RESUMO
Adrenocortical insufficiency (AI) is a clinical condition defined by deficient production of glucocorticoids that can result in life-threatening complications. We examined the prevalence of AI in children with brain tumors and those undergoing hematopoietic cell transplantation. Adrenocorticotropic hormone stimulation (stim) testing was used for the assessment of adrenocortical function. On the basis of 155 stim tests in 117 patients, AI was diagnosed in 27.4% of patients with brain tumors and in 21% of hematopoietic cell transplantation recipients. A number of risk factors associated with AI were identified. Adrenocorticotropic hormone stim testing led to a definitive diagnosis of AI or recovery of adrenal function and unambiguous medical management.
Assuntos
Insuficiência Adrenal , Neoplasias Encefálicas , Transplante de Células-Tronco Hematopoéticas , Insuficiência Adrenal/diagnóstico , Insuficiência Adrenal/etiologia , Hormônio Adrenocorticotrópico , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/terapia , Criança , Glucocorticoides , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , HidrocortisonaRESUMO
BACKGROUND: Pleraxifor for peripheral blood stem cell (PBSC) mobilization in children with malignancies is often given following failure of standard mobilization (SM) rather than as a primary mobilizing agent. STUDY DESIGN AND METHODS: In this retrospective multicenter study, we report the safety of plerixafor-based PBSC mobilization in children with malignancies and compare outcomes between patients who received plerixafor upfront with SM (Group A) with those who received plerixafor following failure of SM (Group B). In the latter pleraxifor was given either following a low peripheral blood (PB) CD34 (<20 cells/cu.mm) (Group B1) or as a second collection process due to an unsuccessful yield (CD34 + < 2 × 106 /kg) (Group B2) following failed SM and first apheresis attempts. RESULTS: The study cohort (n = 47) with a median age of 8 (range 0.6-21) year, comprised 19 (40%) Group A and 28 (60%) Group B patients (B1 = 12 and B2 = 16). Pleraxifor mobilization was successful in 87.2% of patients, similar between Groups A and B (84.2% vs 89.2%) and resulted in a median 4-fold increase in PB CD34. Median number of apheresis attempts was 2 in Groups A and B1 but 4 in Group B2. In Group B2, median total CD34+ yield post-plerixafor was 9-fold higher than after SM (P = .0013). Mild to moderate transient adverse events affected 8.5% of patients. Among patients who proceeded to autologous transplant (n = 39), all but one engrafted. CONCLUSION: Plerixafor-based PBSC collection was safe and effective in our cohort and supports consideration as a primary mobilizing agent in children with malignancies.
Assuntos
Benzilaminas/uso terapêutico , Ciclamos/uso terapêutico , Mobilização de Células-Tronco Hematopoéticas/métodos , Neoplasias/tratamento farmacológico , Neoplasias/terapia , Células-Tronco de Sangue Periférico/efeitos dos fármacos , Adolescente , Antígenos CD34/sangue , Remoção de Componentes Sanguíneos , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Linfoma/tratamento farmacológico , Linfoma/terapia , Masculino , Meduloblastoma/tratamento farmacológico , Meduloblastoma/radioterapia , Meduloblastoma/terapia , Neuroblastoma/tratamento farmacológico , Neuroblastoma/radioterapia , Neuroblastoma/terapia , Células-Tronco de Sangue Periférico/metabolismo , Estudos Retrospectivos , Sarcoma/tratamento farmacológico , Sarcoma/terapia , Adulto JovemRESUMO
Anemia is one of the most common extraintestinal manifestations of inflammatory bowel disease (IBD). It can be asymptomatic or associated with nonspecific symptoms, such as irritability, headaches, fatigue, dizziness, and anorexia. In IBD patients, the etiology of anemia is often multifactorial. Various causes include iron deficiency, anemia of inflammation and chronic disease, vitamin deficiencies, hemolysis, or myelosuppressive effect of drugs. Anemia and iron deficiency in these patients may be underestimated because of their insidious onset, lack of standardized screening practices, and possibly underappreciation that treatment of anemia is also required when treating IBD. Practitioners may hesitate to use oral preparations because of their intolerance whereas intravenous preparations are underutilized because of fear of adverse events, availability, and cost. Several publications in recent years have documented the safety and comparative efficacy of various intravenous preparations. This article reviews management of anemia in children with IBD, including diagnosis, etiopathogenesis, evaluation of a patient, protocol to screen and monitor patients for early detection and response to therapy, treatment including parenteral iron therapy, and newer approaches in management of anemia of chronic disease. This report has been compiled by a group of pediatric gastroenterologists serving on the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) IBD committee, in collaboration with a pediatric hematologist, pharmacist, and a registered dietician who specializes in pediatric IBD (IBD Anemia Working Group), after an extensive review of the current literature. The purpose of this review is to raise awareness of under-diagnosis of anemia in children with IBD and make recommendations for screening, testing, and treatment in this population.
Assuntos
Anemia Ferropriva , Anemia , Colite , Gastroenterologia , Doenças Inflamatórias Intestinais , Anemia/diagnóstico , Anemia/etiologia , Anemia/terapia , Anemia Ferropriva/diagnóstico , Anemia Ferropriva/etiologia , Anemia Ferropriva/terapia , Criança , Humanos , Doenças Inflamatórias Intestinais/complicações , Estado Nutricional , Estados UnidosRESUMO
Germline mutations in SAMD9 and SAMD9L genes cause MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy) (OMIM: *610456) and ataxia-pancytopenia (OMIM: *611170) syndromes, respectively, and are associated with chromosome 7 deletions, myelodysplastic syndrome (MDS), and bone marrow failure. In this retrospective series, we report outcomes of allogeneic hematopoietic cell transplantation (HCT) in patients with hematologic disorders associated with SAMD9/SAMD9L mutations. Twelve patients underwent allogeneic HCT for MDS (nâ¯=â¯10), congenital amegakaryocytic thrombocytopenia (nâ¯=â¯1), and dyskeratosis congenita (nâ¯=â¯1). Exome sequencing revealed heterozygous mutations in SAMD9 (nâ¯=â¯6) or SAMD9L (nâ¯=â¯6) genes. Four SAMD9 patients had features of MIRAGE syndrome. Median age at HCT was 2.8 years (range, 1.2 to 12.8 years). Conditioning was myeloablative in 9 cases and reduced intensity in 3 cases. Syndrome-related comorbidities (diarrhea, infections, adrenal insufficiency, malnutrition, and electrolyte imbalance) were present in MIRAGE syndrome cases. One patient with a familial SAMD9L mutation, MDS, and morbid obesity failed to engraft and died of refractory acute myeloid leukemia. The other 11 patients achieved neutrophil engraftment. Acute post-transplant course was complicated by syndrome-related comorbidities in MIRAGE cases. A patient with SAMD9L-associated MDS died of diffuse alveolar hemorrhage. The other 10 patients had resolution of hematologic disorder and sustained peripheral blood donor chimerism. Ten of 12 patients were alive with a median follow-up of 3.1 years (range, 0.1 to 14.7 years). More data are needed to refine transplant approaches in SAMD9/SAMD9L patients with significant comorbidities and to develop guidelines for their long-term follow-up.
Assuntos
Doenças Genéticas Inatas , Mutação em Linhagem Germinativa , Transplante de Células-Tronco Hematopoéticas , Peptídeos e Proteínas de Sinalização Intracelular/genética , Síndromes Mielodisplásicas , Proteínas Supressoras de Tumor/genética , Aloenxertos , Pré-Escolar , Intervalo Livre de Doença , Feminino , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/mortalidade , Doenças Genéticas Inatas/terapia , Humanos , Lactente , Masculino , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/terapia , Estudos Retrospectivos , Taxa de Sobrevida , SíndromeRESUMO
BACKGROUND: The purpose of this study was to determine the feasibility and tolerability of tandem courses of high-dose thiotepa with autologous hematopoietic cell rescue (AHCR) in patients with recurrent, refractory solid tumors who were ineligible for a single course of high-dose therapy due to greater than minimal residual disease. Patients with decreased hearing or poor renal function were eligible. PROCEDURE: Thiotepa was administered intravenously at a dose of 200 mg/m2 /day (6.67 mg/kg/day) daily for 3 days followed by AHCR. A second course of thiotepa was given 4 weeks later provided blood counts recovered sufficiently without evidence of tumor progression. RESULTS: Fifty-eight patients received 96 courses. Thirty-eight (65%) patients received two courses of therapy. Twenty-seven courses (28%) were administered completely in the outpatient setting. A toxic mortality rate of 3.4% was observed. Five of 26 patients with medulloblastoma were alive at a median of 35 months, whereas 21 patients died at a median of 11.7 months. Four of five patients with central nervous system germ cell tumors (CNS GCT) were alive 68-103 months following AHCR. CONCLUSIONS: Two cycles of high-dose thiotepa with AHCR were well tolerated even in these heavily pretreated patients. This therapy may provide prolonged survival in patients with recurrent malignant brain tumors, particularly medulloblastoma and CNS GCT.
Assuntos
Neoplasias Encefálicas , Transplante de Células-Tronco Hematopoéticas , Meduloblastoma , Tiotepa/administração & dosagem , Adolescente , Adulto , Autoenxertos , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/terapia , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Masculino , Meduloblastoma/mortalidade , Meduloblastoma/terapia , Taxa de Sobrevida , Tiotepa/efeitos adversosRESUMO
We describe the safety and feasibility of a forced deflation pulmonary function test (dPFT) in infants and young children. Fifty-two dPFT studies were performed in 26 patients (median age, 1.4 years). Forced vital capacity (FVC) and forced expiratory flow (FEF75 ) were normal in all except one case, but respiratory system compliance (Crs) was reduced in 24% patients. There were no significant differences in pre-blood and marrow transplantation FVC, FEF75 , and Crs between those patients who did and those who did not have posttransplant pulmonary complications. A larger study is needed to determine the prevalence and significance of PFT abnormalities in this age group.
Assuntos
Transplante de Medula Óssea/efeitos adversos , Volume Expiratório Forçado/fisiologia , Pneumopatias/terapia , Testes de Função Respiratória/métodos , Insuficiência Respiratória/fisiopatologia , Criança , Pré-Escolar , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Lactente , Masculino , Prognóstico , Insuficiência Respiratória/etiologia , Taxa de SobrevidaRESUMO
Mycophenolate mofetil (MMF), an ester prodrug of mycophenolic acid (MPA), is used increasingly for graft-versus-host disease (GVHD) prophylaxis. Empiric fixed-dose-escalation strategies in pediatric hematopoietic cell transplantation (HCT) recipients have failed to achieve target MPA exposure. We evaluated the safety and feasibility of a pharmacokinetics-based dosing approach using a novel continuous infusion (CI) method of administration of MMF in pediatric HCT recipients. All patients received a myeloablative conditioning with cyclosporine A and MMF for GVHD prophylaxis. MMF was initiated on day 0 at a dose of 15 mg/kg every 8 hours. Based on steady-state pharmacokinetics, MMF was converted to CI to target a total MPA AUC(0-24) of 40 to 80 µg·hour/mL. The MMF dose was adjusted to maintain a total MPA steady-state concentration (Css) of 1.7 to 3.3 µg/mL. During the CI schedule, MPA AUC(0-24) was maintained at a mean of 40.1 µg·hour/mL (range, 20.6 to 63.8), and 17 of 19 patients (89%) achieved MPA Css within target of 1.7 to 3.3 µg/mL. Eighteen of 19 patients (95%) achieved neutrophil engraftment at a median of 13 days (range, 8 to 41) post-transplant and platelet engraftment at 39 days (range, 17 to 298) days post-transplant. Six of 18 assessable patients (33%) developed stages II to IV acute GVHD and 2 of 15 (13%) developed chronic GVHD. The MMF dose was reduced in 9 patients due to gastrointestinal symptoms (n = 6), low blood counts (n = 4), and viral infection (n = 3). Five patients with acute lymphoblastic leukemia relapsed, of whom 4 have died. Fifteen of 19 patients are alive with a median follow-up of 2.4 years (range, .4 to 4.9), with 3-year event-free and overall survival rates of 68% and 79%, respectively. In this pilot study of pharmacokinetically directed MMF dosing, we observed no toxic deaths, excellent engraftment, and low rates of grades III to IV acute and chronic GVHD. We found significantly lower half-life and higher drug clearance in pediatric HCT recipients compared with stable pediatric renal transplant patients or adult transplant patients. This regimen deserves further validation in a larger cohort of pediatric patients undergoing myeloablative transplantation.
Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Imunossupressores/uso terapêutico , Ácido Micofenólico/uso terapêutico , Condicionamento Pré-Transplante , Adolescente , Adulto , Área Sob a Curva , Criança , Pré-Escolar , Ciclosporina/uso terapêutico , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/patologia , Meia-Vida , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/patologia , Humanos , Imunossupressores/farmacocinética , Lactente , Infusões Intravenosas , Ácido Micofenólico/farmacocinética , Agonistas Mieloablativos/uso terapêutico , Projetos Piloto , Estudos Prospectivos , Análise de SobrevidaRESUMO
Sirolimus has activity against acute lymphoblastic leukemia (ALL) in xenograft models and efficacy in preventing acute graft-versus-host disease (aGVHD). We tested whether addition of sirolimus to GVHD prophylaxis of children with ALL would decrease aGVHD and relapse. Patients were randomized to tacrolimus/methotrexate (standard) or tacrolimus/methotrexate/sirolimus (experimental). The study met futility rules for survival after enrolling 146 of 259 patients. Rate of Grade 2-4 aGVHD was 31% vs 18% (standard vs experimental, P = .04), however, grade 3-4 aGVHD was not different (13% vs 10%, P = .28). Rates of veno-occlusive disease (VOD) and thrombotic microangiopathy (TMA) were lower in the nonsirolimus arm (9% vs 21% VOD, P = .05; 1% vs 10% TMA, P = .06). At 2 years, event free survival (EFS) and overall survival (OS) were 56% vs 46%, and 65% vs 55% (standard vs experimental), respectively (P = .28 and .23). Multivariate analysis showed increased relapse risk in children with ≥0.1% minimal residual disease (MRD) pretransplant, and decreased risk in patients with grades 1-3 aGVHD (P = .04). Grades 1-3 aGVHD were associated with improved EFS (P = .02), whereas grade 4 aGVHD and extramedullary disease at diagnosis led to inferior OS. Although addition of sirolimus decreased aGVHD, survival was not improved. This study is registered with ClinicalTrials.gov as #NCT00382109.
Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Imunossupressores/administração & dosagem , Metotrexato/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Sirolimo/administração & dosagem , Tacrolimo/administração & dosagem , Adolescente , Criança , Pré-Escolar , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Masculino , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Irradiação Corporal Total , Adulto JovemRESUMO
Idiopathic pneumonia syndrome (IPS) is an acute, noninfectious lung disorder associated with high morbidity and mortality after hematopoietic cell transplantation. Previous studies have suggested a role for TNFα in the pathogenesis of IPS. We report a multicenter phase II trial investigating a soluble TNF-binding protein, etanercept (Enbrel, Amgen, Thousand Oaks, CA), for the treatment of pediatric patients with IPS. Eligible patients were < 18 years old, within 120 days after transplantation, and with radiographic evidence of a diffuse pneumonitis. All patients underwent a pretherapy broncho-alveolor lavage (BAL) to establish the diagnosis of IPS. Systemic corticosteroids (2.0 mg/kg/day) plus etanercept (.4 mg/kg twice weekly × 8 doses) were administered. Response was defined as survival and discontinuation of supplemental oxygen support by day 28 of study. Thirty-nine patients (median age, 11 years; range, 1 to 17) were enrolled, with 11 of 39 patients nonevaluable because of identification of pathogens from their pretherapy BAL. In the remaining 28 patients, the median fraction of inspired oxygen at study entry was 45%, with 17 of 28 requiring mechanical ventilation. Complete responses were seen in 20 (71%) patients, with a median time to response of 10 days (range, 1 to 24). Response rates were higher for patients not requiring mechanical ventilation at study entry (100% versus 53%, P = .01). Overall survival at 28 days and 1 year after therapy were 89% (95% confidence interval [CI], 70% to 96%) and 63% (95% CI, 42% to 79%), respectively. Plasma levels of proinflammatory cytokines were significantly increased at onset of therapy, subsequently decreasing in responding patients. The addition of etanercept to high-dose corticosteroids was associated with high response rates and survival in children with IPS.
Assuntos
Corticosteroides/uso terapêutico , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Pneumonias Intersticiais Idiopáticas/terapia , Imunoglobulina G/uso terapêutico , Imunossupressores/uso terapêutico , Receptores do Fator de Necrose Tumoral/uso terapêutico , Adolescente , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Criança , Pré-Escolar , Citocinas/biossíntese , Citocinas/imunologia , Quimioterapia Combinada , Etanercepte , Feminino , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/patologia , Humanos , Pneumonias Intersticiais Idiopáticas/etiologia , Pneumonias Intersticiais Idiopáticas/mortalidade , Pneumonias Intersticiais Idiopáticas/patologia , Lactente , Masculino , Receptores do Fator de Necrose Tumoral/antagonistas & inibidores , Respiração Artificial , Irmãos , Análise de Sobrevida , Transplante Homólogo , Resultado do Tratamento , Doadores não RelacionadosRESUMO
Acute graft-versus-host disease (GVHD) is a common and serious complication of allogeneic blood and marrow transplantation. Acute GVHD is commonly graded according to modified Glucksberg criteria. There is considerable within-grade heterogeneity with different patterns of skin, liver, or gut involvement. In this commentary, we provide an analytical review of ambiguities in acute GVHD severity scoring and offer specific proposals meant to generate discussion in the BMT community for adoption, refinement, and where appropriate, validation studies.
Assuntos
Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Transfusão de Sangue/normas , Transplante de Medula Óssea/efeitos adversos , Transplante de Medula Óssea/normas , Humanos , Guias de Prática Clínica como Assunto , Projetos de Pesquisa , Índice de Gravidade de Doença , Reação Transfusional , Transplante HomólogoRESUMO
Sirolimus-induced ILD is a known but rare complication in adults who have undergone SOT. However, little is known about this adverse effect in children. Diagnosis of sirolimus-induced ILD can be challenging, especially in patients who have difficulty participating in lung function testing. We present a case of presumed sirolimus-induced ILD in a pediatric stem cell transplant patient who developed polycythemia and hypoxemia. To our knowledge, no other cases of sirolimus-induced pulmonary toxicity in children after HCT have been reported.
Assuntos
Imunossupressores/efeitos adversos , Doenças Pulmonares Intersticiais/induzido quimicamente , Sirolimo/efeitos adversos , Transplante de Células-Tronco/efeitos adversos , Criança , Humanos , Hipóxia/etiologia , Pulmão/efeitos dos fármacos , Masculino , Policitemia/etiologia , Radiografia Torácica , Testes de Função RespiratóriaRESUMO
We investigated the incidence of phototoxic skin reactions in pediatric BMT recipients treated with voriconazole. Nine out of 40 patients (22.5%), all Caucasian, developed skin lesions in sun-exposed distributions. Dermatologic findings included sunburn-like erythema, pseudo-porphyria, linear papulovesicular lesions, severe erosive cheilitis, dermatoheliosis and lentigines. Patients were treated with sun avoidance, high-potency sunscreens, and topical steroids with significant improvement in all cases. Prolonged voriconazole use requires close monitoring for chronic skin toxicities. Long-term risks including the risk of skin cancer need to be investigated.
Assuntos
Antifúngicos/efeitos adversos , Transplante de Medula Óssea , Transtornos de Fotossensibilidade/induzido quimicamente , Pirimidinas/efeitos adversos , Luz Solar/efeitos adversos , Triazóis/efeitos adversos , Aloenxertos , Antifúngicos/administração & dosagem , Criança , Feminino , Humanos , Masculino , Transtornos de Fotossensibilidade/patologia , Transtornos de Fotossensibilidade/prevenção & controle , Pirimidinas/administração & dosagem , Estudos Retrospectivos , Neoplasias Cutâneas/prevenção & controle , Protetores Solares/administração & dosagem , Triazóis/administração & dosagem , VoriconazolRESUMO
This study examined the pharmacokinetics of sirolimus in pediatric allogeneic blood and marrow transplantation (BMT) recipients in the presence and absence of concomitant fluconazole. Forty pediatric BMT recipients received a daily oral dose of sirolimus and a continuous i.v. infusion of tacrolimus for graft-versus-host disease prophylaxis. Fluconazole was administered i.v. to 19 patients and orally to 6 patients. Full pharmacokinetic profiles of sirolimus within a single dosing interval were collected. Whole-blood sirolimus concentrations were measured by HPLC/mass spectrometry. Noncompartmental analysis was performed using WinNonlin. Nonlinear mixed-effects pharmacokinetic models were developed using NONMEM following standard procedures. The mean ± SD sirolimus trough level before the dose (C0) was 8.0 ± 4.6 ng/mL (range, 1.8-21.6 ng/mL). The peak concentration was 19.9 ± 11.8 ng/mL (range, 3.9-46.1 ng/mL), and the trough level 24 hours later (C24) was 9.1 ± 5.3 ng/mL (range, 1.0-19.1 ng/mL). The terminal disposition half-life (T1/2) was 24.5 ± 11.2 hours (range, 5.8-53.2 hours), and the area under the concentration-versus-time curve (AUC0-24) was 401.1 ± 316.3 ng·h/mL (range, 20.7-1332.3 ng·h/mL). In patients at steady state, C0 and C24 were closely correlated (R(2) = 0.77) with a slope of 0.99, indicating the achievement of steady state. C24 was 1.7-fold greater (P = .036) and AUC0-24 was 2-fold greater (P = .012) in Caucasian patients (n = 22) compared with Hispanic patients (n = 9). The average apparent oral clearance was 3-fold greater (P = .001) and the apparent oral volume of distribution was 2-fold greater (P = .018) in patients age ≤12 years compared with those age >12 years. C24 was significantly lower in patients (n = 10) who developed grade III-IV aGVHD (n = 10) than in those with grade 0-II aGVHD (n = 22) (6.1 ± 2.9 ng/mL versus 9.4 ± 5.5 ng/mL; P = .044). Dose-normalized sirolimus trough concentrations were significantly higher in patients receiving concomitant fluconazole therapy compared with those not receiving fluconazole (C0: 3.9 ± 2.5 versus 2.4 ± 1.5 ng/mL/mg, P = .030; C24: 4.8 ± 3.3 versus 2.5 ± 1.7 ng/mL/mg, P = .018). This pharmacokinetic study of sirolimus in pediatric patients documents a large interindividual variability in the exposure of sirolimus. Steady-state trough blood concentrations were correlated with drug exposure. Trough concentrations were higher with a concomitant use of fluconazole and were higher in Caucasian patients than in Hispanic patients. Oral clearance was greater in children age ≤12 years than in older children and adolescents. With therapeutic drug monitoring, the majority (79%) of sirolimus trough levels could be maintained within the target range (3-12 ng/mL). This study provides a rationale and support for dose adjustments of sirolimus based on steady-state blood concentrations aimed at achieving a target concentration to minimize toxicity and maximize therapeutic benefits in pediatric BMT recipients.
Assuntos
Transplante de Medula Óssea , Doença Enxerto-Hospedeiro/sangue , Transplante de Células-Tronco Hematopoéticas , Imunossupressores/farmacocinética , Sirolimo/farmacocinética , Adolescente , Antifúngicos/uso terapêutico , Área Sob a Curva , Criança , Pré-Escolar , Monitoramento de Medicamentos , Feminino , Fluconazol/uso terapêutico , Doença Enxerto-Hospedeiro/prevenção & controle , Meia-Vida , Humanos , Imunossupressores/sangue , Imunossupressores/uso terapêutico , Masculino , Agonistas Mieloablativos/uso terapêutico , Sirolimo/sangue , Sirolimo/uso terapêutico , Tacrolimo/uso terapêutico , Condicionamento Pré-Transplante , Transplante Homólogo , Adulto JovemAssuntos
Linfócitos B/patologia , Células da Medula Óssea/patologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Doenças Hematológicas/genética , Adolescente , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Criança , Pré-Escolar , Feminino , Mutação em Linhagem Germinativa , Humanos , Masculino , Células Precursoras de Linfócitos B/patologia , Adulto JovemAssuntos
Proteínas de Ligação a DNA/genética , Proteínas de Homeodomínio/genética , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Proteínas Nucleares/genética , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Autoimunidade , Criança , Pré-Escolar , Humanos , Lactente , Recém-NascidoRESUMO
BACKGROUND: Current guidelines recommend the use of combined hormonal contraceptive pills for menstrual suppression in pediatric blood and marrow transplant (BMT) recipients but recent research reveals that provider practice varies. This study was designed to describe the current practice for managing menstrual issues, that is, menstrual suppression and uterine bleeding, in pediatric BMT patients and to better understand health care providers' practices in the use of gonadotropin-releasing hormone agonists (GnRHa). PROCEDURE: A cross sectional survey consisting of 53 questions was distributed via email to principal investigators in the Pediatric Blood and Marrow Transplant Consortium (PBMTC). Responses were collected using www.surveymonkey.com. RESULTS: Menstrual suppression and uterine bleeding in pediatric BMT patients are primarily managed by pediatric oncologists (97%). The most frequently reported hormonal method used for induction of therapeutic amenorrhea was GnRHa (41%). The top three reasons for choosing a method were greater likelihood of amenorrhea, concerns about side effects, and possible gonadal protection. Continuous combined hormonal contraceptive pills were the most commonly used method for the management of clinically significant uterine bleeding regardless of primary method used for menstrual suppression. CONCLUSION: Despite the 2002 PBMTC guidelines, wide variation in menstrual suppression management practices still exists. Our data show that use of GnRHa is more common than previously reported. Additional research is needed to develop evidence-based practice guidelines in pediatric BMT patients.
Assuntos
Amenorreia/etiologia , Amenorreia/terapia , Pesquisas sobre Atenção à Saúde/métodos , Menorragia/tratamento farmacológico , Hemorragia Uterina/etiologia , Hemorragia Uterina/terapia , Transfusão de Sangue , Transplante de Medula Óssea , Criança , Anticoncepcionais Orais Combinados/uso terapêutico , Estudos Transversais , Gerenciamento Clínico , Feminino , Hormônio Liberador de Gonadotropina/uso terapêutico , Humanos , Menorragia/etiologia , Padrões de Prática MédicaRESUMO
The role of reduced-intensity conditioning (RIC) regimens in pediatric cancer treatment is unclear. To define the efficacy of a busulfan/fludarabine/antithymocyte globulin RIC regimen in pediatric patients ineligible for myeloablative transplantation, we completed a trial at 23 institutions in the Pediatric Blood and Marrow Transplant Consortium. Forty-seven patients with hematologic malignancies were enrolled. Sustained engraftment occurred in 98%, 89%, and 90%, and full donor chimerism was achieved in 88%, 76%, and 78% of evaluable related bone marrow/peripheral blood stem cells (BM/PBSCs), unrelated BM/PBSCs, and unrelated cord blood recipients. With a median follow-up of 24 months (range, 11-53 months), 2-year event-free survival, overall survival (OS), transplantation-related mortality, and relapse were 40%, 45%, 11%, and 43%, respectively. Univariate analysis revealed an inferior outcome when patients had undergone previous total body irradiation (TBI)-containing myeloablative transplantation (2-year OS, 23% vs 63% vs 52%, previous TBI transplantation vs no TBI transplantation vs no transplantation, P = .02) and when patients not previously treated with TBI had detectable disease at the time of the RIC procedure (2-year OS, 0% vs 63%, detectable vs nondetectable disease, P = .01). Favorable outcomes can be achieved with RIC approaches in pediatric patients in remission who are ineligible for myeloablative transplantation. This study was registered at www.clinicaltrials.gov as #NCT00795132.
Assuntos
Transplante de Medula Óssea , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco de Sangue Periférico , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Neoplasias Hematológicas/mortalidade , Humanos , Lactente , Masculino , Agonistas Mieloablativos/administração & dosagem , Recidiva , Taxa de Sobrevida , Fatores de Tempo , Transplante Homólogo , Irradiação Corporal TotalRESUMO
Dyskeratosis congenita (DC) is a rare inherited form of bone marrow failure (BMF) caused by mutations in telomere maintaining genes including TERC and TERT. Here we studied the prevalence of TERC and TERT gene mutations and of telomere shortening in an unselected population of patients with BMF at our medical center and in a selected group of patients referred from outside institutions. Less than 5% of patients with BMF had pathogenic mutations in TERC or TERT. In patients with BMF, pathogenic TERC or TERT gene mutations were invariably associated with marked telomere shortening (<< 1st percentile) in peripheral blood mononuclear cells (PBMCs). In asymptomatic family members, however, telomere length was not a reliable predictor for the presence or absence of a TERC or TERT gene mutation. Telomere shortening was not pathognomonic of DC, as approximately 30% of patients with BMF due to other causes had PBMC telomere lengths at the 1st percentile or lower. We conclude that in the setting of BMF, measurement of telomere length is a sensitive but nonspecific screening method for DC. In the absence of BMF, telomere length measurements should be interpreted with caution.
Assuntos
Doenças da Medula Óssea/genética , Disceratose Congênita/genética , Mutação , RNA/genética , Telomerase/genética , Telômero/genética , Adulto , Doenças da Medula Óssea/metabolismo , Doenças da Medula Óssea/patologia , Criança , Pré-Escolar , Disceratose Congênita/metabolismo , Disceratose Congênita/patologia , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , RNA/metabolismo , Telomerase/metabolismo , Telômero/metabolismo , Telômero/patologia , Adulto JovemRESUMO
An in silico approach comprising of decision tree (DT), random forest (RF) and moving average analysis (MAA) was successfully employed for development of models for prediction of anti-tumor activity of bisphosphonates. A dataset consisting of 65 analogues of both nitrogen-containing and non-nitrogen-containing bisphosphonates was selected for the present study. Four refinements of eccentric distance sum topochemical index termed as augmented eccentric distance sum topochemical indices 1-4 [formula: see text] have been proposed so as to significantly augment discriminating power. Proposed topological indices (TIs) along with the exiting TIs (>1,400) were subsequently utilized for development of models for prediction of anti-tumor activity of bisphosphonates. A total of 43 descriptors of diverse nature, from a large pool of molecular descriptors, calculated through E-Dragon software (version 1.0) and an in-house computer program were selected for development of suitable models by employing DT, RF and MAA. DT identified two TIs as most important and classified the analogues of the dataset with an accuracy of 97% in training set and 90.7% in tenfold cross-validated set. Random forest correctly classified the analogues with an accuracy of 89.2%. Four independent models developed through MAA predicted the activity of analogues of the dataset with an accuracy of 87.6% to 89%. The statistical significance of proposed models was assessed through intercorrelation analysis, specificity, sensitivity and Matthew's correlation coefficient. The proposed models offer a vast potential for providing lead structures for development of potent anti-tumor agents for treatment of cancer that has spread to the bone.
Assuntos
Antineoplásicos/farmacologia , Difosfonatos/farmacologia , Descoberta de Drogas/métodos , Modelos Teóricos , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Difosfonatos/química , HumanosRESUMO
BACKGROUND: Tisagenlecleucel, an anti-CD19 chimeric antigen receptor T (CAR-T) cell therapy, has demonstrated durable efficacy and a manageable safety profile in pediatric and young adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) in the ELIANA pivotal trial and real-world experience. Experience from investigator-led studies prior to ELIANA suggests that infections and inflammatory conditions may exacerbate the severity of cytokine release syndrome (CRS) associated with CAR-T cell therapy, leading to extreme caution and strong restrictions for on-study and commercial infusion of tisagenlecleucel in patients with active infection. CRS intervention with interleukin (IL)-6 blockade and/or steroid therapy was introduced late in the course during clinical trials due to concern for potential negative effect on efficacy and persistence. However, earlier CRS intervention is now viewed more favorably. Earlier intervention and consistency in management between providers may promote broader use of tisagenlecleucel, including potential curative therapy in patients who require remission and recovery of hematopoiesis for management of severe infection. MAIN BODY: Patient 1 was diagnosed with B-ALL at 23 years old. Fourteen days before tisagenlecleucel infusion, the patient developed fever and neutropenia and was diagnosed with invasive Mucorales infection and BK virus hemorrhagic cystitis. Aggressive measures were instituted to control infection and to manage prolonged cytopenias during CAR-T cell manufacturing. Adverse events, including CRS, were manageable despite elevated inflammatory markers and active infection. The patient attained remission and recovered hematopoiesis, and infections resolved. The patient remains in remission ≥1 year postinfusion.Patient 2 was diagnosed with pre-B-ALL at preschool age. She developed severe septic shock 3 days postinitiation of lymphodepleting chemotherapy. After receiving tisagenlecleucel, she experienced CRS with cardiac dysfunction and extensive lymphadenopathy leading to renovascular compromise. The patient attained remission and was discharged in good condition to her country of origin. She remained in remission but expired on day 208 postinfusion due to cardiac arrest of unclear etiology. CONCLUSIONS: Infusion was feasible, and toxicity related to tisagenlecleucel was manageable despite active infections and concurrent inflammation, allowing attainment of remission in otherwise refractory pediatric/young adult ALL. This may lead to consideration of tisagenlecleucel as a potential curative therapy in patients with managed active infections.