RESUMEN
The role of anti-HLA antibodies in allogeneic stem cell transplantation setting is still unclear. In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC) set up its fourth annual series of workshops which brought together practitioners from all of its member centers. These workshops took place in September 2013 in Lille. This article offers the recommendations of the group that considered the impact that have anti-HLA antibodies on outcomes in allogeneic stem cell transplantation.
Asunto(s)
Antígenos HLA/inmunología , Isoanticuerpos/efectos adversos , Trasplante de Células Madre , Trasplante Homólogo , Resultado del Tratamiento , Francia , Prueba de Histocompatibilidad , Humanos , Isoanticuerpos/análisis , Donantes de TejidosRESUMEN
The purpose of this paper is to describe the outcome of patients who underwent double allogeneic hematopoietic stem cell transplantation (AHSCT) with reduced-intensity conditioning regimens (RIC). Forty-five patients who received double RIC-AHSCT between 1997 and 2006 were retrospectively studied. The predominant diagnosis was acute myeloid leukemia (AML) (n = 17). Other diagnoses were aplasic anemia (AA) (n = 5), myelodysplasic disorder (n = 5), acute lymphoblastic leukemia (ALL) (n = 4), chronic myelomonocytic leukemia (CML) (n = 3), myeloma (n = 3), non-Hodgkin lymphoma (NHL) (n = 3), chronic lymphocytic leukemia (CLL) (n = 2), Hodgkin's disease (HD) (n = 2), and chronic myelomonocytic leukemia (n = 1). Main indications for RIC-AHSCT 2 were relapse (n = 25, 56%) and early (n = 8, 18%) or late (n = 12, 26%) graft failure. Median delays to reach a neutrophil count of 0.5 × 10(9)/L and platelet counts of 50 × 10(9)/L were significantly smaller after the second AHSCT. Among 25 patients who relapsed after RIC-AHSCT 1, 14 patients (56%) presented a response improvement after RIC-AHSCT 2. In this group, 9 patients sustained a complete response and 5 patients a partial response. Moreover, among the 20 patients who had early or late graft failure following RIC-AHSCT 1, 9 (45%) finally reached an engraftment. Disease-free survival (DFS) was significantly improved after RIC-AHSCT 2. Thirteen patients (28%) died of transplant-related mortality (TRM) at a median delay of 69 days (range: 0-451) after RIC-AHSCT 2. Double RIC-AHSCT is a feasible procedure that allows a response or engraftment not observed after RIC-AHSCT 1. The main indication is relapse. However, TRM remains high.
Asunto(s)
Neoplasias Hematológicas/mortalidad , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas , Adolescente , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Rechazo de Injerto/sangre , Rechazo de Injerto/mortalidad , Supervivencia de Injerto , Neoplasias Hematológicas/sangre , Humanos , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Recuento de Plaquetas , Estudios Retrospectivos , Tasa de Supervivencia , Factores de Tiempo , Trasplante HomólogoRESUMEN
BACKGROUND: CBL missense mutations have recently been associated with juvenile myelomonocytic leukaemia (JMML), an aggressive myeloproliferative and myelodysplastic neoplasm of early childhood characterised by excessive macrophage/monocyte proliferation. CBL, an E3 ubiquitin ligase and a multi-adaptor protein, controls proliferative signalling networks by downregulating the growth factor receptor signalling cascades in various cell types. METHODS AND RESULTS: CBL mutations were screened in 65 patients with JMML. A homozygous mutation of CBL was found in leukaemic cells of 4/65 (6%) patients. In all cases, copy neutral loss of heterozygosity of the 11q23 chromosomal region, encompassing the CBL locus, was demonstrated. Three of these four patients displayed additional features suggestive of an underlying developmental condition. A heterozygous germline CBL p.Y371H substitution was found in each of them and was inherited from the father in one patient. The germline mutation represents the first hit, with somatic loss of heterozygosity being the second hit positively selected in JMML cells. The three patients display a variable combination of dysmorphic features, hyperpigmented skin lesions and microcephaly that enable a 'CBL syndrome' to be tentatively delineated. Learning difficulties and postnatal growth retardation may be part of the phenotype. CONCLUSION: A report of germline mutations of CBL in three patients with JMML is presented here, confirming the existence of an unreported inheritable condition associated with a predisposition to JMML.
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Mutación de Línea Germinal , Trastornos del Crecimiento , Leucemia Mielomonocítica Juvenil/genética , Microcefalia , Proteínas Proto-Oncogénicas c-cbl/genética , Niño , Preescolar , Discapacidades del Desarrollo/complicaciones , Discapacidades del Desarrollo/genética , Femenino , Predisposición Genética a la Enfermedad , Trastornos del Crecimiento/complicaciones , Trastornos del Crecimiento/genética , Humanos , Leucemia Mielomonocítica Juvenil/complicaciones , Masculino , Microcefalia/complicaciones , Microcefalia/genética , SíndromeRESUMEN
INTRODUCTION: Oral busulfan clearance is age-dependent and children experience a wide variability in plasma exposure. BSA- or age-based dosing is used with therapeutic drug monitoring (TDM) to reduce this variability. PURPOSE: A new intravenous (IV) dosing of busulfan (Bu) based on body weight, designed to improve AUC targeting without TDM and dose-adjustment, was prospectively evaluated. METHOD: Bu was administered as a 2 h IV infusion every 6 h over 4 days (16 administrations). Five dose levels were defined on body weight as follows: 1.0 mg/kg for <9 kg; 1.2 mg/kg for 9 to <16 kg; 1.1 mg/kg for 16-23 kg; 0.95 mg/kg for >23-34 kg; 0.80 mg/kg for >34 kg. Bu treatment was followed by Cyclophosphamide or Melphalan prior to allogeneic or autologous transplantation in 55 children aged 0.3-17.2 years (median 5.6 years). RESULTS: No difference in AUC values was observed between weight strata (mean +/- SD 1248 +/- 205 micromol.min), whereas a significant difference in Bu clearance was demonstrated. This new dosing enabled to achieve a mean exposure comparable to that in adults. At dose 1, 91% of patients achieved the targeted AUC range (900-1500 micromol.min) while no patients were underexposed. At doses 9 and 13, over 75% of patients remained within that target whilst most of the others were slightly above. Successful engraftment was achieved in all patients. In conclusion, from infants to adults this new dosing enabled, without TDM and dose adjustment, to successfully target a therapeutic AUC window.
Asunto(s)
Antineoplásicos Alquilantes/farmacocinética , Busulfano/farmacocinética , Enfermedades Hematológicas/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Adolescente , Factores de Edad , Antineoplásicos Alquilantes/administración & dosificación , Área Bajo la Curva , Peso Corporal , Busulfano/administración & dosificación , Niño , Preescolar , Ciclofosfamida/uso terapéutico , Relación Dosis-Respuesta a Droga , Monitoreo de Drogas , Femenino , Humanos , Lactante , Infusiones Intravenosas , Masculino , Melfalán/uso terapéutico , Modelos Biológicos , Estudios Prospectivos , Trasplante de Células MadreRESUMEN
Despite progress in diagnosis and treatment, invasive aspergillosis (IA) remains a principal cause of mortality due to infection after allogeneic hematopoietic stem cell transplantation (AHSCT). In order to clarify the course of IA among children receiving an AHSCT before the advent of new drugs such as voriconazole or caspofungin, we retrospectively reviewed the medical records of all proven and probable IA between January 1986 and December 2000. 1) Ten children developed IA after AHSCT, mostly long after transplantation. Overall incidence was 2.7%. Seven of those children experienced 1 or more complications after AHSCT and before IA. Mortality was 90% with a median survival of 23 days (2-90). 2) Five children underwent AHSCT after a previous episode of IA. All patients were treated with systemic antifungal therapy combined with surgery. Median time between IA and AHSCT was 110 days (73-370). Two children were diagnosed with IA relapse after transplantation. One child was cured while the other died of IA and AHSCT complications. AHSCT could be considered even in the setting of previous IA, but established strategies implementing newer less toxic antifungal agents as treatment or prophylaxis in high-risk patients are needed.
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Aspergilosis/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Adolescente , Aspergilosis/prevención & control , Aspergilosis/terapia , Niño , Preescolar , Humanos , Lactante , Estudios Retrospectivos , Trasplante HomólogoRESUMEN
BACKGROUND: The application of population pharmacokinetic models and Bayesian methods offers the potential to develop individualized therapeutic approaches. OBJECTIVES: The current study presents an external evaluation of a vancomycin pharmacokinetic model in a pediatric cancer population and proposes an easy-to-use chart for clinicians for a priori vancomycin schedule adaptation to achieve target concentration. METHODS: External evaluation of a population pharmacokinetic model of vancomycin administered via continuous infusion was realized in a new retrospective dataset of pediatric patients with cancer. The published population pharmacokinetic model was implemented in NONMEM 7.3 with the structural and variance parameter values set equal to estimates previously reported. Predictive performance was assessed by quantifying bias and accuracy of model prediction. Normalized prediction distribution errors were also evaluated. Dosage simulations were performed according to the target concentration. RESULTS: A total of 77 patients were included in this study, representing 146 vancomycin courses and 289 concentrations. The model adequately predicted vancomycin concentrations (median prediction error % of - 9.4%, median |PE|% of 24.1%). Based on simulation results, vancomycin dosage (mg/kg) should be adapted for each child on the basis of body weight and cyclosporine coadministration. CONCLUSION: The model previously proposed by Guilhaumou et al. in pediatric patients with solid or hematological malignant disease was externally validated. Simulations have enabled the description of new dosage schedules and creation of a chart to help clinicians adapt vancomycin dosage.
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Antibacterianos/farmacocinética , Cálculo de Dosificación de Drogas , Neoplasias Hematológicas/sangre , Modelos Biológicos , Vancomicina/farmacocinética , Antibacterianos/administración & dosificación , Teorema de Bayes , Niño , Preescolar , Monitoreo de Drogas , Emolientes , Femenino , Humanos , Masculino , Neoplasias/sangre , Estudios Retrospectivos , Vancomicina/administración & dosificaciónRESUMEN
This prospective study focused on risk factors and clinical outcome of pulmonary and cardiac late effects after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We prospectively evaluated 162 children by pulmonary function tests (PFTs) and cardiac shortening fraction (SF) before allo-HSCT and yearly up to the 5th year of follow-up. The 5-year cumulative incidence of lung and cardiac impairment was 35 (hazard rate=0.03) and 26% (hazard rate=0.06), respectively. Patients presenting abnormal PFTs and SF at last follow-up were 19 and 13%, respectively, with a median Lansky performance status of 90% (70-100). Chronic graft-versus-host disease (c-GVHD) was the major risk factor for reduced lung function in univariate (P=0.02) and multivariate analysis (P=0.02). Total body irradiation (TBI) alone and TBI together with pre-transplant anthracycline administration were significant risk factors for reduced cardiac function in univariate analysis, only (P=0.04 and 0.004, respectively). In conclusion, our prospective study demonstrates an asymptomatic post-allo-HSCT deterioration of pulmonary and cardiac function in some long-term survivors, who had been transplanted in childhood, and thus emphasizes the need for lifelong cardiopulmonary monitoring and the development of new strategies both to reduce pre-transplant cardiotoxic regimens and to treat more efficiently c-GVHD.
Asunto(s)
Antraciclinas/administración & dosificación , Enfermedad Injerto contra Huésped/prevención & control , Cardiopatías/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedades Pulmonares/etiología , Acondicionamiento Pretrasplante/efectos adversos , Adolescente , Antraciclinas/efectos adversos , Gasto Cardíaco , Niño , Preescolar , Ecocardiografía , Femenino , Enfermedad Injerto contra Huésped/fisiopatología , Humanos , Lactante , Masculino , Estudios Prospectivos , Pruebas de Función Respiratoria , Trasplante Homólogo/efectos adversos , Resultado del TratamientoRESUMEN
Allogeneic hematopoietic stem cell transplantation (SCT) contributes to improved outcome in childhood acute leukemia (AL). However, therapeutic options are poorly defined in the case of post-transplantation relapse. We aimed to compare treatment strategies in 334 consecutive children with acute leukemia relapse or progression after SCT in a recent 10-year period. Data could be analyzed in 288 patients (157 ALL, 123 AML and 8 biphenotypic AL) with a median age of 8.16 years at transplantation. The median delay from first SCT to relapse or progression was 182 days. The treatment consisted of chemotherapy alone (n=108), chemotherapy followed by second SCT (n=70), supportive/palliative care (n=67), combination of chemotherapy and donor lymphocyte infusion (DLI; n=30), or isolated reinfusion of donor lymphocytes (DLI; n=13). The median OS duration after relapse was 164 days and differed according to therapy: DLI after chemotherapy=385 days, second allograft=391 days, chemotherapy=174 days, DLI alone=140 days, palliative care=43 days. A second SCT or a combination of chemotherapy and DLI yielded similar outcome (hazard ratio (HR)=0.85, P=0.53) unlike chemotherapy alone (HR=1.43 P=0.04), palliative care (HR=4.24, P<0.0001) or isolated DLI (HR=1,94, P<0.04). Despite limitations in this retrospective setting, strategies including immunointervention appear superior to other approaches, mostly in AML.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia/terapia , Enfermedad Aguda , Niño , Progresión de la Enfermedad , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Leucemia/mortalidad , Leucemia Bifenotípica Aguda/mortalidad , Leucemia Bifenotípica Aguda/terapia , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Transfusión de Linfocitos , Cuidados Paliativos , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Estudios Retrospectivos , Tasa de Supervivencia , Trasplante Homólogo , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
We analyzed the impact of cytogenetics on 193 children enrolled in two successive French trials (LAME89/91 and ELAM02), who received hematopoietic stem cell transplantation during CR1. Detailed karyotype was available for 66/74 (89%) in LAME89/91 and 118/119 (99%) in ELAM02. Several karyotype and transplant characteristics differed according to therapeutic protocol: unfavorable karyotypes were more frequent in ELAM02 (36% vs 18%), pretransplant chemotherapy included high-dose cytarabine in ELAM02 and not in LAME89/91, IV replaced oral busulfan in the conditioning regimen, methotrexate was removed from post-transplant immunosuppression, and matched unrelated donor and cord blood transplantation were introduced. Five-year overall survival (OS) was 78.2% in LAME89 and 81.4% in ELAM02. OS was significantly lower for the unfavorable cytogenetic risk group in LAME89/91 when compared with intermediate and favorable groups (50% vs 90.6 and 86.4%, P=0.001). This difference was no longer apparent in ELAM02 (80.9% vs 71.3% and 5/5, respectively). Survival improvement for children with unfavorable karyotype was statistically significant (P=0.026) and was due to decrease in relapse risk. Five-year transplantation-related mortality was 6.75% in LAME89/91. In ELAM02, it was 3.2% for patients with a sibling donor and 10.9% with an unrelated donor or cord blood. We conclude that the outcome of children with unfavorable karyotype transplanted in CR1 has improved.
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Citogenética , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Niño , Femenino , Francia , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Cariotipificación , Leucemia Mieloide Aguda/mortalidad , Masculino , Inducción de Remisión , Análisis de Supervivencia , Trasplante Homólogo , Resultado del TratamientoRESUMEN
Human herpesvirus 6 (HHV-6) encephalitis may induce neurological sequelae and death; the diagnosis is difficult because of an initially poor symptomatology and of the absence of specific biochemical, electric and radiological signs. We report on a 7-year-old boy with relapsed acute lymphoblastic leukaemia, who developed HHV-6 encephalitis after bone marrow transplantation; the patient recovered after treatment with ganciclovir.
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Trasplante de Médula Ósea/efectos adversos , Encefalitis Viral , Herpesvirus Humano 6 , Infecciones por Roseolovirus , Antivirales/administración & dosificación , Antivirales/uso terapéutico , Niño , Encefalitis Viral/tratamiento farmacológico , Encefalitis Viral/etiología , Encefalitis Viral/virología , Estudios de Seguimiento , Ganciclovir/administración & dosificación , Ganciclovir/uso terapéutico , Enfermedad Injerto contra Huésped/complicaciones , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Recurrencia , Infecciones por Roseolovirus/tratamiento farmacológico , Infecciones por Roseolovirus/virología , Factores de Tiempo , Resultado del TratamientoRESUMEN
UNLABELLED: Cancer is rare in children, and pediatric malignancies represent only 1% of all cancers. OBJECTIVES: The cure rate is high and increasing, and ongoing data collection is therefore warranted. MATERIALS AND METHODS: Here we report the incidence and survival rates of childhood cancers between 1987 and 1999 in the Rhône-Alpes region of France. RESULTS: A total of 1945 cases were recorded during the study period, with an average of 149.6 new cases per year. The approximate incidence rate was 134.1/10(6) per year and the age-standardized incidence rate was 139.2/10(6) per year. The histological distribution and 5-year survival rates were respectively 30.2 and 73% for leukemia, 12.3 and 91.6% for lymphoma, 24.7 and 60.1% for CNS tumors, 9.1 and 71.1% for neuroblastoma, 2.5 and 94.1% for retinoblastoma, 5.8% and 89.9% for renal tumors, 1 and 75% for liver tumors, 6.1 and 60.9% for bone tumors, 4.1 and 58.6% for soft-tissue tumors, 1.1 and 71% for germ cell tumors, and 2.4 and 85.1% for carcinomas. CONCLUSION: The overall survival rate was 75%. Long-term treatment complications warrant further studies of children who survive into adulthood.
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Neoplasias/epidemiología , Adolescente , Niño , Preescolar , Femenino , Francia/epidemiología , Humanos , Incidencia , Lactante , Recién Nacido , Masculino , Sistema de Registros , Tasa de SupervivenciaRESUMEN
The purpose of this study was to identify risk factors for hypothyroidism after bone marrow transplantation (BMT) for high-risk or relapsed acute lymphoblastic leukaemia (ALL) in children. In all, 388 children with acute lymphoblastic leukaemia underwent allogeneic bone marrow transplantation between 1984 and 1994. Overall 5-year survival was 54.6%. Thyroid function was assessed in the 153 patients with more than 5 years of follow-up. In total, 16 patients developed uncompensated hypothyroidism (UH) and 46 compensated hypothyroidism (CH) a median of 2.9 and 2.7 years, respectively, after BMT. Thyroid dysfunction-free survival rates were 73.2% after 5 years and 59.2% after 10 years. Three factors were significantly associated with the onset of hypothyroidism, namely age, bone marrow transplantation in second remission, and single-dose total body irradiation (TBI). Ultrasonography of the thyroid showed nodules in 10 of 35 patients. The median time from BMT to nodule detection was 7.8 years. Cytology (n=5) and surgery (n=4) showed no evidence of thyroid cancer. Four of the 14 patients who received cytoreduction without TBI but with busulphan and cyclophosphamide developed UH (n=2) or CH (n=2). We concluded that children who undergo BMT for ALL are at a high risk of subsequent thyroid dysfunction.
Asunto(s)
Trasplante de Médula Ósea/efectos adversos , Hipotiroidismo/etiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Factores de Riesgo , Sobrevivientes , Trasplante Homólogo , Irradiación Corporal Total/efectos adversosRESUMEN
Thrombocytosis is frequently observed in pediatric patients. Among them the secondary thrombocytosis are the most frequent and result from several causes. The rarely primary thrombocytosis can be either constitutive (and often familial) or acquired (essential thrombocythemia). The purpose of this article is to give diagnostic orientation and to suggest which biological tests should be performed.
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Trombocitosis/diagnóstico , Tiempo de Sangría , Niño , Diagnóstico Diferencial , Humanos , Recuento de Plaquetas , Pruebas de Función Plaquetaria , Trombocitemia Esencial/diagnóstico , Trombocitosis/sangre , Trombocitosis/etiologíaRESUMEN
Trichobezoars are made up of concretions of ingested hair and food. A history of occlusive syndrome in a context of trichotillomania and psychological problems must lead to this diagnosis. Bezoars can be fortuitously recognised by palpation of an epigastric abdominal mass while investigating anemia or esophageal reflux. This deviance is particularly dangerous. The first case of this series illustrates the Rapunzel syndrome with many perforations and necrosis of the small bowel. The 4 others are strict intragastric bezoars, quickly identified by echography. Treatment is exclusively surgical, digestion by papain or endoscopic extraction being impossible. Psychological assistance is mandatory.
Asunto(s)
Bezoares/patología , Intestino Delgado/patología , Estómago/patología , Adolescente , Bezoares/complicaciones , Niño , Preescolar , Humanos , Perforación Intestinal/etiología , Masculino , Necrosis , PronósticoRESUMEN
In order to determine optimal CsA trough blood concentrations (TBC) in the early post transplantation period, we analysed relationships between TBC and acute graft-versus-host disease (aGVHD) in paediatric SCT. A total of 94 children consecutively underwent allogeneic stem cell transplantation (SCT) from: matched-sibling (MSD) (n=36), mismatched-related (MMRD) (n=3) and unrelated donors (UD) (n=55). GVHD prophylaxis usually included CsA alone or with methotrexate. Antithymocyte globulin was added in UD-SCT. TBC during the first weeks of post transplantation were estimated retrospectively by a Bayesian pharmacokinetic method and statistically associated with aGVHD. In MSD-SCT, the mean TBC during the first 2 weeks post transplantation were 42+/-10 and 90+/-7 ng/ml, respectively, in patients with grade II-IV and 0-I aGVHD (P=0.001). In SCT from UD and MMRD, TBC were 73+/-4 vs 95+/-8 ng/ml (P=0.284). For TBC >85 ng/ml, no patient developed grade II-IV aGVHD, 10 developed mild aGVHD and 30 had no aGVHD. For TBC <65 ng/ml, 7/11 patients receiving an MSD-SCT and 4/18 receiving an UD- or MMRD-SCT developed grade II-IV aGVHD. The mean TBC corresponding to each grade were: no GVHD: 101+/-10 ng/ml, mild: 77+/-11 ng/ml, moderate: 61+/-13 ng/ml, severe: 56+/-15 ng/ml (P <0.001). These results reveal a strong relationship between TBC during the early post transplantation period and the severity of aGVHD in paediatric SCT.
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Ciclosporina/sangre , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Inmunosupresores/sangre , Enfermedad Aguda , Adolescente , Teorema de Bayes , Trasplante de Médula Ósea/efectos adversos , Niño , Preescolar , Ciclosporina/efectos adversos , Femenino , Enfermedad Injerto contra Huésped/epidemiología , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Inmunosupresores/efectos adversos , Incidencia , Lactante , Masculino , Índice de Severidad de la Enfermedad , Hermanos , Donantes de Tejidos , Trasplante HomólogoRESUMEN
In order to control busulfan pharmacokinetic variability and toxicity, a specific monitoring protocol was instituted in our bone marrow transplant BMT paediatric patients including a test dose, daily Bayesian forecasting of busulfan plasma levels, and Bayesian individualization of busulfan dosage regimens. Twenty-nine children received BMT after a busulfan-based conditioning regimen. Individual pharmacokinetic parameters were obtained following a 0.5 mg*kg test dose and were used for daily individualization of dosage regimens during the subsequent 4-day course of treatment. Doses were adjusted to reach a target mean AUC per 6 h between 4 and 6 microg.h.ml(+1). Plasma busulfan assays were performed by liquid chromatography. Pharmacokinetic analysis used the USC*PACK software. The performance of the test dose to predict AUC during the busulfan regimen was evaluated. Incidence of toxicity, chimerism and relapse, overall Kaplan-Meier survival, and VOD-free survival were compared after matching our patients (group A) with patients conditioned by using standard doses of busulfan (group B). Busulfan doses were decreased in 69% of patients compared to conventional doses. Expected AUC was significantly correlated with observed AUC and predictability of the test dose was 101.9 +/- 17.9%. Incidence of VOD in group A was 3.4% vs 24.1% in group B, while the incidence of stomatitis was similar. Engraftment was successful in all patients in group A. The rate of full engraftment at 3 months post-BMT was higher in group A (P = 0.012). Long-term overall survival did not differ between the two groups, in contrast to the 90-day survival. VOD-free survival was higher in group A (P = 0.026). Pharmacokinetic monitoring and individualization of busulfan dosage regimen are useful in improving clinical outcome and reducing early mortality in paediatric bone marrow transplant recipients.
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Alquilantes/farmacocinética , Trasplante de Médula Ósea , Busulfano/farmacocinética , Acondicionamiento Pretrasplante/métodos , Adolescente , Alquilantes/administración & dosificación , Alquilantes/sangre , Área Bajo la Curva , Teorema de Bayes , Trasplante de Médula Ósea/efectos adversos , Trasplante de Médula Ósea/estadística & datos numéricos , Busulfano/administración & dosificación , Busulfano/sangre , Niño , Preescolar , Ciclofosfamida/administración & dosificación , Etopósido/administración & dosificación , Femenino , Enfermedades Genéticas Congénitas/terapia , Supervivencia de Injerto , Neoplasias Hematológicas/terapia , Enfermedad Veno-Oclusiva Hepática/epidemiología , Enfermedad Veno-Oclusiva Hepática/etiología , Humanos , Incidencia , Lactante , Tablas de Vida , Masculino , Melfalán/administración & dosificación , Estudios Prospectivos , Inmunodeficiencia Combinada Grave/terapia , Acondicionamiento Pretrasplante/efectos adversos , Trasplante Homólogo/efectos adversos , Resultado del TratamientoRESUMEN
The aim of this study was to identify the risk factors for acute graft-versus-host disease (aGVHD) in children transplanted from a matched-sibling donor (MSD) or an unrelated donor (UD). In all, 87 children consecutively underwent allogeneic bone marrow transplantation (BMT) from MSD (n=36), and UD (n=51). GVHD prophylaxis included CsA alone (n=33) or with MTX (n=51). ATG was added in UD-BMT and thalassemic recipients. CsA whole-blood concentrations were measured by EMIT and the dosing regimen was monitored by Bayesian pharmacokinetic modelling. Trough blood concentration (TBC) during the first 2 weeks post transplantation was lower in children who developed grade II-IV aGVHD than those developing no GVHD or only grade I (57+/-9 vs 94+/-8 ng/ml, P=0.007), whereas peak blood concentration and area under concentration curve vs time were similar in both groups. TBC <85 ng/ml and 'use of MTX' were associated with aGVHD in MSD-SCT (P=0.003 and 0.007, respectively) as well as in UD-SCT (P=0.006 and 0.003). Donor age >or=8 years was significant only in MSD-BMT. Our results have shown the significant decisive role of pharmacological factors such as CSA TBC or use of MTX in the occurrence of GVHD in MSD as well as in UD paediatric BMT.
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Trasplante de Médula Ósea/efectos adversos , Monitoreo de Drogas/métodos , Enfermedad Injerto contra Huésped/prevención & control , Histocompatibilidad , Donantes de Tejidos , Enfermedad Aguda , Adolescente , Área Bajo la Curva , Teorema de Bayes , Trasplante de Médula Ósea/inmunología , Trasplante de Médula Ósea/métodos , Niño , Preescolar , Ciclosporina/administración & dosificación , Ciclosporina/sangre , Ciclosporina/farmacocinética , Femenino , Enfermedad Injerto contra Huésped/etiología , Humanos , Incidencia , Lactante , Masculino , Metotrexato/administración & dosificación , Factores de RiesgoRESUMEN
Between September 1986 and June 1997, 24 children with high-risk ALL in CR1 were allografted after TAM (fractionated TBI, high-dose Ara-C, and melphalan; n = 10) or BAM protocol (busulfan, high-dose Ara-C, and melphalan; n = 14). The EFS for transplants from sibling donors was 33% with TAM and 62% with BAM (P = 0.148). The probability of acute GvHD was 70% with TAM and 15% with BAM (P = 0.003). Four of 17 evaluable patients relapsed: one after TAM and three after BAM. In all, 46 other children transplanted in CR beyond CR1 were studied for sequelae. Long-term side effects were more frequent in TAM vs BAM. In children with ALL, busulfan may be a good alternative to TBI to improve the quality of life.
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Trasplante de Médula Ósea/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Acondicionamiento Pretrasplante , Trasplante Homólogo/métodos , Adolescente , Busulfano/administración & dosificación , Niño , Preescolar , Citarabina/administración & dosificación , Femenino , Enfermedad Injerto contra Huésped , Humanos , Inmunofenotipificación , Cariotipificación , Masculino , Melfalán/administración & dosificación , Organofosfatos/administración & dosificación , Recurrencia , Factores de Tiempo , Resultado del TratamientoRESUMEN
Over the last 15 years, we have performed a total of 30 haematopoietic stem cell transplants on 27 children suffering from Hurler's syndrome. These children were of median age 11 months at the time of diagnosis and 25 months at the time of transplantation. The phenotype was severe in 21 cases (78%). The donor was familial in 13 cases: nine genotypically identical, one phenotypically identical father and three HLA-mismatched donors. Unrelated donors were selected in 17 cases: four phenotypically identical and 13 with 1-4 HLA mismatches. The conditioning regimen generally consisted of busulphan 600 mg/m(2) plus cyclophosphamide (Endoxan) 260 mg/kg and cyclosporin with methotrexate for GvHD prophylaxis. Rabbit anti-thymocyte globulin (Thymoglobuline) was given for all unrelated or familial mismatched transplantations. The median nucleated cell dose infused was 6.00 x 10(8) TNC/kg. No bone marrow (apart from one) was T cell depleted. For first transplants, engraftment was observed in 23/27 patients (pts) (85%). Primary graft failure was observed in 4/27 patients (16%), two were retransplanted from an unrelated donor, one with success. Four patients have died. The primary cause of death was infection in three cases (TRM : 11%) and disease progression in one case, after primary graft failure. Of the 23 living patients, two have disease progression after graft failure and 21 (78%) have functional grafts with a favourable long-term outcome after a median follow-up of 4.7 years, having either full or mixed chimaerism. Among surviving patients with functional grafts, 13 (62%) were transplanted from unrelated donors of whom 10 (77 %) had HLA disparities. There was a remarkably low incidence of GvHD. In our experience, haematopoietic stem cell transplantation using an HLA-matched familial donor or an HLA-matched or -mismatched unrelated donor without T cell depletion or irradiation can achieve a favourable outcome in Hurler's syndrome, with improved cognitive function, but with a limited effect on the corneas and skeleton.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Mucopolisacaridosis I/terapia , Adolescente , Niño , Preescolar , Quimera , Familia , Femenino , Francia/epidemiología , Supervivencia de Injerto , Enfermedad Injerto contra Huésped/etiología , Antígenos HLA , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Lactante , Masculino , Mucopolisacaridosis I/mortalidad , Mucopolisacaridosis I/fisiopatología , Mucopolisacaridosis I/psicología , Donantes de Tejidos , Acondicionamiento Pretrasplante , Resultado del TratamientoRESUMEN
Mesenchymal stem cells (MSC) fail to induce allogeneic responses in mixed lymphocyte reaction assays. Because MSC express HLA class I molecules, here we investigated whether they could be recognized as allogeneic targets by cytolytic T lymphocytes (CTL). With this aim, CTL precursor (CTLp) frequencies were measured following stimulation of T cells with either allogeneic mononuclear cells (MNC) or MSC originated from the same human bone marrow donor. Lysis of MSC was measured at day 10 of culture in standard chromium release assays. In addition, allogeneic PHA blast T cells or B-EBV lymphoblastoid cell lines (LCLs) generated from the same donor were used as positive controls of lysis. Our results showed that when allogeneic MNC were used to stimulate T cells, a high CTLp frequency was detected towards MSC targets. However, when MSC were used as stimulators, CTLp frequencies were markedly altered whatever the targets used, i.e.: MSC, PHA blast T cells or EBV-B LCLs. Moreover, when graded concentrations of MSC were added together with MNC upon stimulation of alloreactive T cells, we observed a dose-dependent decrease in CTLp frequencies towards MSC targets. This inhibition of MSC lysis was partially overcome by adding exogenous rh-IL-2 from the beginning of cultures. In addition, this suppressive effect was totally reproduced when, instead of MSC, supernatant harvested from MSC cultures was added to allogeneic MNC, upon stimulation of alloreactive T cells. In conclusion, our results demonstrate that MSC which can be recognized as targets by pre-activated alloreactive CTLs, may be able to suppress differentiation of CTL precursors into CTL effectors through secretion of suppressive factors.