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1.
J Clin Oncol ; 42(2): 218-227, 2024 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-37890117

RESUMO

PURPOSE: Patients with Down syndrome (DS) and B-ALL experience increased rates of relapse, toxicity, and death. We report results for patients with DS B-ALL enrolled on Children's Oncology Group trials between 2003 and 2019. METHODS: We analyzed data for DS (n = 743) and non-DS (n = 20,067) patients age 1-30 years on four B-ALL standard-risk (SR) and high-risk trials. RESULTS: Patients with DS exhibited more frequent minimal residual disease (MRD) ≥0.01% at end induction (30.8% v 21.5%; P < .001). This difference persisted at end consolidation only in National Cancer Institute (NCI) high-risk patients (34.0% v 11.7%; P < .0001). Five-year event-free survival (EFS) and overall survival (OS) were significantly poorer for DS versus non-DS patients overall (EFS, 79.2% ± 1.6% v 87.5% ± 0.3%; P < .0001; OS, 86.8% ± 1.4% v 93.6% ± 0.2%; P < .0001), and within NCI SR and high-risk subgroups. Multivariable Cox regression analysis of the DS cohort for risk factors associated with inferior EFS identified age >10 years, white blood count >50 × 103/µL, and end-induction MRD ≥0.01%, but not cytogenetics or CRLF2 overexpression. Patients with DS demonstrated higher 5-year cumulative incidence of relapse (11.5% ± 1.2% v 9.1% ± 0.2%; P = .0008), death in remission (4.9% ± 0.8% v 1.7% ± 0.1%; P < .0001), and induction death (3.4% v 0.8%; P < .0001). Mucositis, infections, and hyperglycemia were significantly more frequent in all patients with DS, while seizures were more frequent in patients with DS on high-risk trials (4.1% v 1.8%; P = .005). CONCLUSION: Patients with DS-ALL exhibit an increased rate of relapse and particularly of treatment-related mortality. Novel, less-toxic therapeutic strategies are needed to improve outcomes.


Assuntos
Síndrome de Down , Criança , Humanos , Adolescente , Adulto Jovem , Lactente , Pré-Escolar , Adulto , Síndrome de Down/complicações , Síndrome de Down/terapia , Resultado do Tratamento , Intervalo Livre de Doença , Recidiva Local de Neoplasia/complicações , Recidiva , Neoplasia Residual
2.
Cancer ; 128(6): 1294-1301, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-34847248

RESUMO

BACKGROUND: Children with leukemia and Down syndrome (DS) are at higher risk of acute treatment toxicities than those without DS. Whether late toxicity risks are also elevated is unknown. METHODS: The authors identified all patients diagnosed with leukemia before the age of 18 years in Ontario, Canada between 1987 and 2013 and who survived greater than 5 years since their last pediatric cancer event. Survivors were divided into those with and without DS, matched by birth year, sex, leukemia type, and receipt of radiation. DS survivors were matched to individuals with DS without childhood cancer (DS controls) in a 1:10 ratio. Outcomes were identified through linkage to population-based health services databases. RESULTS: DS survivors (n = 79) experienced inferior overall survival compared to non-DS survivors (n = 231) (20-year overall survival, 81.7% ± 6.8% vs 98.3% ± 1.2%; hazard ratio [HR], 12.8; P < .0001) and to DS controls (n = 790; 96.3% ± 1.2%; HR, 5.4 P < .0001). Pulmonary and infectious deaths were noted among DS survivors. There was no difference in the incidence of congestive heart failure between DS survivors and either control cohort, nor of hearing loss or dementia between DS survivors and DS controls. CONCLUSIONS: DS survivors were at substantially higher risk of late mortality than non-DS survivors or DS controls. This excess risk was not attributable to cardiac- or subsequent malignant neoplasm-related late effects, historically main causes of premature death among non-DS survivors. Chronic morbidities associated with DS were not increased compared to DS controls. DS-specific surveillance guidelines may be warranted.


Assuntos
Síndrome de Down , Leucemia Mieloide Aguda , Adolescente , Criança , Estudos de Coortes , Síndrome de Down/complicações , Humanos , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/epidemiologia , Morbidade , Ontário/epidemiologia , Sobreviventes
3.
Science ; 373(6551)2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34244384

RESUMO

Children with Down syndrome have a 150-fold increased risk of developing myeloid leukemia, but the mechanism of predisposition is unclear. Because Down syndrome leukemogenesis initiates during fetal development, we characterized the cellular and developmental context of preleukemic initiation and leukemic progression using gene editing in human disomic and trisomic fetal hematopoietic cells and xenotransplantation. GATA binding protein 1 (GATA1) mutations caused transient preleukemia when introduced into trisomy 21 long-term hematopoietic stem cells, where a subset of chromosome 21 microRNAs affected predisposition to preleukemia. By contrast, progression to leukemia was independent of trisomy 21 and originated in various stem and progenitor cells through additional mutations in cohesin genes. CD117+/KIT proto-oncogene (KIT) cells mediated the propagation of preleukemia and leukemia, and KIT inhibition targeted preleukemic stem cells.


Assuntos
Proteínas de Ciclo Celular/genética , Síndrome de Down/genética , Fator de Transcrição GATA1/genética , Células-Tronco Hematopoéticas/fisiologia , Leucemia Mieloide/genética , Pré-Leucemia/genética , Animais , Antígenos CD34/análise , Proteínas de Ciclo Celular/metabolismo , Linhagem da Célula , Proliferação de Células , Transformação Celular Neoplásica , Proteínas Cromossômicas não Histona/genética , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 21/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Síndrome de Down/complicações , Feminino , Fator de Transcrição GATA1/metabolismo , Hematopoese , Transplante de Células-Tronco Hematopoéticas , Xenoenxertos , Humanos , Leucemia Mieloide/metabolismo , Leucemia Mieloide/patologia , Fígado/embriologia , Masculino , Megacariócitos/fisiologia , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Mutação , Pré-Leucemia/metabolismo , Pré-Leucemia/patologia , Inibidores de Proteínas Quinases/farmacologia , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-kit/análise , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , Coesinas
4.
Cell Rep Med ; 2(12): 100470, 2021 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-35028611

RESUMO

Acute lymphoblastic leukemia (ALL) dissemination to the central nervous system (CNS) is a challenging clinical problem whose underlying mechanisms are poorly understood. Here, we show that primary human ALL samples injected into the femora of immunodeficient mice migrate to the skull and vertebral bone marrow and provoke bone lesions that enable passage into the subarachnoid space. Treatment of leukemia xenografted mice with a biologic antagonist of receptor activator of nuclear factor κB ligand (RANKL) blocks this entry route. In addition to erosion of cranial and vertebral bone, samples from individuals with B-ALL also penetrate the blood-cerebrospinal fluid barrier of recipient mice. Co-administration of C-X-C chemokine receptor 4 (CXCR4) and RANKL antagonists attenuate both identified routes of entry. Our findings suggest that targeted RANKL and CXCR4 pathway inhibitors could attenuate routes of leukemia blast CNS invasion and provide benefit for B-ALL-affected individuals.


Assuntos
Sistema Nervoso Central/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Animais , Crise Blástica/patologia , Linhagem Celular Tumoral , Proteínas de Fusão bcr-abl/metabolismo , Rearranjo Gênico , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Camundongos Endogâmicos NOD , Modelos Biológicos , Proteína de Leucina Linfoide-Mieloide/metabolismo , Invasividade Neoplásica , Osteoprotegerina/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras B/líquido cefalorraquidiano , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Ligante RANK/antagonistas & inibidores , Ligante RANK/metabolismo , Receptores CXCR4/metabolismo , Coluna Vertebral/patologia , Espaço Subaracnóideo/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Sci Transl Med ; 12(561)2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938796

RESUMO

Although most children survive B cell acute lymphoblastic leukemia (B-ALL), they frequently experience long-term, treatment-related health problems, including osteopenia and osteonecrosis. Because some children present with fractures at ALL diagnosis, we considered the possibility that leukemic B cells contribute directly to bone pathology. To identify potential mechanisms of B-ALL-driven bone destruction, we examined the p53 -/-; Rag2 -/-; Prkdcscid/scid triple mutant (TM) mice and p53 -/-; Prkdcscid/scid double mutant (DM) mouse models of spontaneous B-ALL. In contrast to DM animals, leukemic TM mice displayed brittle bones, and the TM leukemic cells overexpressed Rankl, encoding receptor activator of nuclear factor κB ligand. RANKL is a key regulator of osteoclast differentiation and bone loss. Transfer of TM leukemic cells into immunodeficient recipient mice caused trabecular bone loss. To determine whether human B-ALL can exert similar effects, we evaluated primary human B-ALL blasts isolated at diagnosis for RANKL expression and their impact on bone pathology after their transplantation into NOD.Prkdcscid/scidIl2rgtm1Wjl /SzJ (NSG) recipient mice. Primary B-ALL cells conferred bone destruction evident in increased multinucleated osteoclasts, trabecular bone loss, destruction of the metaphyseal growth plate, and reduction in adipocyte mass in these patient-derived xenografts (PDXs). Treating PDX mice with the RANKL antagonist recombinant osteoprotegerin-Fc (rOPG-Fc) protected the bone from B-ALL-induced destruction even under conditions of heavy tumor burden. Our data demonstrate a critical role of the RANK-RANKL axis in causing B-ALL-mediated bone pathology and provide preclinical support for RANKL-targeted therapy trials to reduce acute and long-term bone destruction in these patients.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Ligante RANK , Animais , Linfócitos B , Humanos , Camundongos , Camundongos Endogâmicos NOD , Osteoclastos
6.
Arch Pathol Lab Med ; 144(4): 466-472, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31429606

RESUMO

CONTEXT.­: Detailed diagnostic features of acute myeloid leukemia in Down syndrome are lacking, leading to potential misdiagnoses as standard acute myeloid leukemia occurring in patients with Down syndrome. OBJECTIVE.­: To evaluate diagnostic features of acute myeloid leukemia and myelodysplastic syndrome in patients with Down syndrome. DESIGN.­: Diagnostic bone marrow samples from 163 patients enrolled in the Children's Oncology Group study AAML0431 were evaluated by using central morphologic review and institutional immunophenotyping. Results were compared to overall survival, event-free survival, GATA1 mutation status, cytogenetics, and minimal residual disease results. RESULTS.­: Sixty myelodysplastic syndrome and 103 acute myeloid leukemia samples were reviewed. Both had distinctive features compared to those of patients without Down syndrome. They showed megakaryocytic and erythroid but little myeloid dysplasia, and marked megakaryocytic hyperplasia with unusual megakaryocyte morphology. In acute myeloid leukemia cases, megakaryoblastic differentiation of blasts was most common (54 of 103, 52%); other cases showed erythroblastic (11 of 103, 11%), mixed erythroid/megakaryoblastic (20 of 103, 19%), or no differentiation (10 of 103, 10%). Myelodysplastic syndrome and acute myeloid leukemia cases had similar event-free survival and overall survival. Leukemic subgroups showed interesting, but not statistically significant, trends for survival and minimal residual disease. Cases with institutional diagnoses of French American British M1-5 morphology showed typical features of Down syndrome disease, with survival approaching that of other cases. CONCLUSIONS.­: Myelodysplastic syndrome and acute myeloid leukemia in Down syndrome display features that allow discrimination from standard cases of disease. These distinctions are important for treatment decisions, and for understanding disease pathogenesis. We propose specific diagnostic criteria for Down syndrome-related subtypes of acute myeloid leukemia and myelodysplastic syndrome.


Assuntos
Síndrome de Down/complicações , Leucemia Mieloide Aguda/diagnóstico , Síndromes Mielodisplásicas/diagnóstico , Criança , Feminino , Humanos , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/patologia , Masculino , Síndromes Mielodisplásicas/etiologia , Síndromes Mielodisplásicas/patologia
7.
Blood ; 129(25): 3304-3313, 2017 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-28389462

RESUMO

Patients with myeloid leukemia of Down syndrome (ML-DS) have favorable event-free survival (EFS), but experience significant treatment-related morbidity and mortality. ML-DS blast cells ex vivo have increased sensitivity to cytarabine (araC) and daunorubicin, suggesting that optimizing drug dosing may improve outcomes while reducing toxicity. The Children's Oncology Group (COG) AAML0431 trial consisted of 4 cycles of induction and 2 cycles of intensification therapy based on the treatment schema of the previous COG A2971 trial with several modifications. High-dose araC (HD-araC) was used in the second induction cycle instead of the intensification cycle, and 1 of 4 daunorubicin-containing induction cycles was eliminated. For 204 eligible patients, 5-year EFS was 89.9% and overall survival (OS) was 93.0%. The 5-year OS for 17 patients with refractory/relapsed leukemia was 34.3%. We determined the clinical significance of minimal residual disease (MRD) levels as measured by flow cytometry on day 28 of induction I. MRD measurements, available for 146 of the 204 patients, were highly predictive of treatment outcome; 5-year disease-free survival for MRD-negative patients (n = 125) was 92.7% vs 76.2% for MRD-positive patients (n = 21) (log-rank P = .011). Our results indicated that earlier use of HD-araC led to better EFS and OS in AAML0431 than in past COG studies. A 25% reduction in the cumulative daunorubicin dose did not impact outcome. MRD, identified as a new prognostic factor for ML-DS patients, can be used for risk stratification in future clinical trials. This trial was registered at www.clinicaltrials.gov as #NCT00369317.


Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Antimetabólitos Antineoplásicos/uso terapêutico , Citarabina/uso terapêutico , Daunorrubicina/uso terapêutico , Síndrome de Down/complicações , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Pré-Escolar , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Análise Citogenética , Daunorrubicina/administração & dosagem , Daunorrubicina/efeitos adversos , Intervalo Livre de Doença , Síndrome de Down/genética , Feminino , Humanos , Lactente , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/genética , Masculino , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/genética , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Resultado do Tratamento
9.
Artigo em Inglês | MEDLINE | ID: mdl-26336377

RESUMO

Childhood cancer survivors frequently experience long-lasting consequences of chemotherapy on health outcomes. Neurocognitive late effects of chemotherapy occur in 40 - 60% of acute lymphoblastic leukemia (ALL) survivors. These deficits affect mental health, school performance, job success, and are associated with poor quality of life, therefore presenting a clinical challenge for psychiatrists. However, not all cancer survivors are impacted by treatment in the same manner and emerging evidence suggests that genetic variation may modulate neurocognitive outcomes. Much like other complex psychopathologies, neurocognitive deficits in cancer survivors are the result of complex interactions between genetic and environmental variables. This review describes adverse neurocognitive outcomes observed in survivors of acute lymphoblastic leukemia (ALL) and discusses genetic variability in biochemical pathways targeted by chemotherapeutic agents as a possible mechanism contributing to psychopathology in ALL survivors.


Les survivants d'un cancer pédiatrique éprouvent souvent des conséquences durables de la chimiothérapie sur leurs résultats de santé. Les effets tardifs neurocognitifs de la chimiothérapie surviennent chez 40% à 60% des survivants de la leucémie lymphoblastique aiguë (LLA). Ces déficits touchent la santé mentale, le rendement scolaire, la réussite professionnelle et sont associés à une piètre qualité de vie, et présentent donc un défi clinique pour les psychiatres. Cependant, les survivants du cancer ne sont pas tous affectés de la même manière par le traitement et de nouvelles données probantes suggèrent que la variation génétique puisse moduler les résultats neurocognitifs. À l'instar d'autres psychopathologies complexes, les déficits neurocognitifs chez les survivants du cancer sont le résultat d'interactions complexes entre les variables génétiques et environnementales. Cette revue décrit les résultats neurocognitifs indésirables observés chez les survivants de la leucémie lymphoblastique aiguë (LLA) et discute de la variabilité génétique des trajectoires biochimiques ciblées par les agents chimiothérapeutiques comme mécanisme possible contribuant à la psychopathologie chez les survivants de la LLA.

10.
Sci Transl Med ; 6(236): 236ra62, 2014 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-24828076

RESUMO

Intensified and central nervous system (CNS)-directed chemotherapy has improved outcomes for pediatric B cell acute lymphoblastic leukemia (B-ALL) but confers treatment-related morbidities. Moreover, many patients suffer relapses, underscoring the need to develop new molecular targeted B-ALL therapies. Using a mouse model, we show that leukemic B cells require pre-B cell receptor (pre-BCR)-independent spleen tyrosine kinase (SYK) signaling in vivo for survival and proliferation. In diagnostic samples from human pediatric and adult B-ALL patients, SYK and downstream targets were phosphorylated regardless of pre-BCR expression or genetic subtype. Two small-molecule SYK inhibitors, fostamatinib and BAY61-3606, attenuated the growth of 69 B-ALL samples in vitro, including high-risk (HR) subtypes. Orally administered fostamatinib reduced heavy disease burden after xenotransplantation of HR B-ALL samples into immunodeficient mice and decreased leukemia dissemination into spleen, liver, kidneys, and the CNS of recipient mice. Thus, SYK activation sustains the growth of multiple HR B-ALL subtypes, suggesting that SYK inhibitors may improve outcomes for HR and relapsed B-ALL.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Células Precursoras de Linfócitos B/citologia , Inibidores de Proteínas Quinases/química , Proteínas Tirosina Quinases/metabolismo , Baço/enzimologia , Administração Oral , Adulto , Aminopiridinas , Animais , Proliferação de Células , Sobrevivência Celular , Criança , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Leucemia/tratamento farmacológico , Masculino , Camundongos , Camundongos SCID , Morfolinas , Mutação , Transplante de Neoplasias , Niacinamida/análogos & derivados , Niacinamida/química , Análise de Sequência com Séries de Oligonucleotídeos , Oxazinas/química , Fosforilação , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/química , Piridinas/química , Pirimidinas/química , Recidiva , Transdução de Sinais , Quinase Syk , Resultado do Tratamento
11.
J Pediatr ; 164(5): 1201-7, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24582006

RESUMO

OBJECTIVE: To report the outcomes of an institutional protocol for periprocedural anticoagulant (AC) management in children with acute lymphoblastic leukemia (ALL). STUDY DESIGN: Children being treated for ALL who received full-dose (therapeutic) anticoagulation before undergoing at least 1 lumbar puncture (LP) were included in this retrospective cohort study. The main outcome was the risk of traumatic LP; exploratory analysis included the risks of symptomatic spinal hematoma and progression/recurrence of the thrombotic event. Analyses were conducted using logistic regression analysis with a generalized estimating equation approach. RESULTS: Twenty-two children with ALL receiving an AC underwent a total of 396 LPs. Although traumatic LP was associated with full-dose AC therapy in univariable analysis, a multiple logistic regression model controlling for other risk factors for traumatic LP showed that AC therapy was not significantly associated with the risk of traumatic LP when the ACs were held as per the institutional protocol. No patient developed symptomatic spinal hematoma. Exploratory analysis revealed that AC dose, a likely marker of thrombus burden, was significantly associated with progression/recurrence of the thrombotic event in univariable analysis. CONCLUSION: In our cohort, recent AC therapy was not statistically associated with an increased risk of bleeding after LP when following a specific protocol for periprocedural AC management. The risk associated with the progression/recurrence of thromboembolic events requires further evaluation.


Assuntos
Anticoagulantes/efeitos adversos , Hematoma/induzido quimicamente , Complicações Pós-Operatórias/induzido quimicamente , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Doenças da Coluna Vertebral/induzido quimicamente , Punção Espinal , Trombose/tratamento farmacológico , Adolescente , Anticoagulantes/uso terapêutico , Criança , Pré-Escolar , Protocolos Clínicos , Progressão da Doença , Esquema de Medicação , Feminino , Seguimentos , Hematoma/prevenção & controle , Heparina/efeitos adversos , Heparina/uso terapêutico , Heparina de Baixo Peso Molecular/efeitos adversos , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Lactente , Modelos Logísticos , Masculino , Análise Multivariada , Complicações Pós-Operatórias/prevenção & controle , Leucemia-Linfoma Linfoblástico de Células Precursoras/cirurgia , Cuidados Pré-Operatórios/métodos , Recidiva , Estudos Retrospectivos , Fatores de Risco , Doenças da Coluna Vertebral/prevenção & controle , Trombose/etiologia , Trombose/prevenção & controle , Resultado do Tratamento
12.
Pediatr Blood Cancer ; 61(6): 1126-8, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24391118

RESUMO

We report on 27 patients with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) who received allogeneic hematopoietic cell transplantation (HCT) between 2000 and 2009. Seventy-eight percent of patients received myeloablative conditioning and 52% underwent transplantation in second remission. Disease-free survival (DFS) was 24% at a median of 3 years. Post-transplant leukemic relapse was more frequent than expected for children with DS-ALL (54%) than for non-DS ALL. These data suggest leukemic relapse rather than transplant toxicity is the most important cause of treatment failure. Advancements in leukemia control are especially needed for improvement in HCT outcomes for DS-ALL.


Assuntos
Síndrome de Down/complicações , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras/cirurgia , Adolescente , Adulto , Aloenxertos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Medula Óssea , Criança , Pré-Escolar , Terapia Combinada , Ciclosporina/efeitos adversos , Ciclosporina/uso terapêutico , Intervalo Livre de Doença , Predisposição Genética para Doença , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Imunossupressores/uso terapêutico , Lactente , Estimativa de Kaplan-Meier , Doadores Vivos , Agonistas Mieloablativos/efeitos adversos , Agonistas Mieloablativos/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Recidiva , Sistema de Registros , Indução de Remissão , Estudos Retrospectivos , Terapia de Salvação , Tacrolimo/efeitos adversos , Tacrolimo/uso terapêutico , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Resultado do Tratamento , Irradiação Corporal Total/efeitos adversos
13.
Biol Blood Marrow Transplant ; 19(6): 893-7, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23467128

RESUMO

Data on outcomes of allogeneic transplantation in children with Down syndrome and acute myelogenous leukemia (DS-AML) are scarce and conflicting. Early reports stress treatment-related mortality as the main barrier; a recent case series points to posttransplantation relapse. We reviewed outcome data for 28 patients with DS-AML reported to the Center for International Blood and Marrow Transplant Research between 2000 and 2009 and performed a first matched-pair analysis of 21 patients with DS-AML and 80 non-DS AML controls. The median age at transplantation for DS-AML was 3 years, and almost half of the cohort was in second remission. The 3-year probability of overall survival was only 19%. In multivariate analysis, adjusting for interval from diagnosis to transplantation, risks of relapse (hazard ratio [HR], 2.84; P < .001; 62% versus 37%) and transplant-related mortality (HR, 2.52; P = .04; 24% versus 15%) were significantly higher for DS-AML compared to non-DS AML. Overall mortality risk (HR, 2.86; P < .001; 21% versus 52%) was significantly higher for DS-AML. Both transplant-related mortality and relapse contribute to higher mortality. Excess mortality in DS-AML patients can only effectively be addressed through an international multicenter effort to pilot strategies aimed at lowering both transplant-related mortality and relapse risks.


Assuntos
Antineoplásicos/uso terapêutico , Transplante de Medula Óssea , Síndrome de Down/terapia , Doença Enxerto-Hospedeiro/terapia , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/terapia , Adolescente , Criança , Pré-Escolar , Síndrome de Down/complicações , Síndrome de Down/imunologia , Síndrome de Down/mortalidade , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/mortalidade , Masculino , Recidiva , Indução de Remissão , Fatores de Risco , Análise de Sobrevida , Transplante Homólogo , Resultado do Tratamento , Adulto Jovem
14.
J Pediatr Hematol Oncol ; 33(6): e261-3, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21768885

RESUMO

Transient leukemia (TL), defined by circulating nonlymphoid blast in the peripheral blood, occurs in approximately 10% of infants with constitutional trisomy 21 (Down syndrome). The TL phenotype may also occur in newborns who do not have clinical signs of Down syndrome but nonconstitutional trisomy 21 due to mosaicism. We report the cases of 3 infants to highlight the specific parental concerns, diagnostic and counseling requirements for this group of infants and their families and suggest a practical approach to diagnosis, follow-up, anticipatory guidance, and discussion of prognosis for families with newborns diagnosed with TL and nonconstitutional trisomy 21.


Assuntos
Cromossomos Humanos Par 21/genética , Leucemia/diagnóstico , Leucemia/genética , Trissomia , Feminino , Humanos , Hibridização in Situ Fluorescente , Recém-Nascido , Leucemia/psicologia , Masculino , Mosaicismo , Prognóstico
15.
Pediatr Blood Cancer ; 49(7 Suppl): 1066-9, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17943965

RESUMO

Children with Down syndrome (DS) have a 10- to 20-fold increased risk of developing acute leukemia. An estimated 10% of newborns with DS develop Transient Myeloproliferative Disease (TMD) or Transient Leukemia (TL), a clonal accumulation of megakaryoblasts that resolves spontaneously within months. Acute megakaryoblastic leukemia (AMKL) develops in approximately 20% of cases of TMD/TL by 4 years of age. Both the blasts of AMKL and TMD/TL in DS harbor somatic mutations of GATA1, an essential transcriptional regulator of megakaryocytic differentiation. The distinct phenotypes of megakaryoblastic leukemia in DS are a unique biological model of the incremental process of leukemic transformation.


Assuntos
Síndrome de Down/complicações , Leucemia Megacarioblástica Aguda/etiologia , Síndrome de Down/terapia , Humanos , Lactente , Recém-Nascido , Leucemia Megacarioblástica Aguda/terapia
16.
J Clin Oncol ; 24(24): 3858-64, 2006 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-16921038

RESUMO

PURPOSE: Cranial radiation therapy (CRT) is associated with neurocognitive morbidity in survivors of childhood acute lymphoblastic leukemia (ALL). For most patients, CRT has been replaced with intensified systemic and intrathecal chemotherapy, often including methotrexate (MTX). The impact of chemotherapy-only protocols on neurocognitive outcomes is unclear, and the importance of systemic MTX dose has not been established. PATIENTS AND METHODS: Seventy nine of 120 eligible children diagnosed with high-risk ALL between the ages of 1.0 and 4.9 years participated in this retrospective cohort study. All patients were treated on a uniform chemotherapy protocol with one of three modalities of CNS prophylaxis, depending on their treatment era. In addition to intrathecal therapy, CNS-directed therapy consisted of CRT (18 Gy in 10 fractions) in 25 patients, high-dose intravenous (IV) MTX (8 g/m2 x 3 doses) in 32 patients and very high-dose IV MTX (33.6 g/m2 x 3 doses) in 22 patients. Participants completed tests of intelligence, academic achievement, attention, and memory. RESULTS: Neurocognitive assessment was conducted at least 5 years after diagnosis (mean, 10.5 years, standard deviation, 2.7 years). No difference was detected on any neurocognitive measure between children treated with high-dose or very high-dose IV MTX. The combined MTX groups scored near the population mean on 17/18 measures. Children treated with CRT performed more poorly than the MTX group on most measures. CONCLUSION: Treatment strategies for young children with ALL that avoid CRT are associated with good long-term neurocognitive outcomes. In this cohort, the dose of IV MTX did not influence these outcomes.


Assuntos
Cognição/efeitos dos fármacos , Cognição/efeitos da radiação , Irradiação Craniana/efeitos adversos , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/radioterapia , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Atenção/efeitos dos fármacos , Atenção/efeitos da radiação , Neoplasias Encefálicas/prevenção & controle , Neoplasias Encefálicas/secundário , Pré-Escolar , Estudos de Coortes , Fracionamento da Dose de Radiação , Escolaridade , Feminino , Humanos , Lactente , Infusões Intravenosas , Testes de Inteligência , Masculino , Memória/efeitos dos fármacos , Memória/efeitos da radiação , Estudos Retrospectivos
17.
Mol Cell Biol ; 26(15): 5809-26, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16847333

RESUMO

Transcription of immediate-early genes--as well as multiple genes affecting muscle function, cytoskeletal integrity, apoptosis control, and wound healing/angiogenesis--is regulated by serum response factor (Srf). Extracellular signals regulate Srf in part via a pathway involving megakaryoblastic leukemia 1 (Mkl1, also known as myocardin-related transcription factor A [Mrtf-a]), which coactivates Srf-responsive genes downstream of Rho GTPases. Here we investigate Mkl1 function using gene targeting and show the protein to be essential for the physiologic preparation of the mammary gland during pregnancy and the maintenance of lactation. Lack of Mkl1 causes premature involution and impairs expression of Srf-dependent genes in the mammary myoepithelial cells, which control milk ejection following oxytocin-induced contraction. Despite the importance of Srf in multiple transcriptional pathways and widespread Mkl1 expression, the spectrum of abnormalities associated with Mkl1 absence appears surprisingly restricted.


Assuntos
Lactação/fisiologia , Glândulas Mamárias Animais/anatomia & histologia , Glândulas Mamárias Animais/fisiologia , Transativadores/metabolismo , Animais , Animais Recém-Nascidos , Apoptose , Criança , Insuficiência de Crescimento , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Marcação de Genes , Coração/anatomia & histologia , Coração/embriologia , Humanos , Lactente , Leucemia Megacarioblástica Aguda , Masculino , Glândulas Mamárias Animais/anormalidades , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Leite , Miócitos Cardíacos/patologia , Miócitos Cardíacos/ultraestrutura , Análise de Sequência com Séries de Oligonucleotídeos , Ocitocina/metabolismo , Gravidez , Prolactina/metabolismo , Fator de Transcrição STAT3 , Fator de Resposta Sérica/genética , Fator de Resposta Sérica/metabolismo , Transativadores/genética
18.
J Pediatr Hematol Oncol ; 27(4): 192-6, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15838389

RESUMO

Myeloproliferative syndromes (MPSs) are clonal stem cell disorders resulting in excessive proliferation of one or more cell lineages. Since MPSs in children occur much less commonly than adults, one can argue that the biology and the categories of the various pediatric MPSs seem to be different from adults. Furthermore, confusion exists between pediatric MPS and other overlapping conditions, such as myelodysplastic syndrome. The authors' objectives were to develop a classification system with a list of disorders relevant to children and to characterize pediatric cases of MPS that were devised according to this classification. Based on the predominant proliferating cell lineage, the authors established a classification system for childhood MPS. Primary MPS was classified into granulocytic proliferation--chronic myelogenous leukemia (CML); monocytic--juvenile myelomonocytic leukemia (JMML); megakaryocytic--essential thrombocythemia (ET), familial thrombocytosis, transient myeloproliferative disorder of Down syndrome (TMD); erythrocytic--polycythemia vera, familial erythrocytosis; fibroblastic--idiopathic myelofibrosis (IMF); eosinophilic--idiopathic hypereosinophilic syndrome (IHES); and mast cells--mastocytosis. Secondary MPS was classified as non-clonal proliferation (eg, infections, drugs, toxins, autoimmune, non-hematologic neoplasm, and trauma), and these were excluded from the study. Next, the classification system was applied to the patient population at the authors' institution. One hundred two cases with primary MPS were identified between 1970 and 2001. Patients were evaluated for clinical manifestations, blood and bone marrow parameters, cytogenetics, and survival following different treatment modalities. Significant proportions of cases of childhood MPS (60%) were unique to the pediatric population and not seen in adults. The most common disorders were JMML (n = 31), TMD of Down syndrome (n = 30), and CML (n = 30); the other disorders were rare: four cases of ET, two of IMF, two of IHES, two of mastocytosis, and one primary erythrocytosis. In contrast to adults, MPS in children is more frequently treated with hematopoietic stem cell transplantation (HSCT), the only available curative option for most of these diseases. HSCT was particularly successful in the more recent cases due to more advanced techniques for HSCT. The authors found that all the cases could be easily classified. MPS in children is different from adult-type MPS in terms of biology, categories, classification, and prognosis.


Assuntos
Transtornos Mieloproliferativos/classificação , Adolescente , Medula Óssea/patologia , Linhagem da Célula , Proliferação de Células , Criança , Pré-Escolar , Análise Citogenética , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Masculino , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/terapia , Prognóstico , Taxa de Sobrevida
19.
Nat Rev Cancer ; 5(1): 11-20, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15630411

RESUMO

Transient megakaryoblastic leukaemia is found in 10% of newborns with Down syndrome, characterized by constitutional trisomy 21. Although in most cases the leukaemic cells disappear spontaneously after the first months of life, irreversible acute megakaryoblastic leukaemia develops in 20% of these individuals within 4 years. The leukaemic cells typically harbour somatic mutations of the gene encoding GATA1, an essential transcriptional regulator of normal megakaryocytic differentiation. Leukaemia that specifically arises in the context of constitutional trisomy 21 and somatic GATA1 mutations is a unique biological model of the incremental process of leukaemic transformation.


Assuntos
Síndrome de Down/complicações , Leucemia Megacarioblástica Aguda/etiologia , Transformação Celular Neoplásica , Criança , Pré-Escolar , Proteínas de Ligação a DNA/genética , Síndrome de Down/genética , Fatores de Ligação de DNA Eritroide Específicos , Fator de Transcrição GATA1 , Humanos , Lactente , Recém-Nascido , Leucemia Megacarioblástica Aguda/genética , Fatores de Transcrição/genética
20.
Oncogene ; 23(20): 3700-7, 2004 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-15116101

RESUMO

Myelodysplasia/acute myeloid leukemia (MDS/AML) is characterized by a t(3;5)(q25.1;q34) chromosomal translocation that forms a fusion gene between nucleophosmin (NPM) and MDS/myeloid leukemia factor 1 (MLF1). We identified a novel protein, MLF1-interacting protein (MLF1IP), that specifically associates with MLF1 by yeast two-hybrid analysis and in pulldown assays, and colocalizes with it in both the nuclei and cytoplasm of cells. The MLF1IP gene locus is at chromosome 4q35.1 and is composed of 14 exons spanning 75.8 kb of genomic DNA. The MLF1IP cDNA encodes a 46-kDa protein that contains two bipartite and two classical nuclear localization signals, two nuclear receptor-binding motifs (LXXLL), two leucine zippers, two PEST residues and several potential phosphorylation sites. MLF1IP transcripts are expressed in a variety of tissues (e.g. fetal liver, bone marrow, thymus and testis). MLF1IP appears to be a lineage-specific gene whose expression is confined exclusively to the CFU-E erythroid precursor cells, but not in mature erythrocytes. These observations, together with previous data demonstrating a role for MLF1 in suppressing red cell maturation, suggest a possible role for MLF1IP and MLF1 deregulation in the genesis of erythroleukemias.


Assuntos
Proteínas Nucleares/genética , Proteínas/metabolismo , Sequência de Aminoácidos , Sequência de Bases , Northern Blotting , Proteínas de Ciclo Celular , DNA Complementar , Proteínas de Ligação a DNA , Imunofluorescência , Células-Tronco Hematopoéticas/metabolismo , Histonas , Humanos , Dados de Sequência Molecular , Proteínas Nucleares/metabolismo , Especificidade de Órgãos , Reação em Cadeia da Polimerase , Técnicas do Sistema de Duplo-Híbrido
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