RESUMEN
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.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidad , Adolescente , Adulto , Estudios de Casos y Controles , Niño , Preescolar , Ciclofosfamida/administración & dosificación , Citarabina/administración & dosificación , Etopósido/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Mercaptopurina/administración & dosificación , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Pronóstico , Estudios Prospectivos , Tasa de Supervivencia , Adulto JovenRESUMEN
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.
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Lesión Renal Aguda/epidemiología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Infecciones Bacterianas/epidemiología , Clofarabina/efectos adversos , Pancreatitis/epidemiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/diagnóstico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Infecciones Bacterianas/inducido químicamente , Niño , Preescolar , Clofarabina/administración & dosificación , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Lactante , Masculino , Pancreatitis/inducido químicamente , Pancreatitis/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Inducción de Remisión/métodos , Índice de Severidad de la Enfermedad , Adulto JovenAsunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Lactante , Niño , Pronóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Recuento de Leucocitos , Sistema Nervioso CentralAsunto(s)
Proteína de la Leucemia Mieloide-Linfoide , Leucemia-Linfoma Linfoblástico de Células Precursoras , Ensayos Clínicos como Asunto , Células Germinativas , Humanos , Lactante , Proteína de la Leucemia Mieloide-Linfoide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Resultado del TratamientoRESUMEN
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.
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Selección de Profesión , Oncología Médica/educación , Tutoría , Pediatría/educación , Femenino , Humanos , Masculino , Mentores , Satisfacción Personal , Proyectos Piloto , Evaluación de Programas y Proyectos de SaludRESUMEN
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.
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Bacteriemia/etiología , Infecciones Relacionadas con Catéteres/etiología , Cateterismo Venoso Central/efectos adversos , Infección Hospitalaria/etiología , Leucemia Mieloide Aguda/complicaciones , Adolescente , Bacterias/aislamiento & purificación , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Unidades de Cuidado Intensivo Pediátrico , Leucemia Mieloide Aguda/microbiología , Masculino , Pronóstico , Estudios Retrospectivos , Factores de RiesgoRESUMEN
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.
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Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Pirroles/uso terapéutico , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , N-Metiltransferasa de Histona-Lisina , Humanos , Indoles , Lactante , Recién Nacido , Proteína de la Leucemia Mieloide-Linfoide/genética , Necrosis/tratamiento farmacológico , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidoresRESUMEN
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.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Infecciones por Bacterias Grampositivas/mortalidad , Quimioterapia de Inducción , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Infecciones por Bacterias Grampositivas/etiología , Humanos , Lactante , Recién Nacido , MasculinoRESUMEN
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.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Factores de Edad , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Reordenamiento Génico , N-Metiltransferasa de Histona-Lisina , Humanos , Lactante , Recién Nacido , Masculino , Proteína de la Leucemia Mieloide-Linfoide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Recurrencia , Factores de Riesgo , Trasplante de Células Madre , Tasa de SupervivenciaRESUMEN
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.
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Clostridioides difficile/aislamiento & purificación , Infecciones por Clostridium/epidemiología , Neoplasias/complicaciones , Adolescente , Derrame de Bacterias , Niño , Preescolar , Infecciones por Clostridium/complicaciones , Infecciones por Clostridium/diagnóstico , Infecciones por Clostridium/microbiología , Diarrea , Heces/microbiología , Humanos , Lactante , Pediatría , Prevalencia , Adulto JovenRESUMEN
Gene expression profiling was performed on 97 cases of infant ALL from Children's Oncology Group Trial P9407. Statistical modeling of an outcome predictor revealed 3 genes highly predictive of event-free survival (EFS), beyond age and MLL status: FLT3, IRX2, and TACC2. Low FLT3 expression was found in a group of infants with excellent outcome (n = 11; 5-year EFS of 100%), whereas differential expression of IRX2 and TACC2 partitioned the remaining infants into 2 groups with significantly different survivals (5-year EFS of 16% vs 64%; P < .001). When infants with MLL-AFF1 were analyzed separately, a 7-gene classifier was developed that split them into 2 distinct groups with significantly different outcomes (5-year EFS of 20% vs 65%; P < .001). In this classifier, elevated expression of NEGR1 was associated with better EFS, whereas IRX2, EPS8, and TPD52 expression were correlated with worse outcome. This classifier also predicted EFS in an independent infant ALL cohort from the Interfant-99 trial. When evaluating expression profiles as a continuous variable relative to patient age, we further identified striking differences in profiles in infants less than or equal to 90 days of age and those more than 90 days of age. These age-related patterns suggest different mechanisms of leukemogenesis and may underlie the differential outcomes historically seen in these age groups.
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Perfilación de la Expresión Génica , Regulación Leucémica de la Expresión Génica , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Factores de Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proteínas Portadoras/genética , Análisis por Conglomerados , Estudios de Cohortes , Proteínas de Unión al ADN/genética , Femenino , Redes Reguladoras de Genes , Proteínas de Homeodominio/genética , Humanos , Lactante , Estimación de Kaplan-Meier , Masculino , Modelos Genéticos , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteínas Nucleares/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Pronóstico , Factores de Transcripción/genética , Factores de Elongación Transcripcional , Resultado del Tratamiento , Proteínas Supresoras de Tumor/genética , Tirosina Quinasa 3 Similar a fms/genéticaRESUMEN
Transient myeloproliferative disorder (TMD), restricted to newborns with trisomy 21, is a megakaryocytic leukemia that although lethal in some is distinguished by its spontaneous resolution. Later development of acute myeloid leukemia (AML) occurs in some. Prospective enrollment (n = 135) elucidated the natural history in Down syndrome (DS) patients diagnosed with TMD via the use of uniform monitoring and intervention guidelines. Prevalent at diagnosis were leukocytosis, peripheral blast exceeding marrow blast percentage, and hepatomegaly. Among those with life-threatening symptoms, most (n = 29/38; 76%) received intervention therapy until symptoms abated and then were monitored similarly. Organomegaly with cardiopulmonary compromise most frequently led to intervention (43%). Death occurred in 21% but only 10% were attributable to TMD (intervention vs observation patients: 13/14 vs 1/15 because of TMD). Among those solely observed, peripheral blasts and all other TMD symptoms cleared at a median of 36 and 49 days from diagnosis, respectively. On the basis of the diagnostic clinical findings of hepatomegaly with or without life-threatening symptoms, 3 groups were identified with differing survival: low risk with neither finding (38%), intermediate risk with hepatomegaly alone (40%), and high risk with both (21%; overall survival: 92% ± 8%, 77% ± 12%, and 51% ± 19%, respectively; P ≤ .001). Among all, AML subsequently occurred in 16% at a median of 441 days (range, 118-1085 days). The trial is registered at http://www.clinicaltrials.gov as NCT00003593.
Asunto(s)
Citarabina/uso terapéutico , Síndrome de Down/complicaciones , Leucemia Megacarioblástica Aguda/tratamiento farmacológico , Trastornos Mieloproliferativos/tratamiento farmacológico , Enfermedad Aguda , Antimetabolitos Antineoplásicos/uso terapéutico , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Estimación de Kaplan-Meier , Leucemia Megacarioblástica Aguda/complicaciones , Leucemia Megacarioblástica Aguda/diagnóstico , Leucemia Mieloide/diagnóstico , Masculino , Trastornos Mieloproliferativos/complicaciones , Trastornos Mieloproliferativos/diagnóstico , Pronóstico , Estudios Prospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
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.
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Predisposición Genética a la Enfermedad , Leucemia Mieloide Aguda/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Niño , N-Metiltransferasa de Histona-Lisina , Humanos , Factor de Transcripción Ikaros/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: Children who are treated for myeloid leukemia associated with Down syndrome (DS) experience superior survival compared with children who have myeloid leukemia without DS. To maintain excellent outcomes while avoiding toxicity, the Children's Oncology Group (COG) conducted the phase 3 trial COG A2971, the first trial solely designed to provide uniform treatment of myeloid leukemia in North American children with DS. A2971 eliminated 2 induction drugs and 3 months of maintenance therapy from the standard-timing regimen of dexamethasone, cytarabine, 6-thioguanine, etoposide, and rubidomycin/daunomycin (DCTER) used in the previous study (Children's Cancer Group [CCG] 2891). METHODS: COG A2971 was a multi-institutional, nonrandomized, clinical trial that enrolled 132 patients who had DS with either acute myeloid leukemia (n = 91) or myelodysplastic syndrome (n = 41). RESULTS: The median follow-up was 4.8 years (range, 0.8-8.6 years), the median age at diagnosis was 1.7 years (range, 0.3-13.6 years), and the median white blood cell count was 6200/µL (range, 900-164,900/µL). The remission rate (92.7% ± 6%) was similar to that reported in the CCG 2891 study (91.3% ± 5%; P = .679). The 5-year event free survival (EFS) rate was 79% ± 7% (vs 77% ± 7% in CCG 2891; P = .589), the disease-free survival (DFS) rate was 89% ± 6% (vs 85% ± 6% in CCG 2891; P = .337), and the overall survival rate was 84% ± 6% (vs 79% ± 7% in CCG 2891; P = .302). Induction day-14 bone marrow response trended toward a more favorable outcome (EFS: P = .12). Age >4 years was an adverse risk factor (5-year EFS rate: 33% ± 38% for children aged >4 years [median, 8.5 years; n = 6] vs 81% ± 7% for children ages 0-4 years [median, 1.7 years; n = 126]; P = .001). CONCLUSIONS: The COG A2971 trial reduced the chemotherapy dose and maintained survival to that achieved by the CCG 2891 trial in children who had myeloid leukemia associated with DS.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Síndrome de Down/complicaciones , Leucemia Mieloide/tratamiento farmacológico , Adolescente , Trasplante de Médula Ósea , Niño , Preescolar , Citarabina/administración & dosificación , Daunorrubicina/administración & dosificación , Dexametasona/administración & dosificación , Supervivencia sin Enfermedad , Esquema de Medicación , Etopósido/administración & dosificación , Femenino , Humanos , Lactante , Estimación de Kaplan-Meier , Leucemia Mieloide/complicaciones , Leucemia Mieloide/cirugía , Masculino , Tioguanina/administración & dosificación , Resultado del TratamientoRESUMEN
The end-of-life (EOL) experience of children who undergo stem cell transplantation (SCT) may differ from that of other children with cancer. To evaluate perspectives and patterns of EOL care after SCT, we surveyed 141 parents of children who died of cancer (response rate, 64%) and their physicians. Chart review provided additional information. Children for whom SCT was the last cancer therapy (n = 31) were compared with those for whom it was not (n = 110). SCT parents and physicians recognized no realistic chance for cure later than non-SCT peers (both P < .001) and were more likely to have a primary goal of cure at death (parents, P < .001; physicians, P = .02). SCT children were more likely to suffer highly from their last cancer therapy and die in the intensive care unit (both P < .001), with less opportunity for EOL preparation. SCT parents who recognized no realistic chance for cure more than 7 days before death along with the physician were more likely to prepare for EOL, and if their primary goal was to reduce suffering, to achieve this (P < .001). SCT is associated with significant suffering and less opportunity to prepare for EOL. Children and families undergoing SCT may benefit from ongoing discussions regarding prognosis, goals, and opportunities to maximize quality of life.
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Neoplasias/mortalidad , Neoplasias/terapia , Cuidados Paliativos , Padres/psicología , Trasplante de Células Madre , Enfermo Terminal/psicología , Actitud Frente a la Muerte , Toma de Decisiones , Femenino , Humanos , Masculino , Evaluación de Resultado en la Atención de Salud , Médicos/psicología , Pronóstico , Calidad de Vida , Estrés Psicológico , Encuestas y Cuestionarios , Tasa de SupervivenciaRESUMEN
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.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Daunorrubicina/administración & dosificación , Daunorrubicina/efectos adversos , Dexametasona/administración & dosificación , Dexametasona/efectos adversos , Supervivencia sin Enfermedad , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Prednisolona/administración & dosificación , Prednisolona/efectos adversos , Estudios Retrospectivos , Tasa de Supervivencia , Factores de TiempoRESUMEN
BACKGROUND: Infant leukemias have a high frequency of mixed lineage leukemia (MLL) gene rearrangements. PROCEDURE: Using data from a large etiologic study, we evaluated the distribution of selected demographic factors among 374 infant leukemia cases by leukemic subtype, MLL status and diagnosis age. RESULTS: Overall, 228 cases were MLL+. Compared to white infants, black infants were significantly less likely to have MLL+ leukemia. Further, there was a statistically significantly higher age at diagnosis for infants with t(9;11) translocations compared to all other translocation partners in both acute lymphoblastic leukemia and acute myeloid leukemia cases. CONCLUSION: These patterns may provide important etiological insight into the biology of infant leukemia.
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Leucemia/epidemiología , Leucemia/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Distribución por Edad , Edad de Inicio , Femenino , Reordenamiento Génico , N-Metiltransferasa de Histona-Lisina , Humanos , Lactante , Recién Nacido , Estimación de Kaplan-Meier , Masculino , Distribución por SexoRESUMEN
OBJECTIVE: Utilizing data from the largest study to date, we examined associations between maternal preconception/prenatal exposure to household chemicals and infant acute leukemia. METHODS: We present data from a Children's Oncology Group case-control study of 443 infants (<1 year of age) diagnosed with acute leukemia [including acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML)] between 1996 and 2006 and 324 population controls. Mothers recalled household chemical use 1 month before and throughout pregnancy. We used unconditional logistic regression adjusted for birth year, maternal age, and race/ethnicity to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: We did not find evidence for an association between infant leukemia and eight of nine chemical categories. However, exposure to petroleum products during pregnancy was associated with AML (OR = 2.54; 95% CI:1.40-4.62) and leukemia without mixed lineage leukemia (MLL) gene rearrangements ("MLL-") (OR = 2.69; 95% CI: 1.47-4.93). No associations were observed for exposure in the month before pregnancy. CONCLUSIONS: Gestational exposure to petroleum products was associated with infant leukemia, particularly AML, and MLL- cases. Benzene is implicated as a potential carcinogen within this exposure category, but a clear biological mechanism has yet to be elucidated.
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Exposición a Riesgos Ambientales/efectos adversos , Productos Domésticos/envenenamiento , Leucemia Mieloide Aguda/inducido químicamente , Exposición Materna/efectos adversos , Efectos Tardíos de la Exposición Prenatal , Estudios de Casos y Controles , Femenino , Humanos , Lactante , Masculino , Embarazo , Factores de RiesgoRESUMEN
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.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carbazoles/uso terapéutico , N-Metiltransferasa de Histona-Lisina/metabolismo , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Femenino , Furanos , Humanos , Lactante , MasculinoRESUMEN
BACKGROUND: Leukemia in infants is rare and has not been well studied apart from leukemia in older children. Differences in survival and the molecular characteristics of leukemia in infants versus older children suggest a distinct etiology, likely involving prenatal factors. PROCEDURE: We examined the association between eight categories of maternally reported congenital abnormalities (CAs) (cleft lip or palate, spina bifida or other spinal defect, large or multiple birthmarks, other chromosomal abnormalities, small head or microcephaly, rib abnormalities, urogenital abnormalities, and other) and infant leukemia in a case-control study. The study included 443 cases diagnosed at <1 year of age at a Children's Oncology Group Institution in the United States or Canada from 1996 to 2006 and 324 controls. Controls were recruited from the cases' geographic area either by random digit dialing (1999-2002) or through birth certificates (2003-2008) and were frequency-matched to cases on birth year. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression after adjustment for birth year and a measure of follow-up time to account for differences in the CA observation period. RESULTS: No statistically significant associations were observed between infant leukemia and any CA (OR = 1.2; 95% CI: 0.8-1.9), birthmarks (OR = 1.4; 95% CI: 0.7-2.5), urogenital abnormalities (OR = 0.7; 95% CI: 0.2-2.0), or other CA (OR = 1.4; 95% CI: 0.7-2.8). Results were similar for acute lymphoblastic and myeloid leukemia cases. Fewer than five subjects were in the remaining CA categories precluding analysis. CONCLUSIONS: Overall, we did not find evidence to support an association between CAs and infant leukemia.