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1.
JAMA Pediatr ; 173(5): e190081, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30882883

RESUMO

Importance: Studies demonstrating improved survival after allogeneic hematopoietic cell transplant generally exclude infants. Objective: To analyze overall survival trends and other outcomes among infants who undergo allogeneic hematopoietic cell transplant. Design, Setting, and Participants: In this cohort study, we used time-trend analysis to evaluate 3 periods: 2000 through 2004, 2005 through 2009, and 2010 through 2014. The study was conducted in a multicenter setting through the Center for International Blood and Marrow Transplant Research, which is made up of a voluntary working group of more than 450 transplant centers worldwide. Two groups of infants aged 1 year or younger in 2 cohorts were included: those with malignant conditions, such as leukemia, and those with nonmalignant disorders, including immunodeficiencies. Data analysis was conducted from July 2017 to December 2018. Exposures: Allogeneic hematopoietic cell transplant. Main Outcomes and Measures: Survival trends, disease relapse, and toxicity. Results: A total of 2498 infants with a median age of 7 months (range, <1-12 months) were included. In the nonmalignant cohort (n = 472), survival rates improved from the first to the second period (hazard ratio, 0.77 [95% CI, 0.63-0.93]; P = .007) but did not change after 2004. Compared with infants with nonmalignant diseases (n = 2026; 3-year overall survival: 2000-2004, 375/577 [65.0%]; 2005-2009, 503/699 [72.0%]; and 2010-2014, 555/750 [74.0%]), those with malignant conditions had poorer survival rates, without improvement over time (3-year overall survival: 2000-2004, 109/199 [54.8%]; 2005-2009, 104/161 [64.6%]; and 2010-2014, 66/112 [58.9%]). From 2000 through 2014, relapse rates increased in infants with malignant conditions (3-year relapse rate: 2000-2004, 19% [95% CI, 14%-25%]; 2005-2009, 23% [95% CI, 17%-30%]; 2010-2014, 36% [95% CI, 27%-46%]; P = .01). Sinusoidal obstruction syndrome was frequent, occurring with a cumulative incidence of 13% (95% CI, 11%-16%) of infants with nonmalignant diseases and 32% (95% CI, 22%-42%) of those with malignant diseases. Generally, recipients of human leukocyte antigen-identical sibling bone marrow grafts had the best outcomes. Conclusions and Relevance: Survival rates have not improved for infants with malignant diseases over the 15-year study period. Infants with nonmalignant diseases had improved survival rates in the earlier but not the later study period. Higher relapses for the malignant cohort and toxicities for all infants remain significant challenges. Strategies to reduce relapse and toxicity and optimize donor and graft selection may improve outcomes in the future.

2.
J Allergy Clin Immunol Pract ; 7(3): 848-855, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30391550

RESUMO

BACKGROUND: Biallelic variations in the dedicator of cytokinesis 8 (DOCK8) gene cause a combined immunodeficiency with eczema, recurrent bacterial and viral infections, and malignancy. Natural disease outcome is dismal, but allogeneic hematopoietic stem cell transplantation (HSCT) can cure the disease. OBJECTIVE: To determine outcome of HSCT for DOCK8 deficiency and define possible outcome variables. METHODS: We performed a retrospective study of the results of HSCT in a large international cohort of DOCK8-deficient patients. RESULTS: We identified 81 patients from 22 centers transplanted at a median age of 9.7 years (range, 0.7-27.2 years) between 1995 and 2015. After median follow-up of 26 months (range, 3-135 months), 68 (84%) patients are alive. Severe acute (III-IV) or chronic graft versus host disease occurred in 11% and 10%, respectively. Causes of death were infections (n = 5), graft versus host disease (5), multiorgan failure (2), and preexistent lymphoma (1). Survival after matched related (n = 40) or unrelated (35) HSCT was 89% and 81%, respectively. Reduced-toxicity conditioning based on either treosulfan or reduced-dose busulfan resulted in superior survival compared with fully myeloablative busulfan-based regimens (97% vs 78%; P = .049). Ninety-six percent of patients younger than 8 years at HSCT survived, compared with 78% of those 8 years and older (P = .06). Of the 73 patients with chimerism data available, 65 (89%) had more than 90% donor T-cell chimerism at last follow-up. Not all disease manifestations responded equally well to HSCT: eczema, infections, and mollusca resolved quicker than food allergies or failure to thrive. CONCLUSIONS: HSCT is curative in most DOCK8-deficient patients, confirming this approach as the treatment of choice. HSCT using a reduced-toxicity regimen may offer the best chance for survival.

3.
Pediatr Dermatol ; 31(6): 716-21, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-23405946

RESUMO

Osteopetrosis, lymphedema, hypohidrotic ectodermal dysplasia, and immunodeficiency (OL-HED-ID) is a rare X-linked disorder with only three reported prior cases in the English-language literature. We describe a case of OL-HED-ID in a male infant who initially presented with congenital lymphedema, leukocytosis, and thrombocytopenia of unknown etiology at 7 days of age. He subsequently developed gram-negative sepsis and multiple opportunistic infections including high-level cytomegalovirus viremia and Pneumocystis jiroveci pneumonia. The infant was noted to have mildly xerotic skin, fine sparse hair, and periorbital wrinkling, all features suggestive of ectodermal dysplasia. Skeletal imaging showed findings consistent with osteopetrosis, and immunologic investigation revealed hypogammaglobulinemia and mixed T- and B-cell dysfunction. Genetic testing revealed a novel mutation in the nuclear factor kappa beta (NF-KB) essential modulator (NEMO) gene, confirming the diagnosis of OL-HED-ID. Mutations in the NEMO gene have been reported in association with hypohidrotic ectodermal dysplasia with immunodeficiency (HED-ID), OL-HED-ID, and incontinentia pigmenti. In this case, we report a novel mutation in the NEMO gene associated with OL-HED-ID. This article highlights the dermatologic manifestations of a rare disorder, OL-HED-ID, and underscores the importance of early recognition and prompt intervention to prevent life-threatening infections.


Assuntos
Displasia Ectodérmica Anidrótica Tipo 1/complicações , Displasia Ectodérmica/complicações , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Síndromes de Imunodeficiência/complicações , Linfedema/complicações , Infecções Oportunistas/complicações , Osteopetrose/complicações , Displasia Ectodérmica/genética , Displasia Ectodérmica/terapia , Displasia Ectodérmica Anidrótica Tipo 1/genética , Displasia Ectodérmica Anidrótica Tipo 1/terapia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/terapia , Recém-Nascido , Linfedema/genética , Linfedema/terapia , Masculino , Infecções Oportunistas/genética , Infecções Oportunistas/terapia , Osteopetrose/genética , Osteopetrose/terapia
4.
Pediatr Blood Cancer ; 60(3): 455-60, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22811079

RESUMO

BACKGROUND: To investigate the immune status among pediatric patients with aplastic anemia (AA) and explore PNH-status, T-regulatory and NK-cell frequency as potential markers of clinical response. METHODS: Data were retrospectively analyzed from twenty-six patients diagnosed with AA. PNH populations, T- and NK-subsets were determined via flow cytometry. RESULTS: At diagnosis, 9/23 patients with severe AA (SAA) versus 1/3 with moderate AA (MAA) were PNH(pos) . Among PNH(pos) patients treated with ATG based immunosuppression, 2/6 had a complete response (CR), while 4/6 had a partial response (PR), similarly 2/6 PNH(neg) patients had a CR and 4/6 had a PR. Lymphocyte subset immunophenotyping revealed that T-regulatory cells represented 7.2% of total lymphocytes at diagnosis. Their frequency varied with disease severity (5.5% for SAA and 14.1% for MAA) and response (8.9% for CR and 1.5% for PR), generally increasing following therapy with IST (14.6%). The NK cell frequency was not substantially different based on disease severity or response. CONCLUSIONS: Neither PNH cell populations, nor NK cell frequency corresponded with disease severity or response. T-regulatory cell frequency, although not statistically significant given the small sample size, corresponded with both severity and response, indicating potential utility as a prognostic tool.


Assuntos
Anemia Aplástica/imunologia , Anemia Aplástica/patologia , Células Matadoras Naturais/imunologia , Linfócitos T/imunologia , Adolescente , Anemia Aplástica/tratamento farmacológico , Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Feminino , Citometria de Fluxo , Hemoglobinúria Paroxística/tratamento farmacológico , Hemoglobinúria Paroxística/imunologia , Hemoglobinúria Paroxística/patologia , Humanos , Imunofenotipagem , Lactente , Masculino , Estudos Retrospectivos
5.
Pediatr Hematol Oncol ; 28(6): 469-78, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21707222

RESUMO

Immunosuppressive therapy (IST) is recommended for children with acquired aplastic anemia (AA) who lack a human leukocyte antigen (HLA)-matched sibling donor for hematopoietic cell transplantation (HCT). Hematopoietic growth factors have often been included in IST supportive care, but prolonged exposure may increase the risk of secondary clonal evolution. The authors evaluated response, survival, and the incidence of clonal evolution following cyclosporine-based IST without hematopoietic growth factor exposure in a population-based pediatric cohort, identified retrospectively. Forty-five patients with a median age of 7.3 years (range 1.2-17.0 years) were included. Partial (PR) and complete (CR) response was achieved in 82% and 64%, at a median of 55 days (range 11-414 days) and 7.6 months (range 2.8-82.2 months), respectively. Patients with associated seronegative hepatitis had an increased likelihood of PR and CR on multivariate analyses (PR: hazard ratio [HR] 3.15, 95% confidence interval [CI] 1.40, 7.11; CR: HR 2.99, 95% CI 1.35, 6.62), whereas older children were less likely to achieve IST response than children younger than 5 years at diagnosis. Five- and 10-year overall survival was 96% ± 4% and 90% ± 7%, respectively, and 5-year failure-free survival was 63% ± 8%. There was no infection-related mortality, although 16.4% of patients had at least 1 episode of documented bacteremia. The 5-year cumulative incidence of relapse was 12.9% and of clonal evolution was 3.2%. The authors conclude that children with AA who receive IST without hematopoietic growth factor support have excellent response and survival outcomes and a low incidence of clonal evolution.


Assuntos
Anemia Aplástica/tratamento farmacológico , Anemia Aplástica/mortalidade , Ciclosporina/administração & dosagem , Fatores de Crescimento de Células Hematopoéticas , Imunossupressão/métodos , Imunossupressores/administração & dosagem , Adolescente , Fatores Etários , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Taxa de Sobrevida
7.
Pediatr Blood Cancer ; 49(3): 306-12, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16972242

RESUMO

BACKGROUND: Prophylaxis with ganciclovir or foscarnet post allogeneic stem cell transplant (AlloSCT) reduces cytomegalovirus (CMV) disease. Combination ganciclovir/foscarnet is more effective than monotherapy in HIV patients with CMV retinitis. We hypothesized that alternate day ganciclovir and foscarnet for the prevention of CMV during the first 100 days after AlloSCT would be safe and effective. PROCEDURE: Fifty-three pediatric and adolescent AlloSCT recipients receiving 57 AlloSCTs where donors and/or recipients were CMV seropositive received ganciclovir (5 mg/kg/48 hr) alternating with foscarnet (90 mg/kg/48 hr) from myeloid recovery (>or=ANC 750/mm3) until Day +100. RESULTS: Patients were: M:F 31:22; age 6 years (0.8-18 years); donor sources: 25 related peripheral blood/bone marrow, 3 unrelated adult peripheral blood, 26 unrelated cord blood, and 3 related cord blood. GVHD prophylaxis included tacrolimus/mycophenolate mofetil (MMF). Median-nucleated and CD34 cell counts were 7.3x10(8)/kg and 5.07x10(6)/kg, respectively, for BM/PBSC; 4.07x10(7)/kg and 1.69x10(5)/kg, respectively, for CB. Despite a 36.5% probability of Grades II-IV acute GVHD, no patient developed systemic CMV disease. Five percent had Grade IV hematological toxicity that required discontinuation of ganciclovir. Twenty-five percent required discontinuation of foscarnet secondary to electrolyte abnormalities and/or renal dysfunction that were presumed to be multifactorial in origin. Probability of 1-year overall survival was 58.8%. CONCLUSIONS: Alternate day ganciclovir/foscarnet in AlloSCT recipients where recipient and/or donor is seropositive appears to be tolerable and 100% effective in preventing CMV systemic disease. A randomized study will be required to determine if this approach is superior to other CMV prophylactic designs.


Assuntos
Antivirais/administração & dosagem , Infecções por Citomegalovirus/prevenção & controle , Foscarnet/administração & dosagem , Ganciclovir/administração & dosagem , Transplante de Células-Tronco/efeitos adversos , Adolescente , Adulto , Antivirais/efeitos adversos , Criança , Pré-Escolar , Infecções por Citomegalovirus/etiologia , Esquema de Medicação , Quimioterapia Combinada , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Foscarnet/efeitos adversos , Ganciclovir/efeitos adversos , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Lactente , Masculino , Projetos Piloto , Condicionamento Pré-Transplante/métodos , Transplante Homólogo
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