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1.
Lancet ; 402(10396): 129-140, 2023 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-37352885

RESUMO

BACKGROUND: Severe combined immunodeficiency (SCID) is fatal unless durable adaptive immunity is established, most commonly through allogeneic haematopoietic cell transplantation (HCT). The Primary Immune Deficiency Treatment Consortium (PIDTC) explored factors affecting the survival of individuals with SCID over almost four decades, focusing on the effects of population-based newborn screening for SCID that was initiated in 2008 and expanded during 2010-18. METHODS: We analysed transplantation-related data from children with SCID treated at 34 PIDTC sites in the USA and Canada, using the calendar time intervals 1982-89, 1990-99, 2000-09, and 2010-18. Categorical variables were compared by χ2 test and continuous outcomes by the Kruskal-Wallis test. Overall survival was estimated by the Kaplan-Meier method. A multivariable analysis using Cox proportional hazards regression models examined risk factors for HCT outcomes, including the variables of time interval of HCT, infection status and age at HCT, trigger for diagnosis, SCID type and genotype, race and ethnicity of the patient, non-HLA-matched sibling donor type, graft type, GVHD prophylaxis, and conditioning intensity. FINDINGS: For 902 children with confirmed SCID, 5-year overall survival remained unchanged at 72%-73% for 28 years until 2010-18, when it increased to 87% (95% CI 82·1-90·6; n=268; p=0·0005). For children identified as having SCID by newborn screening since 2010, 5-year overall survival was 92·5% (95% CI 85·8-96·1), better than that of children identified by clinical illness or family history in the same interval (79·9% [69·5-87·0] and 85·4% [71·8-92·8], respectively [p=0·043]). Multivariable analysis demonstrated that the factors of active infection (hazard ratio [HR] 2·41, 95% CI 1·56-3·72; p<0·0001), age 3·5 months or older at HCT (2·12, 1·38-3·24; p=0·001), Black or African-American race (2·33, 1·56-3·46; p<0·0001), and certain SCID genotypes to be associated with lower overall survival during all time intervals. Moreover, after adjusting for several factors in this multivariable analysis, HCT after 2010 no longer conveyed a survival advantage over earlier time intervals studied (HR 0·73, 95% CI 0·43-1·26; p=0·097). This indicated that younger age and freedom from infections at HCT, both directly driven by newborn screening, were the main drivers for recent improvement in overall survival. INTERPRETATION: Population-based newborn screening has facilitated the identification of infants with SCID early in life, in turn leading to prompt HCT while avoiding infections. Public health programmes worldwide can benefit from this definitive demonstration of the value of newborn screening for SCID. FUNDING: National Institute of Allergy and Infectious Diseases, Office of Rare Diseases Research, and National Center for Advancing Translational Sciences.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Imunodeficiência Combinada Severa , Humanos , Recém-Nascido , Transplante de Células-Tronco Hematopoéticas/métodos , Estudos Longitudinais , Triagem Neonatal , Modelos de Riscos Proporcionais , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/terapia , Imunodeficiência Combinada Severa/genética
2.
Pediatr Hematol Oncol ; 41(6): 389-398, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38712383

RESUMO

Melanoma is the most common skin cancer in children. While the current literature establishes treatment protocols for adult-type melanoma, very few pediatric-specific studies exist, and children are often excluded from melanoma clinical trials2. We report a case series of 23 pediatric patients aged 2-20 years old diagnosed with melanoma at the University of Rochester Medical Center between 1/1/2011 and 1/1/2022. 9/23 patients were Stage III; all patients underwent wide local excision and 9 received adjuvant therapies. 2/23 (8.7%) patients had recurrence of their malignancy after therapy while 21/23 (91.3%) remained without disease progression; 1 patient died from unknown cause, but the rest are alive and currently without disease. All patients whose initial therapy included nivolumab in addition to wide local excision did not have recurrence or progression of their disease. This case series highlights trends in the presentation, treatment, and outcomes of pediatric melanoma; however, additional multi-center studies are needed to establish the clinical utility of such features in pediatric melanoma.


Assuntos
Inibidores de Checkpoint Imunológico , Melanoma , Humanos , Melanoma/tratamento farmacológico , Melanoma/patologia , Criança , Adolescente , Inibidores de Checkpoint Imunológico/uso terapêutico , Masculino , Feminino , Pré-Escolar , Linfonodo Sentinela/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Estadiamento de Neoplasias , Adulto Jovem , Nivolumabe/uso terapêutico , Adulto , Quimioterapia Adjuvante
3.
Pediatr Blood Cancer ; 70(3): e30139, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36573296

RESUMO

BACKGROUND: Pediatric central nervous system (CNS) tumors are the leading cause of pediatric cancer mortality. Research addressing genomic biomarkers and clinical outcomes is needed to inform therapeutic decision-making. METHODS: We conducted a retrospective analysis of pediatric patients (age <21) diagnosed with a primary CNS tumor at four upstate New York hospitals from 2008 to 2021. Clinical and histopathologic data were identified from each patient, including genomic analysis of somatic mutations and tumor mutational burden (TMB) where available. These variables were each compared with overall survival using Cox regression analyses. Multivariable analysis was conducted to identify patient characteristics that may independently predict survival. RESULTS: We identified 119 patients. Common tumor types included low-grade glioma (N = 51), high-grade glioma (N = 29), and medulloblastoma (N = 11). Common driver mutations included TP53 inactivation (N = 16), BRAF-KIAA1549 fusion (N = 16), FGFR1 amplification (N = 12), BRAF V600E mutation (N = 12), NF1 loss (N = 12), and H3F3A K28M mutation (N = 6). Median TMB was one mutation/megabase (mut/Mb, range = 0-132). Overall survival was 79.9%. Variables associated with poorer survival on univariable analysis were higher TMB (p = .002, HR 4.97), high-grade tumors (p = .009, HR 84.3), and high-grade glioma histology (p = .021, HR 3.14). Multivariable analyses further identified TMB (p = .011, HR 4.46) and high-grade histology (p = .015, HR 5.28) as independently predictive of worse survival. Tumor progression was more common in high-TMB (N = 15, 44%) than in low-TMB tumors (N = 19, 35%). CONCLUSIONS: High TMB is correlated with higher rates of progression and death as compared to low-TMB tumors. These findings may help identify patients who may benefit from alternative treatments, such as immunotherapies.


Assuntos
Neoplasias do Sistema Nervoso Central , Neoplasias Cerebelares , Glioma , Humanos , Criança , Estudos Retrospectivos , Proteínas Proto-Oncogênicas B-raf/genética , Biomarcadores Tumorais/genética , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/terapia , Glioma/genética , Glioma/terapia , Glioma/patologia , Mutação
4.
J Pediatr Hematol Oncol ; 44(6): e960-e963, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35895317

RESUMO

T-cell large granular lymphocytic (T-LGL) leukemia is a rare, typically indolent neoplasm with a median age of onset above 60 years. Pathogenesis involves clonal T-cell expansion, and nearly all reported pediatric cases have been associated with concurrent autoimmune disease. Immunosuppressive therapy often mitigates sequelae, but definitive cure is not routinely achieved. Here we present an otherwise healthy 13-year-old with T-LGL leukemia refractory to all standard treatments. Our patient ultimately underwent allogeneic bone marrow transplant (BMT) and is now stable in remission 3 years post-BMT. BMT may offer a viable definitive cure for refractory T-LGL leukemia in very young patients.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Linfocítica Granular Grande , Adolescente , Transplante de Medula Óssea/efeitos adversos , Criança , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Leucemia Linfocítica Granular Grande/terapia , Pessoa de Meia-Idade , Linfócitos T/patologia
5.
J Pediatr Hematol Oncol ; 44(1): e264-e267, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33843815

RESUMO

BACKGROUND: Infant acute myeloid leukemia is a rare but aggressive form of leukemia. OBSERVATION: We report 2 children who presented with hyperleukocytosis, subsequently diagnosed with infant acute myeloid leukemia, and both developed isolated central nervous system relapse while on chemotherapy. Both infants underwent successful bone marrow transplantation with myeloablative conditioning (thiotepa, busulfan, and cyclophosphamide) without radiation, followed by 12 empiric post-transplant lumbar punctures with intrathecal cytarabine. Both patients tolerated these therapies well, and are without infections, chronic graft-versus-host disease, or any post-transplant sequelae. CONCLUSION: Nonradiation-based conditioning followed by empiric central nervous system-directed intrathecal chemotherapy may be considered for high-risk infants with leukemia.


Assuntos
Transplante de Medula Óssea , Neoplasias do Sistema Nervoso Central/terapia , Citarabina/administração & dosagem , Leucemia Mieloide Aguda/terapia , Agonistas Mieloablativos/administração & dosagem , Condicionamento Pré-Transplante , Aloenxertos , Feminino , Humanos , Lactente , Injeções Espinhais , Recidiva
6.
Pediatr Hematol Oncol ; 39(5): 453-467, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34918996

RESUMO

Chronic myeloid leukemia (CML) is effectively treated with long-term tyrosine kinase inhibitor (TKI) therapy, yet little is known about risks of prolonged TKI exposure in young patients, and long-term effect monitoring is not standardized. We surveyed North American pediatric oncologists (n = 119) to evaluate perceived risk of and surveillance practices for potential toxicities associated with prolonged TKI exposure in children and adolescents/young adults (AYAs) with CML. Survey domains included general and specific risk perceptions and surveillance practices for asymptomatic patients on chronic TKI therapy. We analyzed data descriptively and explored relationships between risk perceptions and surveillance. Risk perceptions varied among oncologists but were similar across six categories (thyroid, cardiac, vascular, metabolic, fertility, psychologic), with less than one-third rating each risk as moderate or high in pediatric and AYA patients. More oncologists perceived moderate or high risk of growth abnormalities in children (62% pediatric, 14% AYA) and financial toxicity in all patients (60% pediatric, 64% AYA). A greater proportion of oncologists with moderate or high perceived risk of thyroid abnormalities reported testing thyroid function compared to those with lower perceived risk; patterns for metabolic risk/lipid tests and cardiac risk/tests were similar. In summary, we found that pediatric oncologists had variable risk perceptions and surveillance practices for potential toxicities associated with prolonged TKI exposure. Standardizing surveillance would help quantify risks and refine recommendations.Supplemental data for this article is available online at https://doi.org/10.1080/08880018.2021.2017085 .


Assuntos
Doença Enxerto-Hospedeiro , Leucemia Mielogênica Crônica BCR-ABL Positiva , Médicos , Adolescente , Criança , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Adulto Jovem
7.
J Pediatr Hematol Oncol ; 43(8): e1223-e1227, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34001790

RESUMO

Malignant central nervous system (CNS) tumors in young children have a poor prognosis and pose a therapeutic challenge. We describe 11 patients with high-risk CNS tumors (6 atypical teratoid/rhabdoid tumor, 4 nonmedulloblastoma CNS embryonal tumors, and 1 glioblastoma multiforme) who received 32 consolidation cycles of myeloablative carboplatin/thiotepa followed by autologous peripheral blood stem cell rescue. All patients underwent successful stem cell harvest without significant complications. Mean time to absolute neutrophil count ≥0.5×103/µL was 10.2±1.3 days and the mean length of hospital stay was 15.7±3.0 days. There were no regimen-related deaths. Five-year event-free survival and overall survival were 45.5±15.0% and 58.4±16.3%, respectively. Tandem carboplatin/thiotepa consolidation with autologous stem cell rescue is well-tolerated in young children with nonmedulloblastoma CNS tumors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Nervoso Central/terapia , Agonistas Mieloablativos/administração & dosagem , Transplante de Células-Tronco de Sangue Periférico/métodos , Células-Tronco/citologia , Condicionamento Pré-Transplante/métodos , Carboplatina/administração & dosagem , Neoplasias do Sistema Nervoso Central/patologia , Pré-Escolar , Terapia Combinada , Feminino , Seguimentos , Humanos , Lactente , Masculino , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Tiotepa/administração & dosagem , Transplante Autólogo
8.
Blood ; 132(13): 1438-1451, 2018 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-29997222

RESUMO

Allogeneic hematopoietic cell transplantation (HCT) with myeloablative conditioning for disorders associated with excessive inflammation such as hemophagocytic lymphohistiocytosis (HLH) is associated with early mortality. A multicenter prospective phase 2 trial of reduced-intensity conditioning with melphalan, fludarabine, and intermediate-timing alemtuzumab was conducted for HLA matched or single HLA locus mismatched related or unrelated donor HCT in a largely pediatric cohort. Graft-versus-host disease (GVHD) prophylaxis was cyclosporine with methylprednisolone. The primary end point was 1-year overall survival (OS). Thirty-four patients with HLH and 12 with other primary immune deficiencies were transplanted. With a median follow-up of 20 months, the 1-year OS for transplanted patients was 80.4% (90% confidence interval [CI], 68.6%-88.2%). Five additional deaths by 16 months yielded an 18-month OS probability of 66.7% (90% CI, 52.9%-77.3%). Two patients experienced primary graft failure, and 18 patients either experienced a secondary graft failure or required a second intervention (mostly donor lymphocyte infusion [DLI]). At 1 year, the proportion of patients alive with sustained engraftment without DLI or second HCT was 39.1% (95% CI, 25.2%-54.6%), and that of being alive and engrafted (with or without DLI) was 60.9% (95% CI, 45.4 %-74.9%). The day 100 incidence of grade II to IV acute GVHD was 17.4% (95% CI, 8.1%-29.7%), and 1-year incidence of chronic GVHD was 26.7% (95% CI, 14.6%-40.4%). Although the trial demonstrated low early mortality, the majority of surviving patients required DLI or second HCT. These results demonstrate a need for future approaches that maintain low early mortality with improved sustained engraftment. The trial was registered at Clinical Trials.gov (NCT 01998633).


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Linfo-Histiocitose Hemofagocítica/terapia , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Alemtuzumab/uso terapêutico , Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Feminino , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Lactente , Masculino , Melfalan/uso terapêutico , Análise de Sobrevida , Resultado do Tratamento , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico , Adulto Jovem
9.
Biol Blood Marrow Transplant ; 25(2): 321-327, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30267760

RESUMO

Chronic myelogenous leukemia (CML) is a rare disease in children for which pediatric evidence-based guidelines are lacking. We designed an anonymous survey for practicing pediatric oncologists and bone marrow transplantation (BMT) physicians to assess their willingness to recommend BMT for a patient with CML based on various clinical scenarios. A total of 274 physicians responded to the survey (13.4% response rate). Nearly all pediatric oncologists and BMT physicians recommended against BMT at time of diagnosis of CML in the chronic phase, with only 8.0% and 1.9% recommending BMT if a matched sibling donor (MSD) and a matched unrelated donor (MUD), respectively, was available. Similarly, after a first poor response to tyrosine kinase inhibitor (TKI) therapy or hematologic relapse, physicians continued to recommend against BMT (39.5% and 23.3% recommended BMT in patients with a matched sibling donor and matched unrelated donor, respectively). However, 81.7% and 69.8% of respondents would recommend BMT after 2 hematologic relapses on TKI therapy, if an MSD and an MUD, respectively, were available. In addition, there was great interest in developing a clinical trial evaluating the safety and efficacy of stopping TKIs in children with CML who achieve and maintain a deep molecular response, with 86.7% of respondents stating they would offer such a trial to their pediatric patients. This survey highlights the need for evidence-based, pediatric-specific guidelines for the management of children and adolescents with CML.


Assuntos
Transplante de Medula Óssea , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Padrões de Prática Médica , Adolescente , Canadá , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Oncologia , Guias de Prática Clínica como Assunto , Irmãos , Transplante Homólogo , Estados Unidos , Doadores não Relacionados
10.
Pediatr Blood Cancer ; 66(9): e27827, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31330093

RESUMO

Chronic myeloid leukemia (CML) accounts for 2-3% of leukemias in children under 15 and 9% in adolescents aged 15-19. The diagnosis and management of CML in children, adolescents, and young adults have several differences compared to that in adults. This review outlines the diagnosis and management of the underlying disease as well as challenges that can occur when dealing with CML in this patient population.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Guias de Prática Clínica como Assunto
11.
Pediatr Blood Cancer ; 65(8): e27218, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29722478

RESUMO

Paroxysmal nocturnal hemoglobinuria (PNH) is an extremely rare cause of bone marrow failure in children. We report two children who presented with pancytopenia, and were diagnosed with PNH with severe aplastic anemia. Both children underwent upfront, successful hematopoietic stem cell transplantation with reduced-intensity conditioning. One patient had a syngeneic donor, and one patient had a 10/10 matched unrelated donor. Neither patient developed graft versus host disease, infections, or recurrent PNH. Reduced-intensity conditioning hematopoietic stem cell transplantation is a reasonable therapy for PNH with marrow failure in children.


Assuntos
Anemia Aplástica/terapia , Transplante de Células-Tronco Hematopoéticas , Hemoglobinúria Paroxística/terapia , Condicionamento Pré-Transplante , Adolescente , Humanos , Masculino
12.
Pediatr Blood Cancer ; 65(4)2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29286561

RESUMO

Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare liver malignancy in adolescents and young adults. Surgery is the mainstay of therapy for primary and metastatic disease. Most patients relapse, with development of both local and distant metastases. Brain metastases from solid tumors are rare in the pediatric and young adult population. Here, we document three patients with brain metastases from FLHCC, confirmed by histology and molecular characterization of the chimeric fusion DNAJB1-PRKACA, each necessitating neurosurgical intervention. These observations highlight the ability of FLHCC to metastasize to the brain and suggest the need for surveillance neuroimaging for patients with advanced-stage disease.


Assuntos
Neoplasias Encefálicas , Carcinoma Hepatocelular , Neoplasias Hepáticas , Neuroimagem , Procedimentos Neurocirúrgicos , Adolescente , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/cirurgia , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/cirurgia , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/genética , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/metabolismo , Feminino , Proteínas de Choque Térmico HSP40/genética , Proteínas de Choque Térmico HSP40/metabolismo , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/cirurgia , Metástase Neoplásica , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo
13.
J Pediatr Hematol Oncol ; 39(3): 167-173, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28060114

RESUMO

Most childhood cancer survivors do not receive risk-based care through a survivorship program, but factors associated with dropping out of care are unclear. This study aimed to identify characteristics of pediatric cancer survivors who do not return to a cancer center survivorship program for recommended care after at least 1 visit compared with those who continue to attend. Patient characteristics (demographics, school functioning, psychiatric history) and treatment characteristics (diagnosis, treatment) were abstracted from medical records for all eligible patients. Unadjusted and multivariable logistic regression analyses examined the associations among patient and treatment characteristics and nonattendance. The charts of 400 eligible patients (children below 18, n=123; adults, n=277) were reviewed. Of these, 60.3% of patients had not been seen in clinic within 1 year of their last recommended follow-up appointment. Adult-aged survivors were less likely to return to clinic than child-aged survivors (P<0.001). For child survivors, longer time off treatment was associated with noncompliance with follow-up. For adult survivors, current age, nonwhite race, and longer time off treatment were associated with noncompliance. Additional methods to identify survivors at risk for noncompliance with follow-up and interventions for at-risk survivors are needed to improve survivorship care.


Assuntos
Cooperação do Paciente , Adolescente , Adulto , Assistência ao Convalescente/estatística & dados numéricos , Criança , Feminino , Humanos , Masculino , Neoplasias/psicologia , Sobreviventes/psicologia , Adulto Jovem
17.
Blood ; 119(8): 1821-30, 2012 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-22210880

RESUMO

Chronic myeloid leukemia (CML) is composed of 3% of pediatric leukemias, making evidence-based recommendations difficult. Imatinib has revolutionized the treatment for adult CML by eliminating allogeneic stem cell transplantation for almost all patients in chronic phase. Shown effective in pediatric CML, imatinib and successive tyrosine kinase inhibitors (TKI) have provided more therapeutic options. Because stem cell transplantation has been better tolerated in children and adolescents, the decision to treat by either TKI or transplantation is controversial. We present a recent case of a 12-month-old boy diagnosed with BCR-ABL(+) CML to highlight the controversies in treatment recommendations. We review the pediatric stem cell transplantation outcomes as well as the pediatric experience with imatinib and other TKIs. Finally, we compare the side effects as well as costs associated with allogeneic stem cell transplantation versus TKI therapy. We recommend that frontline therapy for pediatric CML in chronic phase is TKI therapy without transplantation. Patients in accelerated or blast crisis or who fail to reach landmarks on TKIs either because of intolerance or resistance should pursue stem cell transplantation. Although we recommend adopting adult clinical experience to guide therapeutic decision making, the issues of infant CML, drug formulation, pharmacokinetics, and adolescent compliance merit clinical investigation.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Transplante de Células-Tronco/métodos , Benzamidas , Cromossomos Humanos Par 22/genética , Cromossomos Humanos Par 9/genética , Terapia Combinada , Evolução Fatal , Proteínas de Fusão bcr-abl/genética , Humanos , Mesilato de Imatinib , Hibridização in Situ Fluorescente , Lactente , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Masculino , Piperazinas/administração & dosagem , Guias de Prática Clínica como Assunto , Pirimidinas/administração & dosagem , Translocação Genética
18.
Biol Blood Marrow Transplant ; 19(12): 1745-52, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24120380

RESUMO

Stem cell transplantation can be associated with significant periods of thrombocytopenia, necessitating platelet transfusions and contributing to the risk of bleeding. Thrombopoietin receptor agonists have been shown to enhance platelet counts in other clinical settings, and so a phase 1 clinical trial was conducted to assess the safety, pharmacokinetics, and maximum tolerated dose of once-daily eltrombopag in patients undergoing stem cell transplantation with conditioning regimens containing total body irradiation ≥400 cGy. Eltrombopag was examined at dosage levels of 75, 150, 225, and 300 mg given orally once daily for 27 days, starting at 24 to 48 hours post-transplantation. Pharmacokinetic sampling was performed over a 24-hour period after the first dose of eltrombopag, as well as during the second week of treatment (steady-state). Nineteen patients were enrolled, 15 of whom completed protocol treatments. Three patients completed each dose level up to 225 mg, and 6 completed treatment at the highest dose of 300 mg. Four patients were replaced because drug compliance was <75% of planned doses. No dose-limiting toxicities were observed in this heterogeneous post-transplantation patient population. Common adverse events were related to standard stem cell transplantation. One episode of pulmonary embolus occurred 9 days after discontinuation of eltrombopag, and the only other thromboembolic episode was a grade 2 catheter-related clot. We conclude that up to 27 days of once-daily dosing of eltrombopag after stem cell transplantation is well tolerated.


Assuntos
Benzoatos/efeitos adversos , Benzoatos/uso terapêutico , Hidrazinas/efeitos adversos , Hidrazinas/uso terapêutico , Pirazóis/efeitos adversos , Pirazóis/uso terapêutico , Transplante de Células-Tronco/métodos , Condicionamento Pré-Transplante/métodos , Irradiação Corporal Total/métodos , Adulto , Idoso , Benzoatos/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/radioterapia , Neoplasias Hematológicas/cirurgia , Neoplasias Hematológicas/terapia , Humanos , Hidrazinas/farmacocinética , Masculino , Pessoa de Meia-Idade , Pirazóis/farmacocinética , Transplante de Células-Tronco/efeitos adversos , Trombocitopenia/tratamento farmacológico , Trombocitopenia/etiologia , Condicionamento Pré-Transplante/efeitos adversos , Transplante Autólogo , Irradiação Corporal Total/efeitos adversos , Adulto Jovem
19.
J Pediatr Hematol Oncol ; 35(6): 486-9, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22935661

RESUMO

Exocrine pancreatic insufficiency and diarrhea have been hallmarks in the diagnosis of Shwachman-Diamond syndrome (SDS). We report 2 cases of genetically confirmed SDS in patients who presented with an unusual phenotype. Patient #1 presented with pancytopenia without other system involvement, while patient #2 presented with severe neutropenia, anemia, and a bifid thumb. Neither patient had diarrhea or malabsorption. Both patients had the classic heterozygous mutations c183_184 TA>CT and c.258+2 T>C in the Shwachman-Bodian-Diamond syndrome gene. Incomplete phenotypes may be more common than previously recognized in bone marrow failure syndromes; gastrointestinal symptoms should not be considered a prerequisite for SDS.


Assuntos
Doenças da Medula Óssea/complicações , Diarreia/genética , Insuficiência Pancreática Exócrina/complicações , Lipomatose/complicações , Pancitopenia/genética , Anemia/genética , Doenças da Medula Óssea/genética , Pré-Escolar , Insuficiência Pancreática Exócrina/genética , Deformidades Congênitas da Mão/genética , Humanos , Lactente , Lipomatose/genética , Masculino , Mutação , Fenótipo , Proteínas/genética , Síndrome de Shwachman-Diamond , Polegar/anormalidades
20.
Blood Adv ; 7(14): 3725-3734, 2023 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-37042921

RESUMO

Overall survival after reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) using alemtuzumab, fludarabine, and melphalan is associated with high rates of mixed chimerism (MC) and secondary graft failure (GF). We hypothesized that peritransplantation alemtuzumab levels or specific patterns of inflammation would predict these risks. We assessed samples from the Bone Marrow Transplant Clinical Trials Network 1204 (NCT01998633) to study the impact of alemtuzumab levels and cytokine patterns on MC and impending or established secondary GF (defined as donor chimerism <5% after initial engraftment and/or requirement of cellular intervention). Thirty-three patients with hemophagocytic lymphohistiocytosis (n = 25) and other IEIs (n = 8) who underwent HCTs with T-cell-replete grafts were included. Patients with day 0 alemtuzumab levels ≤0.32 µg/mL had a markedly lower incidence of MC, 14.3%, vs 90.9% in patients with levels >0.32 µg/mL (P = .008). Impending or established secondary GF was only observed in patients with day 0 alemtuzumab levels >0.32 µg/mL (P = .08). Unexpectedly, patients with impending or established secondary GF had lower CXCL9 levels. The cumulative incidence of impending or established secondary GF in patients with a day 14+ CXCL9 level ≤2394 pg/mL (day 14+ median) was 73.6% vs 0% in patients with a level >2394 pg/mL (P = .002). CXCL9 levels inversely correlated with alemtuzumab levels. These data suggest a model in which higher levels of alemtuzumab at day 0 deplete donor T cells, inhibit the graft-versus-marrow reaction (thereby suppressing CXCL9 levels), and adversely affect sustained engraftment in the nonmyeloablative HCT setting. This trial was registered at www.clinicaltrials.gov as #NCT01998633.


Assuntos
Anticorpos Monoclonais Humanizados , Transplante de Células-Tronco Hematopoéticas , Humanos , Alemtuzumab/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Melfalan/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doadores de Tecidos , Quimiocina CXCL9
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