RESUMO
Severe aplastic anemia (SAA) is a rare potentially fatal hematologic disorder. Although overall outcomes with treatment are excellent, there are variations in management approach, including differences in treatment between adult and pediatric patients. Certain aspects of treatment are under active investigation in clinical trials. Because of the rarity of the disease, some pediatric hematologists may have relatively limited experience with the complex management of SAA. The following recommendations reflect an up-to-date evidence-based approach to the treatment of children with newly diagnosed SAA.
Assuntos
Anemia Aplástica , Humanos , Anemia Aplástica/terapia , Anemia Aplástica/diagnóstico , Criança , Medicina Baseada em Evidências , Guias de Prática Clínica como Assunto/normasRESUMO
Severe aplastic anemia (SAA) is a rare potentially fatal hematologic disorder. Although overall outcomes with treatment are excellent, there are variations in management approach, including differences in treatment between adult and pediatric patients. Certain aspects of treatment are under active investigation in clinical trials. Because of the rarity of the disease, some pediatric hematologists may have relatively limited experience with the complex management of SAA. The following recommendations reflect an up-to-date evidence-based approach to the treatment of children with relapsed or refractory SAA.
Assuntos
Anemia Aplástica , Humanos , Anemia Aplástica/terapia , Criança , Recidiva , Medicina Baseada em Evidências , Transplante de Células-Tronco HematopoéticasRESUMO
BACKGROUND: Capillary lymphatic venous malformations (CLVM) and associated syndromes, including Klippel-Trenaunay syndrome (KTS) and congenital lipomatous overgrowth, vascular malformation, epidermal nevi, skeletal, and spinal syndrome (CLOVES), are underrecognized disorders associated with high morbidity from chronic pain, recurrent infections, bleeding, and clotting complications. The rarity of these disorders and heterogeneity of clinical presentations make large-scale randomized clinical drug trials challenging. Identification of PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [gene]) mutations in CLVM has made targeted medications, such as sirolimus, attractive treatment options. The aim of this study was to investigate the safety and efficacy of sirolimus therapy in CLVM. PROCEDURE: A combined prospective and retrospective cohort of pediatric and young adult patients with CLVM treated with sirolimus was evaluated for disease response, including symptom improvement, quality of life (QOL), and radiologic response. Sirolimus dosing regimens and toxicities were also assessed. RESULTS: Twenty-nine patients with CLVM, including KTS and CLOVES, were included. Ninety-three percent of patients reported improved QOL, and 86% had improvement in at least one symptom. Most significantly, improvement was noted in 100% of patients with bleeding and 89% with thrombotic complications with corresponding decreases in mean D-dimer (p = .008) and increases in mean fibrinogen (p = .016). No patients had progressive disease on sirolimus. Most common side effects included neutropenia, lymphopenia, infection, and aphthous ulcers/stomatitis. No toxicities were life-threatening, and none required long-term discontinuation of sirolimus. CONCLUSION: Sirolimus appears to be effective at reducing complications and improving QOL in patients with CLVM and associated syndromes. In this patient cohort, sirolimus was well tolerated and resulted in few treatment-related toxicities.
Assuntos
Síndrome de Klippel-Trenaunay-Weber , Malformações Vasculares , Criança , Humanos , Adulto Jovem , Síndrome de Klippel-Trenaunay-Weber/diagnóstico , Síndrome de Klippel-Trenaunay-Weber/genética , Estudos Prospectivos , Qualidade de Vida , Estudos Retrospectivos , Sirolimo , Malformações Vasculares/diagnósticoRESUMO
OBJECTIVES: Patients born with bilateral head and neck lymphatic malformations (BHNLMs) often require multiple invasive treatments, including tracheostomy. We hypothesized that primary targeted medical therapy (pTMT) with diagnostic needle aspiration reduces the need for invasive therapy such as surgical resection and/or sclerotherapy. METHODS: Retrospective case review was performed of infants with BHNLMs (Grade 2 or De Serres stage IV and V) treated only at our institution from 2000 to 2021. Patients were divided into two cohorts: those managed with pTMT and those managed with observation, sclerotherapy, or surgical intervention (non-pTMT). Data regarding interventions, clinical outcomes, morbidity, and mortality were analyzed with descriptive statistics. RESULTS: Nine children with BHNLMs met inclusion criteria. Three (33%) were in the pTMT cohort and six (66%) were non-pTMT. Eight (89%) malformations were genotyped, and all demonstrated hotspot PIK3CA variants. All pTMT patients had sirolimus initiated in the first month of life and underwent needle aspiration of malformation cyst fluid for cell-free DNA samples. All pTMT patients tolerated medical therapy. For the non-pTMT cohort, primary treatment included none (deceased, n = 1, 17%), observation with needle aspiration (n = 1, 17%), surgical resection (n = 2, 33%), or combination surgery and sclerotherapy (n = 2, 33%). Intubation duration, intensive care and initial hospital length of stay were not different between cohorts. Four non-pTMT patients (67%) required tracheostomy, and two (33%) died prior to discharge. All pTMT patients survived and none required tracheostomy. Non-pTMT patients required a median of two invasive therapies prior to discharge (IQR 1-4) and a mean total of 13 over the course of their lifetime (IQR 1-16), compared to the pTMT group who did not require any lifetime invasive therapy, even after initial pTMT and discharge home. CONCLUSION: This study compares patients with BHNLMs (Grade 2) treated with pTMT versus those treated with observation or invasive therapy. Patients treated with pTMT required no surgical or invasive procedural treatment of their malformations, no tracheostomy placement, no unplanned readmissions after discharge, and had no mortalities. Needle aspiration was useful as a therapeutic adjunct for cell-free DNA diagnosis of PIK3CA variants, which guided TMT.
Assuntos
Cabeça , Anormalidades Linfáticas , Criança , Lactente , Humanos , Estudos Retrospectivos , Resultado do Tratamento , Pescoço , Anormalidades Linfáticas/cirurgia , EscleroterapiaRESUMO
Blue rubber bleb nevus syndrome (BRBNS) commonly presents with anemia from bleeding gastrointestinal (GI) vascular malformations. Management is highly variable, as no consensus guidelines for medical treatment currently exist. Sirolimus has been used in BRBNS to decrease GI bleeding and seems well tolerated, though questions remain regarding dosing, duration of therapy, and adverse effects. Here, we report our single-center experience of four pediatric patients with BRBNS who were successfully treated with sirolimus and review the existing literature regarding sirolimus for treatment of GI bleeding in BRBNS. Further prospective studies are needed to establish optimal dosage, drug monitoring, and duration.
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Neoplasias Gastrointestinais , Nevo Azul , Neoplasias Cutâneas , Criança , Neoplasias Gastrointestinais/complicações , Neoplasias Gastrointestinais/tratamento farmacológico , Humanos , Nevo Azul/complicações , Nevo Azul/tratamento farmacológico , Sirolimo/efeitos adversos , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/complicações , Neoplasias Cutâneas/tratamento farmacológico , SíndromeRESUMO
Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure syndrome with leukemia predisposition. An understanding of the hematologic complications of SDS with age could guide clinical management, but data are limited for this rare disease. We conducted a cohort study of 153 subjects from 143 families with confirmed biallelic SBDS mutations enrolled on the North American Shwachman Diamond Registry or Bone Marrow Failure Registry. The SBDS c.258 + 2T>C variant was present in all but 1 patient. To evaluate the association between blood counts and age, 2146 blood counts were analyzed for 119 subjects. Absolute neutrophil counts were positively associated with age (P < .0001). Hemoglobin was also positively associated with age up to 18 years (P < .0001), but the association was negative thereafter (P = .0079). Platelet counts and marrow cellularity were negatively associated with age (P < .0001). Marrow cellularity did not correlate with blood counts. Severe marrow failure necessitating transplant developed in 8 subjects at a median age of 1.7 years (range, 0.4-39.5), with 7 of 8 requiring transplant prior to age 8 years. Twenty-six subjects (17%) developed a myeloid malignancy (16 myelodysplasia and 10 acute myeloid leukemia) at a median age of 12.3 years (range, 0.5-45.0) and 28.4 years (range, 14.4-47.3), respectively. A lymphoid malignancy developed in 1 patient at the age of 16.9 years. Hematologic complications were the major cause of mortality (17/20 deaths; 85%). These data inform surveillance of hematologic complications in SDS.
Assuntos
Doenças da Medula Óssea , Insuficiência Pancreática Exócrina , Doenças Hematológicas , Adolescente , Adulto , Doenças da Medula Óssea/complicações , Doenças da Medula Óssea/genética , Doenças da Medula Óssea/patologia , Criança , Pré-Escolar , Estudos de Coortes , Insuficiência Pancreática Exócrina/complicações , Insuficiência Pancreática Exócrina/genética , Doenças Hematológicas/complicações , Humanos , Lactente , Pessoa de Meia-Idade , Síndrome de Shwachman-Diamond , Adulto JovemRESUMO
The overlap in clinical presentation and bone marrow features of acquired and inherited causes of hypocellular marrow failure poses a significant diagnostic challenge in real case scenarios, particularly in nonsevere disease. The distinction between acquired aplastic anemia (aAA), hypocellular myelodysplastic syndrome (MDS), and inherited bone marrow failure syndromes presenting with marrow hypocellularity is critical to inform appropriate care. Here, we review the workup of hypocellular marrow failure in adolescents through adults. Given the limitations of relying on clinical stigmata or family history to identify patients with inherited etiologies, we outline a diagnostic approach incorporating comprehensive genetic testing in patients with hypocellular marrow failure that does not require immediate therapy and thus allows time to complete the evaluation. We also review the clinical utility of marrow array to detect acquired 6p copy number-neutral loss of heterozygosity to support a diagnosis of aAA, the complexities of telomere length testing in patients with aAA, short telomere syndromes, and other inherited bone marrow failure syndromes, as well as the limitations of somatic mutation testing for mutations in myeloid malignancy genes for discriminating between the various diagnostic possibilities.
Assuntos
Transtornos da Insuficiência da Medula Óssea/diagnóstico , Adolescente , Adulto , Anemia Aplástica/diagnóstico , Anemia Aplástica/genética , Medula Óssea/patologia , Transtornos da Insuficiência da Medula Óssea/genética , Aberrações Cromossômicas , Diagnóstico Diferencial , Feminino , Testes Genéticos , Mutação em Linhagem Germinativa , Humanos , Masculino , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Adulto JovemRESUMO
The North American Pediatric Aplastic Anemia Consortium (NAPAAC) is a group of pediatric hematologist-oncologists, hematopathologists, and bone marrow transplant physicians from 46 institutions in North America with interest and expertise in aplastic anemia, inherited bone marrow failure syndromes, and myelodysplastic syndromes. The NAPAAC Bone Marrow Failure Diagnosis and Care Guidelines Working Group was established with the charge of harmonizing the approach to the diagnostic workup of aplastic anemia in an effort to standardize best practices in the field. This document outlines the rationale for initial evaluations in pediatric patients presenting with signs and symptoms concerning for severe aplastic anemia.
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Anemia Aplástica/diagnóstico , Anemia Aplástica/patologia , Medula Óssea/patologia , Criança , Diagnóstico Diferencial , Hemoglobina Fetal/análise , Antígenos HLA/análise , Humanos , América do Norte , Índice de Gravidade de DoençaRESUMO
Studies of genetic blood disorders have advanced our understanding of the intrinsic regulation of hematopoiesis. However, such genetic studies have only yielded limited insights into how interactions between hematopoietic cells and their microenvironment are regulated. Here, we describe two affected siblings with infantile myelofibrosis and myeloproliferation that share a common de novo mutation in the Rho GTPase CDC42 (Chr1:22417990:C>T, p.R186C) due to paternal germline mosaicism. Functional studies using human cells and flies demonstrate that this CDC42 mutant has altered activity and thereby disrupts interactions between hematopoietic progenitors and key tissue microenvironmental factors. These findings suggest that further investigation of this and other related disorders may provide insights into how hematopoietic cell-microenvironment interactions play a role in human health and can be disrupted in disease. In addition, we suggest that deregulation of CDC42 may underlie more common blood disorders, such as primary myelofibrosis.
Assuntos
Mutação/genética , Mielofibrose Primária/diagnóstico , Proteína cdc42 de Ligação ao GTP/genética , Ciclo Celular , Microambiente Celular , Células HEK293 , Hematopoese/genética , Humanos , Lactente , Recém-Nascido , Mielofibrose Primária/genética , Irmãos , Sequenciamento do ExomaRESUMO
Allogeneic hematopoietic cell transplant (HCT) is often the only curative therapy for patients with nonmalignant diseases; however, many patients do not have an HLA-matched donor. Historically, poor survival has been seen after HLA-haploidentical HCT because of poor immune reconstitution, increased infections, graft-versus-host disease (GVHD), and graft failure. Encouraging results have been reported using a nonmyeloablative T cell-replete HLA-haploidentical transplant approach in patients with hematologic malignancies. Here we report the outcomes of 23 patients with various nonmalignant diseases using a similar approach. Patients received HLA-haploidentical bone marrow (n = 17) or granulocyte colony-stimulating factor-mobilized peripheral blood stem cell (n = 6) grafts after conditioning with cyclophosphamide 50 mg/kg, fludarabine 150 mg/m2, and 2 or 4 Gy total body irradiation. Postgrafting immunosuppression consisted of cyclophosphamide, mycophenolate mofetil, tacrolimus, ± sirolimus. Median patient age at HCT was 10.8 years. Day 100 transplant-related mortality (TRM) was 0%. Two patients died at later time points, 1 from intracranial hemorrhage/disseminated fungal infection in the setting of graft failure and 1 from infection/GVHD. The estimated probabilities of grades II to IV and III to IV acute GVHD at day 100 and 2-year National Institutes of Health consensus chronic GVHD were 78%, 26%, and 42%, respectively. With a median follow-up of 2.5 years, the 2-year overall and event-free rates of survival were 91% and 78%, respectively. These results are encouraging and demonstrate favorable disease-specific lineage engraftment with low TRM in patients with nonmalignant diseases using nonmyeloablative conditioning followed by T cell-replete HLA-haploidentical grafts. However, additional strategies are needed for GVHD prevention to make this a viable treatment approach for patients with nonmalignant diseases.
Assuntos
Doença Enxerto-Hospedeiro , Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Ciclofosfamida/uso terapêutico , Doença Enxerto-Hospedeiro/terapia , Antígenos HLA , Haplótipos , Neoplasias Hematológicas/terapia , Humanos , Condicionamento Pré-Transplante , Transplante HomólogoRESUMO
Shwachman-Diamond syndrome (SDS) is an autosomal recessive multisystem disorder characterized by exocrine pancreatic dysfunction, bone marrow failure, and leukemia predisposition. Approximately 90% of cases are due to biallelic mutations in the Shwachman-Bodian-Diamond (SBDS) gene. Additional phenotypic features variably associated with SDS include skeletal, neurologic, hepatic, cardiac, endocrine, and dental abnormalities. We report five subjects with SDS who developed a range of inflammatory manifestations. Three patients developed inflammatory eye conditions. Single cases of juvenile idiopathic arthritis, chronic recurrent multifocal osteomyelitis, and scleroderma were also noted. Clinical presentation and treatment responses are described. Proteomic analysis revealed increased inflammatory signatures in SDS subjects as compared to controls. Treatment of inflammatory manifestations in patients with SDS may be complicated by potential myelosuppressive toxicities of anti-rheumatic medications. Further research is needed to better understand the potential link between inflammatory disorders and SDS to inform effective treatment strategies.
Assuntos
Doenças Autoimunes/genética , Inflamação/genética , Proteínas/genética , Síndrome de Shwachman-Diamond/genética , Adolescente , Adulto , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/patologia , Doenças da Medula Óssea/diagnóstico , Doenças da Medula Óssea/genética , Criança , Pré-Escolar , Sistema Endócrino/patologia , Feminino , Humanos , Inflamação/diagnóstico , Inflamação/patologia , Lipomatose/diagnóstico , Lipomatose/genética , Lipomatose/patologia , Masculino , Mutação/genética , Fenótipo , Proteômica , Síndrome de Shwachman-Diamond/diagnóstico , Síndrome de Shwachman-Diamond/patologia , Adulto JovemRESUMO
Quality of response to immunosuppressive therapy and long-term outcomes for pediatric severe aplastic anemia remain incompletely characterized. Contemporary evidence to inform treatment of relapsed or refractory severe aplastic anemia for pediatric patients is also limited. The clinical features and outcomes for 314 children treated from 2002 to 2014 with immunosuppressive therapy for acquired severe aplastic anemia were analyzed retrospectively from 25 institutions in the North American Pediatric Aplastic Anemia Consortium. The majority of subjects (n=264) received horse anti-thymocyte globulin (hATG) plus cyclosporine (CyA) with a median 61 months follow up. Following hATG/CyA, 71.2% (95%CI: 65.3,76.6) achieved an objective response. In contrast to adult studies, the quality of response achieved in pediatric patients was high, with 59.8% (95%CI: 53.7,65.8) complete response and 68.2% (95%CI: 62.2,73.8) achieving at least a very good partial response with a platelet count ≥50×109L. At five years post-hATG/CyA, overall survival was 93% (95%CI: 89,96), but event-free survival without subsequent treatment was only 64% (95%CI: 57,69) without a plateau. Twelve of 171 evaluable patients (7%) acquired clonal abnormalities after diagnosis after a median 25.2 months (range: 4.3-71 months) post treatment. Myelodysplastic syndrome or leukemia developed in 6 of 314 (1.9%). For relapsed/refractory disease, treatment with a hematopoietic stem cell transplant had a superior event-free survival compared to second immunosuppressive therapy treatment in a multivariate analysis (HR=0.19, 95%CI: 0.08,0.47; P=0.0003). This study highlights the need for improved therapies to achieve sustained high-quality remission for children with severe aplastic anemia.
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Anemia Aplástica/tratamento farmacológico , Soro Antilinfocitário/administração & dosagem , Ciclosporina/administração & dosagem , Terapia de Imunossupressão , Anemia Aplástica/epidemiologia , Anemia Aplástica/patologia , Soro Antilinfocitário/efeitos adversos , Pré-Escolar , Ciclosporina/efeitos adversos , Feminino , Seguimentos , Humanos , Lactente , Masculino , Estudos Retrospectivos , Estados Unidos/epidemiologiaRESUMO
Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder with isolated thrombocytopenia and hemorrhagic risk. While many children with ITP can be safely observed, treatments are often needed for various reasons, including to decrease bleeding, or to improve health related quality of life (HRQoL). There are a number of available second-line treatments, including rituximab, thrombopoietin-receptor agonists, oral immunosuppressive agents, and splenectomy, but data comparing treatment outcomes are lacking. ICON1 is a prospective, multi-center, observational study of 120 children starting second-line treatments for ITP designed to compare treatment outcomes including platelet count, bleeding, and HRQoL utilizing the Kids ITP Tool (KIT). While all treatments resulted in increased platelet counts, romiplostim had the most pronounced effect at 6 months (P = .04). Only patients on romiplostim and rituximab had a significant reduction in both skin-related (84% to 48%, P = .01 and 81% to 43%, P = .004) and non-skin-related bleeding symptoms (58% to 14%, P = .0001 and 54% to 17%, P = .0006) after 1 month of treatment. HRQoL significantly improved on all treatments. However, only patients treated with eltrombopag had a median improvement in KIT scores at 1 month that met the minimal important difference (MID). Bleeding, platelet count, and HRQoL improved in each treatment group, but the extent and timing of the effect varied among treatments. These results are hypothesis generating and help to improve our understanding of the effect of each treatment on specific patient outcomes. Combined with future randomized trials, these findings will help clinicians select the optimal second-line treatment for an individual child with ITP.
Assuntos
Púrpura Trombocitopênica Idiopática , Qualidade de Vida , Receptores Fc/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Rituximab/administração & dosagem , Trombopoetina/administração & dosagem , Adolescente , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Masculino , Contagem de Plaquetas , Estudos Prospectivos , Púrpura Trombocitopênica Idiopática/sangue , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Taxa de Sobrevida , Fatores de TempoRESUMO
Germline mutations in RUNX1 result in autosomal dominant familial platelet disorder with associated myeloid malignancy (FPDMM). To characterize the hematopathologic features associated with a germline RUNX1 mutation, we reviewed a total of 42 bone marrow aspirates from 14 FPDMM patients, including 24 cases with no cytogenetic clonal abnormalities, and 18 with clonal karyotypes or leukemia. We found that all aspirate smears had ≥10% atypical megakaryocytes, predominantly characterized by small forms with hypolobated and eccentric nuclei, and forms with high nuclear-to-cytoplasmic ratios. Core biopsies showed variable cellularity and variable numbers of megakaryocytes with similar features to those in the aspirates. Granulocytic and/or erythroid dysplasia (≥10% cells per lineage) were present infrequently. Megakaryocytes with separate nuclear lobes were increased in patients with myelodysplastic syndrome (MDS) and acute leukemia. Comparison to an immune thrombocytopenic purpura cohort confirms increased megakaryocytes with hypolobated eccentric nuclei in FPDMM patients. As such, patients with FPDMM often have atypical megakaryocytes with small hypolobated and eccentric nuclei even in the absence of clonal cytogenetic abnormalities; these findings are related to the underlying RUNX1 germline mutation and not diagnostic of MDS. Isolated megakaryocytic dysplasia in patients with unexplained thrombocytopenia should raise the possibility of an underlying germline RUNX1 mutation.
Assuntos
Transtornos Herdados da Coagulação Sanguínea/patologia , Transtornos Plaquetários/patologia , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Leucemia Mieloide Aguda/patologia , Adolescente , Adulto , Transtornos Herdados da Coagulação Sanguínea/genética , Transtornos Plaquetários/genética , Plaquetas/patologia , Medula Óssea/patologia , Criança , Pré-Escolar , Aberrações Cromossômicas , Estudos de Coortes , Progressão da Doença , Feminino , Mutação em Linhagem Germinativa , Humanos , Cariótipo , Leucemia Mieloide Aguda/genética , Masculino , Megacariócitos/patologia , Isoformas de Proteínas , Adulto JovemRESUMO
PURPOSE OF REVIEW: This chapter will summarize the most recent literature regarding the current state of medical treatment for vascular anomalies. RECENT FINDINGS: Research into the biology of these anomalies has strengthened our understanding of each anomaly and has helped to pave the way for more tailored treatment options involving molecular and/or genetic targets. SUMMARY: While there is still a role for surgical intervention, medical therapies that target the etiology of vascular anomalies may represent an alternative or adjunctive approach in the management of these lesions.
RESUMO
OBJECTIVES: To evaluate the utility of flow cytometry, karyotype, and a fluorescence in situ hybridization (FISH) panel in screening children for myelodysplastic syndrome (MDS). METHODS: Bone marrow morphology, flow cytometry, karyotype, and FISH reports from 595 bone marrow specimens (246 patients) were analyzed. RESULTS: By morphology, 8.7% of cases demonstrated at least unilineage dysplasia and/or increased blasts. Flow cytometry identified definitive abnormalities in 2.8% of cases, all of which had abnormal morphology. Of the 42 cases (7.2%) with acquired karyotypic abnormalities, 26 had no morphologic dysplasia. With a 98.2% concordance between karyotype and MDS FISH, FISH only identified two additional cases, both with low-level (<4%) abnormalities. Peripheral blood count evaluation only identified the absence of thrombocytopenia to correlate with an absence of abnormal ancillary tests. CONCLUSIONS: The combination of morphologic evaluation and karyotype with judicious use of flow cytometry and MDS FISH is sufficient to detect abnormalities for these indications.
Assuntos
Contagem de Células Sanguíneas/métodos , Aberrações Cromossômicas , Citometria de Fluxo/métodos , Hibridização in Situ Fluorescente/métodos , Cariotipagem/métodos , Síndromes Mielodisplásicas/diagnóstico , Serviços Técnicos Hospitalares , Medula Óssea/patologia , Criança , Feminino , Humanos , Masculino , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Estudos RetrospectivosRESUMO
Hematopoietic cell transplantation (HCT) is effective in the treatment of inherited marrow failure disorders and other nonmalignant diseases. Conventional myeloablative conditioning regimens have been associated with high transplant-related mortality, particularly in patients with comorbid conditions. Here we report on 14 patients with marrow failure disorders (Shwachman-Diamond syndrome, n = 3; Diamond Blackfan anemia, n = 4; GATA2 deficiency, n = 2; paroxysmal nocturnal hemoglobinuria, n = 4; and an undefined marrow failure disorder, n = 1) who underwent HCT on a prospective, phase II, multicenter clinical trial. Patients were given HLA-matched related (n = 2) or unrelated (n = 12) grafts after conditioning with treosulfan (42 g/m2), fludarabine (150 mg/m2), ± thymoglobulin (n = 11; 6 mg/kg). All patients engrafted. At a median follow-up of 3 years, 13 patients are alive with complete correction of their underlying disease. These results indicate that the combination of treosulfan, fludarabine, and thymoglobulin is effective at establishing donor engraftment with a low toxicity profile and excellent disease-free survival in patients with marrow failure disorders.
Assuntos
Doenças da Medula Óssea/terapia , Bussulfano/análogos & derivados , Transplante de Células-Tronco Hematopoéticas/métodos , Condicionamento Pré-Transplante/métodos , Adolescente , Soro Antilinfocitário/uso terapêutico , Bussulfano/uso terapêutico , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Sobrevivência de Enxerto , Humanos , Lactente , Masculino , Transplante Homólogo , Resultado do Tratamento , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico , Adulto JovemAssuntos
Deficiência de Proteína C/genética , Criança , Pré-Escolar , Hemorragia/genética , Heterozigoto , Humanos , Lactente , Masculino , Proteína C/genética , Proteína C/uso terapêutico , Deficiência de Proteína C/complicações , Deficiência de Proteína C/tratamento farmacológico , Púrpura FulminanteAssuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mieloide/genética , Síndromes Mielodisplásicas/genética , Proteínas Nucleares/genética , Trombocitopenia/genética , Regiões 5' não Traduzidas/genética , Doença Aguda , Saúde da Família , Predisposição Genética para Doença/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , MutaçãoRESUMO
Congenital amegakaryocytic thrombocytopenia (CAMT) is clinically characterized by thrombocytopenia presenting at birth in a child without congenital or skeletal malformations, reduced or absent bone marrow megakaryocytes, and eventual progression to bone marrow failure. Molecular studies in most cases confirm homozygous or compound heterozygous mutations in the thrombopoietin receptor c-Mpl. In addition to the clinical importance of recognizing this disorder, characterization of mutations identified in patients with CAMT has led to insights into thrombopoietin receptor structure and function. This review will summarize the diagnosis, pathophysiology, and management of CAMT.