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4.
Leukemia ; 35(5): 1279-1290, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33623141

RESUMO

Infants with KMT2A-rearranged acute lymphoblastic leukemia (KMT2A-r ALL) have a poor prognosis. KMT2A-r ALL overexpresses FLT3, and the FLT3 inhibitor (FLT3i) lestaurtinib potentiates chemotherapy-induced cytotoxicity in preclinical models. Children's Oncology Group (COG) AALL0631 tested whether adding lestaurtinib to post-induction chemotherapy improved event-free survival (EFS). After chemotherapy induction, KMT2A-r infants received either chemotherapy only or chemotherapy plus lestaurtinib. Correlative assays included FLT3i plasma pharmacodynamics (PD), which categorized patients as inhibited or uninhibited, and FLT3i ex vivo sensitivity (EVS), which categorized leukemic blasts as sensitive or resistant. There was no difference in 3-year EFS between patients treated with chemotherapy plus lestaurtinib (n = 67, 36 ± 6%) vs. chemotherapy only (n = 54, 39 ± 7%, p = 0.67). However, for the lestaurtinib-treated patients, FLT3i PD and FLT3i EVS significantly correlated with EFS. For FLT3i PD, EFS for inhibited/uninhibited was 59 ± 10%/28 ± 7% (p = 0.009) and for FLTi EVS, EFS for sensitive/resistant was 52 ± 8%/5 ± 5% (p < 0.001). Seventeen patients were both inhibited and sensitive, with an EFS of 88 ± 8%. Adding lestaurtinib did not improve EFS overall, but patients achieving potent FLT3 inhibition and those whose leukemia blasts were sensitive FLT3-inhibition ex vivo did benefit from the addition of lestaurtinib. Patient selection and PD-guided dose escalation may enhance the efficacy of FLT3 inhibition for KMT2A-r infant ALL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carbazóis/uso terapêutico , Histona-Lisina N-Metiltransferase/metabolismo , Proteína de Leucina Linfoide-Mieloide/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Feminino , Furanos , Humanos , Lactente , Masculino
5.
J Clin Oncol ; 38(23): 2628-2638, 2020 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-32496902

RESUMO

PURPOSE: The high-risk stratum of Children's Oncology Group Study AALL1131 was designed to test the hypothesis that postinduction CNS prophylaxis with intrathecal triple therapy (ITT) including methotrexate, hydrocortisone, and cytarabine would improve the postinduction 5-year disease-free survival (DFS) compared with intrathecal methotrexate (IT MTX), when given on a modified augmented Berlin-Frankfurt-Münster backbone. PATIENTS AND METHODS: Children with newly diagnosed National Cancer Institute (NCI) high-risk B-cell acute lymphoblastic leukemia (HR B-ALL) or NCI standard-risk B-ALL with defined minimal residual disease thresholds during induction were randomly assigned to receive postinduction IT MTX or ITT. Patients with CNS3-status disease were not eligible. Postinduction IT therapy was given for a total of 21 to 26 doses. Neurocognitive assessments were performed during therapy and during 1 year off therapy. RESULTS: Random assignment was closed to accrual in March 2018 after a futility boundary had been crossed, concluding that ITT could not be shown to be superior to IT MTX. The 5-year postinduction DFS and overall survival rates (± SE) of children randomly assigned to IT MTX versus ITT were 93.2% ± 2.1% v 90.6% ± 2.3% (P = .85), and 96.3% ± 1.5% v 96.7% ± 1.4% (P = .77), respectively. There were no differences in the cumulative incidence of isolated bone marrow relapse, isolated CNS relapse, or combined bone marrow and CNS relapse rates, or in toxicities observed for patients receiving IT MTX compared with ITT. There were no significant differences in neurocognitive outcomes for patients receiving IT MTX compared with ITT. CONCLUSION: Postinduction CNS prophylaxis with ITT did not improve 5-year DFS for children with HR B-ALL. The standard of care for CNS prophylaxis for children with B-ALL and no overt CNS involvement remains IT MTX.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Metotrexato/administração & dosagem , Neoplasias do Sistema Nervoso/prevenção & controle , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Criança , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Feminino , Humanos , Hidrocortisona/administração & dosagem , Hidrocortisona/efeitos adversos , Injeções Espinhais , Masculino , Metotrexato/efeitos adversos , Prednisona/administração & dosagem , Prednisona/efeitos adversos
6.
Oncogene ; 38(13): 2241-2262, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30478448

RESUMO

The poor outcomes in infant acute lymphoblastic leukemia (ALL) necessitate new treatments. Here we discover that EIF4E protein is elevated in most cases of infant ALL and test EIF4E targeting by the repurposed antiviral agent ribavirin, which has anticancer properties through EIF4E inhibition, as a potential treatment. We find that ribavirin treatment of actively dividing infant ALL cells on bone marrow stromal cells (BMSCs) at clinically achievable concentrations causes robust proliferation inhibition in proportion with EIF4E expression. Further, we find that ribavirin treatment of KMT2A-rearranged (KMT2A-R) infant ALL cells and the KMT2A-AFF1 cell line RS4:11 inhibits EIF4E, leading to decreases in oncogenic EIF4E-regulated cell growth and survival proteins. In ribavirin-sensitive KMT2A-R infant ALL cells and RS4:11 cells, EIF4E-regulated proteins with reduced levels of expression following ribavirin treatment include MYC, MCL1, NBN, BCL2 and BIRC5. Ribavirin-treated RS4:11 cells exhibit impaired EIF4E-dependent nuclear to cytoplasmic export and/or translation of the corresponding mRNAs, as well as reduced phosphorylation of the p-AKT1, p-EIF4EBP1, p-RPS6 and p-EIF4E signaling proteins. This leads to an S-phase cell cycle arrest in RS4:11 cells corresponding to the decreased proliferation. Ribavirin causes nuclear EIF4E to re-localize to the cytoplasm in KMT2A-AFF1 infant ALL and RS4:11 cells, providing further evidence for EIF4E inhibition. Ribavirin slows increases in peripheral blasts in KMT2A-R infant ALL xenograft-bearing mice. Ribavirin cooperates with chemotherapy, particularly L-asparaginase, in reducing live KMT2A-AFF1 infant ALL cells in BMSC co-cultures. This work establishes that EIF4E is broadly elevated across infant ALL and that clinically relevant ribavirin exposures have preclinical activity and effectively inhibit EIF4E in KMT2A-R cases, suggesting promise in EIF4E targeting using ribavirin as a means of treatment.


Assuntos
Fator de Iniciação 4E em Eucariotos/genética , Terapia de Alvo Molecular/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Ribavirina/uso terapêutico , Linhagem Celular Tumoral , Pré-Escolar , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Fator de Iniciação 4E em Eucariotos/fisiologia , Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Indóis , Lactente , Análise em Microsséries , Família Multigênica/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Biossíntese de Proteínas/efeitos dos fármacos , Pirróis/uso terapêutico , Transdução de Sinais/efeitos dos fármacos
7.
Haematologica ; 104(5): 986-992, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30545921

RESUMO

With modern chemotherapy, approximately 90% of patients with pediatric acute lymphoblastic leukemia are now cured. However, subsets of patients can be identified who remain at very high risk of relapse with expected 4-year disease-free survival rates <80%; such patients are appropriate candidates for intensive therapeutic strategies designed to improve survival. The AALL1131 trial was designed to determine, in a randomized fashion, whether substitution with cyclophosphamide/etoposide (experimental arm 1) would improve the 4-year disease-free survival of children, adolescents, and young adults with very high-risk B-cell acute lymphoblastic leukemia compared to a modified Berlin-Frankfurt-Münster regimen (control arm). Patients 1-30 years of age with newly diagnosed very high-risk B-cell acute lymphoblastic leukemia were randomized after induction in a 1:2 fashion to the control arm or experimental arm 1 in which they were given cyclophosphamide (440 mg/m2 days 1-5)/etoposide (100 mg/m2 days 1-5) during part 2 of consolidation and delayed intensification. Prospective interim monitoring rules for efficacy and futility were included where futility would be determined for a one-sided P-value ≥0.7664. The study was stopped for futility as the interim monitoring boundary was crossed [hazard ratio 0.606 (95% confidence interval: 0.297 - 1.237)] and the very high-risk arm of AALL1131 was closed in February 2017. Using data current as of December 31, 2017, 4-year disease-free survival rates were 85.5±6.8% (control arm) versus 72.3±6.3% (experimental arm 1) (P-value = 0.76). There were no significant differences in grade 3/4 adverse events between the two arms. Substitution of this therapy for very high-risk B-cell acute lymphoblastic leukemia patients on the Children's Oncology Group AALL1131 trial (NCT02883049) randomized to cyclophosphamide/etoposide during part 2 of consolidation and delayed intensification did not improve disease-free survival.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Ciclofosfamida/administração & dosagem , Citarabina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Seguimentos , Humanos , Lactente , Masculino , Mercaptopurina/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , Adulto Jovem
9.
PLoS One ; 13(1): e0191232, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29329346

RESUMO

Bloodstream infections (BSI) and Clostridium difficile infections (CDI) in pediatric oncology/hematology/bone marrow transplant (BMT) populations are associated with significant morbidity and mortality. The objective of this study was to explore possible associations between altered microbiome composition and the occurrence of BSI and CDI in a cohort of pediatric oncology patients. Stool samples were collected from all patients admitted to the pediatric oncology floor from Oct.-Dec. 2012. Bacterial profiles from patient stools were determined by bacterial 16S rRNA gene profiling. Differences in overall microbiome composition were assessed by a permutation-based multivariate analysis of variance test, while differences in the relative abundances of specific taxa were assessed by Kruskal-Wallis tests. At admission, 9 of 42 patients (21%) were colonized with C. difficile, while 6 of 42 (14%) subsequently developed a CDI. Furthermore, 3 patients (7%) previously had a BSI and 6 patients (14%) subsequently developed a BSI. Differences in overall microbiome composition were significantly associated with disease type (p = 0.0086), chemotherapy treatment (p = 0.018), BSI following admission from any cause (p < 0.0001) or suspected gastrointestinal organisms (p = 0.00043). No differences in baseline microbiota were observed between individuals who did or did not subsequently develop C. difficile infection. Additionally, multiple bacterial groups varied significantly between subjects with post-admission BSI compared with no BSI. Our results suggest that differences in gut microbiota not only are associated with type of cancer and chemotherapy, but may also be predictive of subsequent bloodstream infection.


Assuntos
Bacteriemia/complicações , Infecções por Clostridium/complicações , Microbioma Gastrointestinal , Neoplasias/complicações , Neoplasias/microbiologia , Adolescente , Bacteriemia/microbiologia , Proteínas de Bactérias/genética , Toxinas Bacterianas/genética , Biodiversidade , Criança , Pré-Escolar , Clostridioides difficile/genética , Infecções por Clostridium/microbiologia , Estudos de Coortes , Estudos Transversais , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal/genética , Genes Bacterianos , Humanos , Masculino , Valor Preditivo dos Testes , RNA Bacteriano/genética , RNA Ribossômico 16S/genética , Adulto Jovem
10.
Cancer ; 124(6): 1150-1159, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29266189

RESUMO

BACKGROUND: Children, adolescents, and young adults with very high-risk (VHR) B acute lymphoblastic leukemia (B-ALL) have poor outcomes, and novel therapies are needed for this subgroup. The AALL1131 study evaluated postinduction therapy using cyclophosphamide (CPM), etoposide (ETOP), and clofarabine (CLOF) for patients with VHR B-ALL. METHODS: Patients who were 1 to 30 years old and had VHR B-ALL received modified Berlin-Frankfurt-Münster therapy after induction and were randomized to 1) CPM, cytarabine, mercaptopurine, vincristine (VCR), and pegaspargase (control arm), 2) CPM, ETOP, VCR, and pegaspargase (experimental arm 1), or 3) CPM, ETOP, CLOF (30 mg/m2 /d × 5), VCR, and pegaspargase (experimental arm 2) during the second half of consolidation and delayed intensification. RESULTS: The rates of grade 4/5 infections and grade 3/4 pancreatitis were significantly increased in experimental arm 2. The dose of CLOF was, therefore, reduced to 20 mg/m2 /d × 5, and myeloid growth factor was required after CLOF administration. Despite these changes, 4 of 39 patients (10.3%) developed grade 4 infections, with 1 of these patients developing a grade 5 acute kidney injury attributed to CLOF, whereas only 1 of 46 patients (2.2%) in experimental arm 1 developed grade 4 infections, and there were no grade 4/5 infections in the control arm (n = 20). Four patients in experimental arm 2 had prolonged cytopenias for >60 days, whereas none did in the control arm or experimental arm 1. Counts failed to recover for 2 of these patients, one having a grade 5 acute kidney injury and the other removed from protocol therapy; both events occurred 92 days after the start of consolidation part 2. CONCLUSIONS: In AALL1131, CLOF, administered with CPM and ETOP, was associated with unacceptable toxicity. Cancer 2018;124:1150-9. © 2017 American Cancer Society.


Assuntos
Injúria Renal Aguda/epidemiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Infecções Bacterianas/epidemiologia , Clofarabina/efeitos adversos , Pancreatite/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/diagnóstico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Infecções Bacterianas/induzido quimicamente , Criança , Pré-Escolar , Clofarabina/administração & dosagem , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Feminino , Humanos , Lactente , Masculino , Pancreatite/induzido quimicamente , Pancreatite/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Indução de Remissão/métodos , Índice de Gravidade de Doença , Adulto Jovem
11.
Pediatr Blood Cancer ; 64(3)2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27616578

RESUMO

BACKGROUND: Effective networking and mentorship are critical determinants of career satisfaction and success in academic medicine. The American Society of Pediatric Hematology/Oncology (ASPHO) mentoring program was developed to support Early Career (EC) members. Herein, the authors report on the initial 2-year outcomes of this novel program. PROCEDURE: Mentees selected mentors with expertise in different subspecialties within the field from mentor profiles at the ASPHO Web site. Of 23 enrolled pairs, 19 mentors and 16 mentees completed electronic program feedback evaluations. The authors analyzed data collected between February 2013 and December 2014. The authors used descriptive statistics for categorical data and thematic analysis for qualitative data. RESULTS: The overall response rate was 76% (35/46). At the initiation of the relationship, career development and research planning were the most commonly identified goals for both mentors and mentees. Participants communicated by phone, e-mail, or met in-person at ASPHO annual meetings. Most mentor-mentee pairs were satisfied with the mentoring relationship, considered it a rewarding experience that justified their time and effort, achieved their goals in a timely manner with objective work products, and planned to continue the relationship. However, time constraints and infrequent communications remained a challenge. CONCLUSIONS: Participation in the ASPHO mentoring program suggests a clear benefit to a broad spectrum of ASPHO EC members with diverse personal and professional development needs. Efforts to expand the mentoring program are ongoing and focused on increasing enrollment of mentors to cover a wider diversity of career tracks/subspecialties and evaluating career and academic outcomes more objectively.


Assuntos
Escolha da Profissão , Oncologia/educação , Tutoria , Pediatria/educação , Feminino , Humanos , Masculino , Mentores , Satisfação Pessoal , Projetos Piloto , Avaliação de Programas e Projetos de Saúde
12.
Pediatr Blood Cancer ; 64(3)2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27616655

RESUMO

BACKGROUND: Central line-associated blood stream infections (CLABSIs) are a source of high morbidity and mortality in children with acute myelogenous leukemia (AML). PROCEDURE: To understand the epidemiology and risk factors associated with the development of CLABSI in children with AML. METHODS: We retrospectively reviewed all patients with AML over a 5-year period between 2007 and 2011 at the Children's Hospital Colorado. Cases and controls were classified on the basis of the presence of a CLABSI as defined by the National Healthcare Safety Network. RESULTS: Of 40 patients in the study, 25 (62.5%) developed at least one CLABSI during therapy. The majority of CLABSIs were due to oral or gastrointestinal organisms (83.0%). Skin organisms accounted for 8.5%. In a multivariable analysis, the strongest risk factors associated with CLABSI were diarrhea (odds ratio [OR] 6.7, 95% confidence interval [CI] 1.6-28.7), receipt of blood products in the preceding 4-7 days (OR 10.0, 95%CI 3.2-31.0), not receiving antibiotics (OR 8.3, 95%CI 2.8-25.0), and chemotherapy cycle (OR 3.5, 95%CI 1.4-8.9). CLABSIs led to increased morbidity, with 13 cases (32.5%) versus two controls (1.9%) requiring transfer to the pediatric intensive care unit (P < 0.001). Three (7.5%) of 40 CLABSI events resulted in or contributed to death. CONCLUSIONS: Intensified line care efforts cannot eliminate all CLABSIs in the patients with AML. Exploring the role of mucosal barrier breakdown and/or the use of antibiotic prophylaxis may be effective strategies for further prevention of CLABSIs, supporting ongoing trials in this patient population.


Assuntos
Bacteriemia/etiologia , Infecções Relacionadas a Cateter/etiologia , Cateterismo Venoso Central/efeitos adversos , Infecção Hospitalar/etiologia , Leucemia Mieloide Aguda/complicações , Adolescente , Bactérias/isolamento & purificação , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Unidades de Terapia Intensiva Pediátrica , Leucemia Mieloide Aguda/microbiologia , Masculino , Prognóstico , Estudos Retrospectivos , Fatores de Risco
13.
Am J Infect Control ; 44(2): 138-45, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26601705

RESUMO

BACKGROUND: We investigated an increase in Clostridium difficile infection (CDI) among pediatric oncology patients. METHODS: CDI cases were defined as first C difficile positive stool tests between December 1, 2010, and September 6, 2012, in pediatric oncology patients receiving inpatient or outpatient care at a single hospital. A case-control study was performed to identify CDI risk factors, infection prevention and antimicrobial prescribing practices were assessed, and environmental sampling was conducted. Available isolates were strain-typed by pulsed-field gel electrophoresis. RESULTS: An increase in hospital-onset CDI cases was observed from June-August 2012. Independent risk factors for CDI included hospitalization in the bone marrow transplant ward and exposure to computerized tomography scanning or cefepime in the prior 12 weeks. Cefepime use increased beginning in late 2011, reflecting a practice change for patients with neutropenic fever. There were 13 distinct strain types among 22 available isolates. Hospital-onset CDI rates decreased to near-baseline levels with enhanced infection prevention measures, including environmental cleaning and prolonged contact isolation. CONCLUSION: C difficile strain diversity associated with a cluster of CDI among pediatric oncology patients suggests a need for greater understanding of modes and sources of transmission and strategies to reduce patient susceptibility to CDI. Further research is needed on the risk of CDI with cefepime and its use as primary empirical treatment for neutropenic fever.


Assuntos
Antibacterianos/uso terapêutico , Cefalosporinas/uso terapêutico , Clostridioides difficile/isolamento & purificação , Infecções por Clostridium/epidemiologia , Infecção Hospitalar/epidemiologia , Controle de Infecções , Adolescente , Estudos de Casos e Controles , Cefepima , Criança , Pré-Escolar , Clostridioides difficile/classificação , Clostridioides difficile/efeitos dos fármacos , Infecções por Clostridium/tratamento farmacológico , Infecções por Clostridium/microbiologia , Infecção Hospitalar/tratamento farmacológico , Infecção Hospitalar/microbiologia , Fezes/microbiologia , Feminino , Hospitalização , Hospitais , Humanos , Lactente , Masculino , Oncologia , Pediatria , Fatores de Risco , Adulto Jovem
14.
J Pediatr Surg ; 50(5): 875-8, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25783332

RESUMO

PURPOSE: Anterior mediastinal masses (AMM) pose a diagnostic challenge to surgeons, oncologists, anesthesiologists, intensivists, and interventional radiologists as induction of general anesthesia can cause airway obstruction and cardiovascular collapse. We hypothesized that in the majority of patients, diagnosis can be obtained through biopsy of extrathoracic tissue. METHODS: We performed a retrospective review of all patients in the solid tumor oncology clinic with a diagnosis of AMM between 2002 and 2012 including preoperative evaluation and management prior to obtaining a tissue diagnosis, clinical course and complications. RESULTS: We identified 69 patients with AMM (mean age 12.2±4.4years, 64% male) secondary to Hodgkin lymphoma (34), Non-Hodgkin lymphoma (26), and other diagnoses (9). The majority of patients (56, 81.2%) underwent biopsy of tissue outside of the mediastinal mass. Local anesthesia with sedation was used for successful biopsy in 21 (30%) patients. Four (5.8%) required repeat biopsy due to inadequate sample obtained at initial procedure. Three (4.4%) suffered respiratory complications with no fatalities or severe complications. CONCLUSIONS: Our data demonstrate that in the majority of children with AMM, tissue biopsy can be successfully obtained from tissue outside of the mass itself with minimal complications and highlight the importance of multidisciplinary preoperative planning to minimize anesthetic risks.


Assuntos
Anestesia/métodos , Diagnóstico por Imagem , Gerenciamento Clínico , Neoplasias do Mediastino/diagnóstico , Neoplasias do Mediastino/cirurgia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Adulto Jovem
15.
Pediatr Blood Cancer ; 62(3): 414-8, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25407157

RESUMO

BACKGROUND: Infants with acute lymphoblastic leukemia (ALL) have a poor prognosis. Intensification of therapy has resulted in fewer relapses but increased early deaths, resulting in failure to improve survival. PROCEDURE: AALL0631 is a Phase 3 study for infants (<366 days of age) with newly diagnosed ALL. Induction initially (Cohort 1) consisted of 3 weeks of therapy based on COG P9407. Due to excessive early mortality, induction was amended to a less intensive 5 weeks of therapy based on Interfant-99. Additionally, enhanced supportive care guidelines were incorporated with hospitalization during induction until evidence of marrow recovery and recommendations for prevention/treatment of infections (Cohort 2). RESULTS: Induction mortality was significantly lower for patients in Cohort 2 (2/123, 1.6%) versus Cohort 1 (4/26, 15.4%; P = 0.009). All induction deaths were infection related except one due to progressive disease (Cohort 2). Sterile site infections were lower for patients in Cohort 2 (24/123, 19.5%) versus Cohort 1 (15/26, 57.7%; P = 0.0002), with a significantly lower rate of Gram positive infections during induction for patients in Cohort 2, P = 0.0002. No clinically significant differences in grades 3-5 non-infectious toxicities were observed between the two cohorts. Higher complete response rates were observed at end induction intensification for Cohort 2 (week 9, 94/100, 94%) versus Cohort 1 (week 7, 17/25, 68%; P = 0.0.0012). CONCLUSION: De-intensification of induction therapy and enhanced supportive care guidelines significantly decreased induction mortality and sterile site infections, without decreasing complete remission rates.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Infecções por Bactérias Gram-Positivas/mortalidade , Quimioterapia de Indução , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Infecções por Bactérias Gram-Positivas/etiologia , Humanos , Lactente , Recém-Nascido , Masculino
16.
Pediatr Blood Cancer ; 62(3): 419-26, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25399948

RESUMO

BACKGROUND: Infants with acute lymphoblastic leukemia (ALL) present with aggressive disease and a poor prognosis. Early relapse within 6-9 months of diagnosis is common. Approximately 75% of infants have MLL-rearranged (MLL-R) ALL with event free survival (EFS) ranging from 20% to 30%. Children's Oncology Group (COG) P9407 used shortened (46 weeks), intensified therapy to address early relapse and poor EFS. PROCEDURE: P9407 therapy was modified three times for induction toxicity resulting in three cohorts of therapy. One hundred forty-seven infants were enrolled in the third cohort. RESULTS: We report an overall 5-year EFS and OS of 42.3 ± 6% and 52.9 ± 6.5% respectively. Poor prognostic factors included age ≤90 days at diagnosis, MLL-R ALL and white cell count ≥50,000/µl. For infants ≤90 days of age, the 5-year EFS was 15.5 ± 10.1% and 48.5 ± 6.7% for those >90 days (P < 0.0001). Among infants >90 days of age, 5-year EFS rates were 43.8 ± 8% for MLL-R versus 69.1 ± 13.6% for MLL-germline ALL (P < 0.0001). CONCLUSIONS: Age ≤90 days at diagnosis was the most important prognostic factor. Despite shortened therapy with early intensification, EFS remained less than 50% overall in MLL-R ALL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Fatores Etários , Intervalo Livre de Doença , Feminino , Seguimentos , Rearranjo Gênico , Histona-Lisina N-Metiltransferase , Humanos , Lactente , Recém-Nascido , Masculino , Proteína de Leucina Linfoide-Mieloide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Recidiva , Fatores de Risco , Transplante de Células-Tronco , Taxa de Sobrevida
17.
Clin Infect Dis ; 59(3): 401-3, 2014 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-24785235

RESUMO

Surveillance testing for Clostridium difficile among pediatric oncology patients identified stool colonization in 29% of patients without gastrointestinal symptoms and in 55% of patients with prior C. difficile infection (CDI). A high prevalence of C. difficile colonization and diarrhea complicates the diagnosis of CDI in this population.


Assuntos
Clostridioides difficile/isolamento & purificação , Infecções por Clostridium/epidemiologia , Neoplasias/complicações , Adolescente , Derrame de Bactérias , Criança , Pré-Escolar , Infecções por Clostridium/complicações , Infecções por Clostridium/diagnóstico , Infecções por Clostridium/microbiologia , Diarreia , Fezes/microbiologia , Humanos , Lactente , Pediatria , Prevalência , Adulto Jovem
18.
Blood ; 121(14): 2689-703, 2013 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-23393050

RESUMO

Survival in infants younger than 1 year who have acute lymphoblastic leukemia (ALL) is inferior whether MLL is rearranged (R) or germline (G). MLL translocations confer chemotherapy resistance, and infants experience excess complications. We characterized in vitro sensitivity to the pan-antiapoptotic BCL-2 family inhibitor obatoclax mesylate in diagnostic leukemia cells from 54 infants with ALL/bilineal acute leukemia because of the role of prosurvival BCL-2 proteins in resistance, their imbalanced expression in infant ALL, and evidence of obatoclax activity with a favorable toxicity profile in early adult leukemia trials. Overall, half maximal effective concentrations (EC50s) were lower than 176 nM (the maximal plasma concentration [Cmax] with recommended adult dose) in 76% of samples, whether in MLL-AF4, MLL-ENL, or other MLL-R or MLL-G subsets, and regardless of patients' poor prognostic features. However, MLL status and partner genes correlated with EC50. Combined approaches including flow cytometry, Western blot, obatoclax treatment with death pathway inhibition, microarray analyses, and/or electron microscopy indicated a unique killing mechanism involving apoptosis, necroptosis, and autophagy in MLL-AF4 ALL cell lines and primary MLL-R and MLL-G infant ALL cells. This in vitro obatoclax activity and its multiple killing mechanisms across molecular cytogenetic subsets provide a rationale to incorporate a similarly acting compound into combination strategies to combat infant ALL.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Pirróis/uso terapêutico , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Histona-Lisina N-Metiltransferase , Humanos , Indóis , Lactente , Recém-Nascido , Proteína de Leucina Linfoide-Mieloide/genética , Necrose/tratamento farmacológico , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores
19.
Pediatr Blood Cancer ; 60(1): 31-4, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22422485

RESUMO

BACKGROUND: The mixed lineage leukemia (MLL) gene is commonly rearranged in infant leukemia (IL). Genetic determinants of susceptibility to IL are unknown. Recent genome-wide association studies for childhood acute lymphoblastic leukemia (ALL) have identified susceptibility loci at IKZF1, ARID5B, and CEBPE. PROCEDURE: We genotyped these loci in 171 infants with leukemia and 384 controls and evaluated associations overall, by subtype [ALL, acute myeloid leukemia (AML)], and by presence (+) or absence (-) of MLL rearrangements. RESULTS: Homozygosity for a variant IKZF1 allele (rs11978267) increased risk of infant AML [Odds ratio (OR) = 3.9, 95% confidence interval (CI) = 1.8-8.4]; the increased risk was similar for AML/MLL+ and MLL- cases. In contrast, risk of ALL/MLL- was increased in infants homozygous for the IKZF1 variant (OR = 5.1, 95% CI = 1.8-14.5) but the variant did not modify risk of ALL/MLL+. For ARID5B (rs10821936), homozygosity for the variant allele increased risk for the ALL/MLL- subgroup only (OR = 7.2, 95% CI = 2.5-20.6). There was little evidence of an association with the CEBP variant (rs2239633). CONCLUSION: IKZF1 is expressed in early hematopoiesis, including precursor myeloid cells. Our data provide the first evidence that IKZF1 modifies susceptibility to infant AML, irrespective of MLL rearrangements, and could provide important new etiologic insights into this rare and heterogeneous hematopoietic malignancy.


Assuntos
Predisposição Genética para Doença , Leucemia Mieloide Aguda/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Criança , Histona-Lisina N-Metiltransferase , Humanos , Fator de Transcrição Ikaros/genética , Proteína de Leucina Linfoide-Mieloide/genética , Polimorfismo de Nucleotídeo Único
20.
Pediatr Blood Cancer ; 59(5): 834-9, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22488662

RESUMO

BACKGROUND: Infants (<366 days of age) with acute lymphoblastic leukemia (ALL) have a poor prognosis. Most treatment failures occur within 6-9 months of diagnosis, primarily from relapse. PROCEDURE: The Children's Oncology Group P9407 study was designed to test if early intensified treatment would improve outcome for infants with ALL. Due to a significant number of early deaths (< 90 days from enrollment), Induction therapy was amended three times. Cohorts 1 + 2 (n = 68), received identical Induction therapy except for reduced daunorubicin dose in Cohort 2. Cohort 3 (n = 141) received prednisone (40 mg/m(2)/day) instead of dexamethasone (10 mg/m(2)/day) and short infusion daunorubicin (30 minutes) instead of continuous infusion (48 hours), as well as additional supportive care measures throughout therapy. RESULTS: Early deaths occurred in 17/68 (25%) infants in Cohorts 1 + 2 and 8/141 (5.7%) infants in Cohort 3 (P < 0.0001). Among infants ≤90 days of age at diagnosis, early death occurred in 10/17 (58.8%) in Cohorts 1 + 2 and 4/27 (14.8%) in Cohort 3 (P = 0.006). Among infants >90 days of age at diagnosis, early death occurred in 7/51 (13.7%) in Cohorts 1 + 2 and 4/114 (3.5%) in Cohort 3 (P = 0.036). Bacterial, viral, and fungal infections were more common in Cohorts 1 + 2 versus Cohort 3. CONCLUSIONS: Early morbidity and mortality for infants with ALL were reduced by substitution of prednisone (40 mg/m(2)/day) for dexamethasone (10 mg/m(2)/day), the delivery of daunorubicin over 30 minutes instead of a continuous infusion for 48 hours, and the provision of more specific supportive care measures.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Daunorrubicina/administração & dosagem , Daunorrubicina/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Prednisolona/administração & dosagem , Prednisolona/efeitos adversos , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de Tempo
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