Países Baixos , Pais , Psicoterapia/economia , Ensaios Clínicos Controlados Aleatórios como AssuntoAssuntos
Linfócitos T CD4-Positivos/citologia , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Leucemia Linfoide/terapia , Leucemia Mieloide/terapia , Doadores não Relacionados , Adolescente , Contagem de Linfócito CD4 , Criança , Pré-Escolar , Estudos de Coortes , Transplante de Células-Tronco de Sangue do Cordão Umbilical/normas , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Leucemia Linfoide/diagnóstico , Leucemia Linfoide/mortalidade , Leucemia Mieloide/diagnóstico , Leucemia Mieloide/mortalidade , Masculino , Prognóstico , Estudos RetrospectivosRESUMO
Allogeneic hematopoietic stem cell transplantation (HSCT) offers the potential to cure patients with an inherited bone marrow failure syndrome (IBMFS). However, the procedure involves the risk of treatment-related mortality and may be associated with significant early and late morbidity. For these reasons, the benefits should be carefully weighed against the risks. IBMFS are rare, whereas case reports and small series in the literature illustrate highly heterogeneous practices in terms of indications for HSCT, timing, stem cell source and conditioning regimens. A consensus meeting was therefore held in Vienna in September 2012 on behalf of the European Group for Blood and Marrow Transplantation to discuss HSCT in the setting of IBMFS. This report summarizes the recommendations from this expert panel, including indications for HSCT, timing, stem cell source and conditioning regimen.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Hemoglobinúria Paroxística/terapia , Condicionamento Pré-Transplante/métodos , Adolescente , Aloenxertos , Anemia Aplástica , Doenças da Medula Óssea , Transtornos da Insuficiência da Medula Óssea , Criança , Pré-Escolar , Feminino , Humanos , Lactente , MasculinoRESUMO
We performed a prospective phase II study to evaluate clinical safety and outcome in 48 patients with steroid-refractory grade II-IV acute graft-versus-host disease (aGVHD) treated with mesenchymal stromal cells (MSCs). Clinical outcomes were correlated to comprehensive analyses of soluble and cellular biomarkers. Complete resolution (CR) of aGVHD at day 28 (CR-28) occurred in 12 (25%) patients, CR lasting >1 month (CR-B) occurred in 24 (50%) patients. One-year overall survival was significantly improved in CR-28 (75 versus 33%, P=0.020) and CR-B (79 versus 8%, P<0.001) versus non-CR patients. A six soluble biomarker-panel was predictive for mortality (HR 2.924; CI 1.485-5.758) when measured before MSC-administration. Suppression of tumorigenicity 2 (ST2) was only predictive for mortality 2 weeks after but not before MSC-administration (HR 2.389; CI 1.144-4.989). In addition, an increase in immature myeloid dendritic cells associated with decreased mortality (HR 0.554, CI 0.389-0.790). Patients had persisting T-cell responses against defined virus- and leukemia-associated antigens. In conclusion, our data emphasize the need to carefully assess biomarkers in cohorts with homogeneous GVHD treatments. Biomarkers might become an additional valuable component of composite end points for the rapid and efficient testing of novel compounds to decrease lifecycle of clinical testing and improve the success rate of phase II/III trials.
Assuntos
Resistência a Medicamentos , Doença Enxerto-Hospedeiro/metabolismo , Doença Enxerto-Hospedeiro/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Doença Aguda , Adolescente , Adulto , Idoso , Antígenos de Neoplasias/imunologia , Biomarcadores/sangue , Biomarcadores/metabolismo , Criança , Pré-Escolar , Ciclosporina/uso terapêutico , Citocinas/sangue , Citocinas/metabolismo , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Imunofenotipagem , Imunossupressores/uso terapêutico , Lactente , Linfócitos/imunologia , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Prognóstico , Esteroides/uso terapêutico , Resultado do Tratamento , Adulto JovemRESUMO
We determined whether assessment of the immunogenicity of individual donor-recipient HLA mismatches based on differences in their amino-acid sequence and physiochemical properties predicts clinical outcome following haematopoietic SCT (HSCT). We examined patients transplanted with 9/10 single HLA class I-mismatched grafts (n=171) and 10/10 HLA-A-, -B-, -C-, -DRB1- and -DQB1-matched grafts (n=168). A computer algorithm was used to determine the physiochemical disparity (electrostatic mismatch score (EMS) and hydrophobic mismatch score (HMS)) of mismatched HLA class I specificities in the graft-versus-host direction. Patients transplanted with HLA-mismatched grafts with high EMS/HMS had increased incidence of ⩾grade II acute GVHD (aGVHD) compared with patients transplanted with low EMS/HMS grafts; patients transplanted with low and medium EMS/HMS grafts had similar incidence of aGVHD to patients transplanted with 10/10 HLA-matched grafts. Mortality was higher following single HLA-mismatched HSCT but was not correlated with HLA physiochemical disparity. Assessment of donor-recipient HLA incompatibility based on physiochemical HLA disparity may enable better selection of HLA-mismatched donors in HSCT.
Assuntos
Bases de Dados Factuais , Doença Enxerto-Hospedeiro , Antígenos HLA , Transplante de Células-Tronco Hematopoéticas , Doadores não Relacionados , Adolescente , Adulto , Algoritmos , Aloenxertos , Criança , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Antígenos HLA/química , Antígenos HLA/genética , Antígenos HLA/imunologia , Humanos , Incidência , Masculino , Países Baixos , Fatores de RiscoRESUMO
Exact data on prognosis of children receiving invasive mechanical ventilation (IMV) after allogeneic hematopoietic SCT (HSCT) is lacking. We therefore started a prospective registry in four European university HSCT centers (Leiden, Paris, Prague and Utrecht) and their pediatric intensive care units (PICUs). The registry started in January 2009. In January 2013, the four centers together had treated a total of 83 admissions with IMV. The case fatality rate in these patients was 52%. Mortality 6 months after PICU discharge was 45%. There were significant differences between centers in the proportion of children who received IMV after HSCT (6-23%, P<0.01), in severity of disease on admission to PICU (predicted mortality 14-37%, P<0.01), in applying noninvasive ventilation before IMV (3-75% of admissions, P<0.01) and in the use of renal replacement therapy (RRT) (8-58% of admissions, P<0.01). Severe impairment in oxygenation, use of RRT and CMV viremia were independent predictors of mortality. Our study shows that mortality in children receiving IMV after HSCT remains high, but has clearly improved compared with older studies. Patient selection and treatment in PICU differed significantly between centers, which underscores the need to standardize and optimize the PICU admission criteria, ventilatory strategies and therapies applied in PICU.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Respiração Artificial/métodos , Condicionamento Pré-Transplante/métodos , Transplante Homólogo/métodos , Adolescente , Criança , Pré-Escolar , Feminino , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Lactente , Masculino , Prognóstico , Estudos Prospectivos , Fatores de Risco , Condicionamento Pré-Transplante/mortalidade , Transplante Homólogo/mortalidade , Resultado do TratamentoRESUMO
INTRODUCTION: Previously we developed a weighted amino acid (AA) mismatch score predictive for cytotoxic T cell (CTL) alloreactivity (in vitro CTLp assay) based on the structure of the HLA class I molecule. The aim of this study is to confirm the clinical relevance of the CTLp assay and to validate the AA mismatch score as an alternative and easy to use tool to predict permissible mismatches in hematopoietic stem cell transplantation (HSCT). METHODS: We selected patients transplanted with a 9/10 single HLA class I mismatched graft (n=171) at three Dutch HSCT centers. A CTLp assay was performed in 73 donor-recipient pairs. As a control we selected 168 10/10 HLA matched pairs that were matched to the 9/10 single HLA class I mismatched pairs for HSCT year, donor type, patient age and diagnosis. RESULTS: We observed that pairs with negative a CTLp assay had statistically significant decreased incidence of mortality after HSCT comparable to that of 10/10 HLA matched pairs. However, the weighted AA mismatch score did not significantly predict any HSCT end point of interest. CONCLUSION: Further investigation is needed to unravel the mechanisms involved in causing the beneficial effect of a negative CTLp assay, before other alternative tools to predict HSCT outcome may be developed.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Transplante de Células-Tronco Hematopoéticas , Antígenos de Histocompatibilidade Classe I/imunologia , Pesquisa Translacional Biomédica , Doadores não Relacionados , Adolescente , Adulto , Fatores Etários , Idoso , Aloenxertos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Países Baixos , Valor Preditivo dos TestesRESUMO
Busulfan (Bu) is used as a myeloablative agent in conditioning regimens before allogeneic hematopoietic cell transplantation (allo-HCT). In line with strategies explored in adults, patient outcomes may be optimized by replacing cyclophosphamide (Cy) with or without melphalan (Mel) with fludarabine (Flu). We compared outcomes in 2 consecutive cohorts of HCT recipients with a nonmalignant HCT indication, a myeloid malignancy, or a lymphoid malignancy with a contraindication for total body irradiation (TBI). Between 2009 and 2012, 64 children received Flu + Bu at a target dose of 80-95 mg·h/L, and between 2005 and 2008, 50 children received Bu targeted to 74-80 mg·h/L + Cy. In the latter group, Mel was added for patients with myeloid malignancy (n = 12). Possible confounding effects of calendar time were studied in 69 patients receiving a myeloablative dose of TBI between 2005 and 2012. Estimated 2-year survival and event-free survival were 82% and 78%, respectively, in the FluBu arm and 78% and 72%, respectively, in the BuCy (Mel) arm (P = not significant). Compared with the BuCy (Mel) arm, less toxicity was noted in the FluBu arm, with lower rates of acute (noninfectious) lung injury (16% versus 36%; P = .007), veno-occlusive disease (3% versus 28%; P = .003), chronic graft-versus-host disease (9% versus 26%; P = .047), adenovirus infection (3% versus 32%; P = .001), and human herpesvirus 6 infection reactivation (21% versus 44%; P = .005). Furthermore, the median duration of neutropenia was shorter in the FluBu arm (11 days versus 22 days; P < .001), and the patients in this arm required fewer transfusions. Our data indicate that Flu (160 mg/m(2)) with targeted myeloablative Bu (90 mg·h/L) is less toxic than and equally effective as BuCy (Mel) in patients with similar indications for allo-HCT.
Assuntos
Bussulfano/uso terapêutico , Ciclofosfamida/uso terapêutico , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Agonistas Mieloablativos/uso terapêutico , Condicionamento Pré-Transplante/métodos , Vidarabina/análogos & derivados , Infecções por Adenoviridae/mortalidade , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/mortalidade , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/patologia , Humanos , Lactente , Recém-Nascido , Pulmão/imunologia , Pulmão/patologia , Masculino , Infecções por Roseolovirus/mortalidade , Análise de Sobrevida , Transplante Homólogo , Resultado do Tratamento , Vidarabina/uso terapêutico , Adulto JovemRESUMO
This study was aimed at finding predictors of invasive fungal infection (IFI) after pediatric allogeneic hematopoietic SCT (HSCT). All children who received allogeneic HSCT in the Wilhelmina Children's Hospital Utrecht between 2004 and 2012 were included. HSCT data were prospectively collected. Patients were retrospectively classified into high- or low-risk groups for developing IFI using criteria based on available literature. Predictors for the occurrence of IFI were analyzed using Cox regression models. We used logistic regression models to analyze the association between other HSCT-related complications and IFI. Secondary outcomes were overall survival and treatment-related mortality (TRM). Two-hundred nine patients were included in the analysis; median age was 6.6 years. The cumulative incidence of IFI was 12%. In patients classified as 'low risk' (n=75), only 5.3% developed IFI (odds ratio (OR): 0.325; P=0.047). In multivariate analysis, a predictor for the occurrence of IFI was an a priori determined HSCT TRM risk >20% (based on EBMT-risk score). Post-HSCT, the administration of high-dose steroids was associated with IFI (OR: 4.458; P=0.010). Patients who developed IFI showed an increased risk of TRM (OR: 3.773; P=0.004). These results confirm that risk group stratification should guide intensity of monitoring for IFI and use of antifungal prophylaxis.
Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Micoses/complicações , Micoses/diagnóstico , Adolescente , Adulto , Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Aspergilose/complicações , Candidíase/complicações , Caspofungina , Criança , Pré-Escolar , Equinocandinas/uso terapêutico , Feminino , Fusariose/complicações , Doença Enxerto-Hospedeiro/tratamento farmacológico , Humanos , Lactente , Lipopeptídeos , Modelos Logísticos , Masculino , Neutrófilos/citologia , Estudos Prospectivos , Pirimidinas/uso terapêutico , Estudos Retrospectivos , Risco , Resultado do Tratamento , Triazóis/uso terapêutico , Voriconazol , Adulto JovemRESUMO
Children with acute lymphoblastic leukemia (ALL) and high minimal residual disease (MRD) levels after initial chemotherapy have a poor clinical outcome. In this prospective, single arm, Phase 2 trial, 111 Dutch and Australian children aged 1-18 years with newly diagnosed, t(9;22)-negative ALL, were identified among 1041 consecutively enrolled patients as high risk (HR) based on clinical features or high MRD. The HR cohort received the AIEOP-BFM (Associazione Italiana di Ematologia ed Oncologia Pediatrica (Italy)-Berlin-Frankfurt-Münster ALL Study Group) 2000 ALL Protocol I, then three novel HR chemotherapy blocks, followed by allogeneic transplant or chemotherapy. Of the 111 HR patients, 91 began HR treatment blocks, while 79 completed the protocol. There were 3 remission failures, 12 relapses, 7 toxic deaths in remission and 10 patients who changed protocol due to toxicity or clinician/parent preference. For the 111 HR patients, 5-year event-free survival (EFS) was 66.8% (±5.5) and overall survival (OS) was 75.6% (±4.3). The 30 patients treated as HR solely on the basis of high MRD levels had a 5-year EFS of 63% (±9.4%). All patients experienced grade 3 or 4 toxicities during HR block therapy. Although cure rates were improved compared with previous studies, high treatment toxicity suggested that novel agents are needed to achieve further improvement.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Asparaginase/administração & dosagem , Asparaginase/efeitos adversos , Criança , Pré-Escolar , Terapia Combinada , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Daunorrubicina/administração & dosagem , Daunorrubicina/efeitos adversos , Feminino , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Mercaptopurina/administração & dosagem , Mercaptopurina/efeitos adversos , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Estudos Prospectivos , Indução de Remissão , Fatores de Risco , Transplante Homólogo , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/efeitos adversosRESUMO
The MHC region on chromosome 6 contains a large number of non-HLA genes next to the HLA genes. Matching for HLA in unrelated hematopoietic SCT (HSCT) does not necessarily mean that these non-HLA genes are also matched. We selected 348 Northwest European patients transplanted with an HLA-A-, -B-, -C-, -DRB1-, -DQB1-matched unrelated donor (MUD) between 1987 and 2008. Patients' haplotypes were identified via descend. We were unable to determine the haplotypes of the donor; therefore we used frequent haplotypes (FH) in high linkage disequilibrium (LD) as a proxy for haplotype matching. Presence of a FH in a patient positively affected the probability and speed of identifying a matched unrelated donor. Competing risk survival analysis showed that patients with one or two FH have a statistically significantly decreased probability of developing ≥ grade II acute GVDH (aGVHD) without increased risk of relapse compared to patients without FH (HR (95% CI): 0.53 (0.31-0.91)). This association was strongest for those FH with the highest LD between both HLA-A and -C or -B, and HLA-C or -B and -DRB1 (HR (95% CI): 0.49 (0.26-0.92)). These results extend evidence that non-HLA allele coding regions have a significant impact on development of ≥ grade II aGVHD. We conclude that there is more to successful HSCT than matching for HLA genes.
Assuntos
Seleção do Doador/métodos , Doença Enxerto-Hospedeiro/mortalidade , Antígenos HLA , Haplótipos , Transplante de Células-Tronco Hematopoéticas , Desequilíbrio de Ligação , Doadores não Relacionados , Doença Aguda , Adolescente , Adulto , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/patologia , Doença Enxerto-Hospedeiro/prevenção & controle , Teste de Histocompatibilidade , Humanos , Lactente , Masculino , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Transplante HomólogoRESUMO
To address the prognostic value of minimal residual disease (MRD) before unrelated cord blood transplantation (UCBT) in children with acute lymphoblastic leukemia (ALL), we analyzed 170 ALL children transplanted in complete remission (CR) after myeloablative conditioning regimen. In all, 72 (43%) were in first CR (CR1), 77 (45%) in second CR (CR2) and 21 (12%) in third CR (CR3). The median interval from MRD quantification to UCBT was 18 days. All patients received single-unit UCBT. Median follow-up was 4 years. Cumulative incidence (CI) of day-60 neutrophil engraftment was 85%. CI of 4 years relapse was 30%, incidence being lower in patients with negative MRD before UCBT (hazard ratio (HR)=0.4, P=0.01) and for those transplanted in CR1 and CR2 (HR=0.3, P=0.002). Probability of 4 years leukemia-free survival (LFS) was 44%, (56, 44 and 14% for patients transplanted in CR1, CR2 and CR3, respectively (P=0.0001)). Patients with negative MRD before UCBT had better LFS after UCBT compared with those with positive MRD (54% vs 29%; HR=2, P=0.003). MRD assessment before UCBT for children with ALL in remission allows identifying patients at higher risk of relapse after transplantation. Approaches that may decrease relapse incidence in children given UCBT with positive MRD should be investigated to improve final outcomes.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Doença Enxerto-Hospedeiro/diagnóstico , Recidiva Local de Neoplasia/mortalidade , Neoplasia Residual/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/terapia , Humanos , Lactente , Masculino , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/terapia , Neoplasia Residual/etiologia , Neoplasia Residual/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Prognóstico , Sistema de Registros , Indução de Remissão , Estudos Retrospectivos , Taxa de Sobrevida , Condicionamento Pré-Transplante , Transplante HomólogoRESUMO
OBJECTIVE: To quantify radiation exposure and mortality risk from computed tomography (CT) and positron emission tomography (PET) imaging with (18)F-fluorodeoxyglucose ((18)F-FDG) in patients with malignant lymphoma (Hodgkin's disease [HD] or non-Hodgkin's lymphoma [NHL]). METHODS: First, organ doses were assessed for a typical diagnostic work-up in children with HD and adults with NHL. Subsequently, life tables were constructed for assessment of radiation risks, also taking into account the disease-related mortality. RESULTS: In children with HD, cumulative effective dose from medical imaging ranged from 66 mSv (newborn) to 113 mSv (15 years old). In adults with NHL the cumulative effective dose from medical imaging was 97 mSv. Average fractions of radiation-induced deaths for children with HD [without correction for disease-related mortality in brackets] were 0.4% [0.6%] for boys and 0.7% [1.1%] for girls, and for adults with NHL 0.07% [0.28%] for men and 0.09% [0.37%] for women. CONCLUSION: Taking into account the disease-related reduction in life expectancy of patients with malignant lymphoma results in a higher overall mortality but substantial lower incidence of radiation induced deaths. The modest radiation risk that results from imaging with CT and (18)F-FDG PET can be considered as justified, but imaging should be performed with care, especially in children.