RESUMEN
Hyperleukocytosis (HL) in pediatric acute myeloid leukemia (AML) is associated with severe complications and inferior outcome. We report results on HL patients included in the NOPHO-DBH AML 2012 study. We recommended immediate start of full dose chemotherapy (etoposide [ETO] monotherapy for 5 days as part of the first course), avoiding leukapheresis (LA) and prephase chemotherapy (PCT). Of 714 included patients, 122 (17.1%) had HL, and 111 were treated according to the recommendations with ETO upfront without preceding LA or PCT. The first dose was applied the same day as the AML diagnosis or the day after in 94%. ETO was administered via peripheral veins in 37% of patients without major complications. After initiation of ETO the remaining WBC on days 2-5 was 69%, 36%, 17% and 8% of the pre-treatment level. On day 3, 81% had a WBC.
RESUMEN
A significant proportion of events in paediatric acute myeloid leukaemia (AML) are caused by resistant disease (RD). We investigated clinical and biological characteristics in 66 patients with RD from 1013 children with AML registered and treated according to the NOPHO-AML 93, NOPHO-AML 2004, DB AML-01 and NOPHO-DBH AML 2012 protocols. Risk factors for RD were age10 years or older and a white-blood-cell count (WBC) of 100 × 109 /L or more at diagnosis. The five-year overall survival (OS) was 38% (95% confidence interval [CI]: 28%-52%). Of the 63 children that received salvage therapy with chemotherapy, 59% (N = 37) achieved complete remission (CR) with OS 57% (95% CI: 42%-75%) compared to 12% (95% CI: 4%-35%) for children that did not achieve CR. Giving more than two salvage chemotherapy courses did not increase CR rates. OS for all 43 patients receiving allogeneic haematopoietic stem cell transplantation (HSCT) was 49% (95% CI: 36%-66%). Those achieving CR and proceeding to HSCT had an OS of 56% (95% CI: 41%-77%, N = 30). This study showed that almost 40% of children with primary resistant AML can be cured with salvage therapy followed by HSCT. Children that did not achieve CR after two salvage courses with chemotherapy did not benefit from additional chemotherapy.
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Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Niño , Humanos , Recuento de Leucocitos , Factores de Riesgo , Terapia Recuperativa , Leucemia Mieloide Aguda/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Estudios Retrospectivos , Inducción de RemisiónRESUMEN
Acute myeloid leukemia (AML) accounts for 15% to 20% of childhood leukemias. Because of high-intensive therapy, up to 5% of patients suffer from treatment-related mortality (TRM). Abdominal complications are frequent, however, literature on this subject is sparse. We aimed to characterize severe abdominal pain (AP) and hyperbilirubinemia experienced by pediatric AML patients treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO)-AML 2004 protocol (n=313). Patients were censored at hematopoietic stem cell transplantation and relapse. Toxicity information was collected prospectively. Additional information was requested retrospectively from the treating centers. Sixteen episodes of hyperbilirubinemia and 107 episodes of AP were reported. The treating centers deemed infection (30%) and typhlitis (18%) as the most frequent causes of AP. Six patients developed appendicitis (2%). Patients experiencing concurrent AP and sepsis had a high risk of TRM (36%, n=4). Eighty percent of episodes with hyperbilirubinemia fulfilled the European Society for Bone and Marrow Transplantation criteria for sinusoidal obstruction syndrome. In conclusion, abdominal complications were frequent with infection considered the predominate cause. Most patients with hyperbilirubinemia fulfilled the criteria for sinusoidal obstruction syndrome. AML treatment might be associated with appendicitis. Patients suffering from concurrent AP and sepsis had a high risk of TRM indicating that high awareness of abdominal complications is essential to reduce mortality, especially during sepsis.
Asunto(s)
Apendicitis , Trasplante de Células Madre Hematopoyéticas , Enfermedad Veno-Oclusiva Hepática , Leucemia Mieloide Aguda , Sepsis , Apendicitis/etiología , Niño , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Veno-Oclusiva Hepática/etiología , Humanos , Hiperbilirrubinemia/etiología , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/terapia , Estudios Retrospectivos , Sepsis/etiologíaRESUMEN
Serial assessments of measurable (or minimal) residual disease (MRD) by qPCR may identify nascent relapse in children with acute myeloid leukaemia (AML) and enable pre-emptive therapy. We investigated the kinetics and prognostic impact of recurrent fusion transcripts (RUNX1-RUNX1T1, CBFB-MYH11, KMT2A-MLLT3 or KMT2A-ELL) in 774 post-induction samples from bone marrow (BM, 347) and peripheral blood (PB, 427) from 75 children with AML. BM MRD persistence during consolidation did not increase the risk of relapse, and MRD at therapy completion did not correlate to outcome (HR = 0·64/MRD log reduction (CI: 0·32-1·26), P = 0·19). In contrast, 8/8 patients with detectable MRD in PB after first consolidation relapsed. Persistence (n = 4) and shifting from negative to positive (n = 10) in PB during follow-up predicted relapse in 14/14 patients. All 253 PB samples collected during follow-up from 36 patients in continuous complete remission were MRD negative. In core-binding factor AML, persistent low-level MRD positivity in BM during follow-up was frequent but an increment to above 5 × 10-4 heralded subsequent haematological relapse in 12/12 patients. We demonstrate that MRD monitoring in PB after induction therapy is highly informative and propose an MRD increment above 5 × 10-4 in PB and BM as a definition of molecular relapse since it always leads to haematological relapse.
Asunto(s)
Leucemia Mieloide Aguda/complicaciones , Neoplasia Residual/diagnóstico , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Adolescente , Biomarcadores de Tumor , Niño , Preescolar , Progresión de la Enfermedad , Femenino , Humanos , Lactante , Recién Nacido , Leucemia Mieloide Aguda/sangre , Masculino , Neoplasia Residual/sangreRESUMEN
BACKGROUND: Measurable/minimal residual disease (MRD) monitoring can predict imminent hematological relapse in acute myeloid leukemia (AML). The majority of childhood AML patients do not harbor fusion genes or mutations applicable as MRD markers and overexpression of Wilms tumor gene 1 (WT1) may constitute a useful monitoring target. However, age-specific reference values in healthy hematopoiesis and standardization of WT1 assessment are prerequisites for clinical utility. PROCEDURE: We investigated WT1 expression across age in hematologically healthy controls (n = 109), during suspected infection (n = 90) and bone marrow (BM) regeneration (n = 13). WT1 expression in AML at diagnosis (n = 91) and during follow-up (n = 30) was compared with age-specific reference values. RESULTS: WT1 expression correlated with age and showed higher levels in both BM and peripheral blood (PB) in children compared with adults (P < 0.001 and P = 0.01). WT1 expression from healthy hematopoiesis was lower in PB compared with BM (WT1BM /WT1PB = 8.6, 95% CI: 5.3-13.7) and not influenced by infection nor BM regeneration. At AML diagnosis, 66% had more than 20-fold WT1 overexpression in PB or BM (PB 74%; BM 45%). WT1 was quantified in 279 PB samples during follow-up. All 11 patients with PB sampling within 4 months of disease recurrence displayed WT1 overexpression by a median of 1.9 months (range, 0.7-9.7) before hematological relapse. CONCLUSIONS: This study defines child-specific reference values for WT1 expression in healthy hematopoiesis and demonstrates that WT1 expression in PB is a useful post-treatment monitoring tool in childhood AML. Based on these observations, we propose definitions for childhood AML molecular relapse using WT1 overexpression.
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Biomarcadores de Tumor/metabolismo , Médula Ósea/metabolismo , Leucemia Mieloide Aguda/patología , Recurrencia Local de Neoplasia/patología , Neoplasia Residual/patología , Proteínas WT1/metabolismo , Adolescente , Adulto , Biomarcadores de Tumor/sangre , Médula Ósea/patología , Estudios de Casos y Controles , Niño , Preescolar , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Lactante , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/terapia , Masculino , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/terapia , Neoplasia Residual/metabolismo , Neoplasia Residual/terapia , Pronóstico , Valores de Referencia , Proteínas WT1/sangreRESUMEN
BACKGROUND: Supportive-care use of granulocyte colony-stimulating factor (G-CSF) in pediatric acute myeloid leukemia (AML) remains controversial due to a theoretical increased risk of relapse and limited impact on neutropenic complications. We describe the use of G-CSF in patients treated according to NOPHO-AML 2004 and DB AML-01 and investigated associations with relapse. PROCEDURE: Patients diagnosed with de novo AML completing the first week of therapy and not treated with hematopoietic stem cell transplantation in the first complete remission were included (n = 367). Information on G-CSF treatment after each course (yes/no) was registered prospectively in the study database and detailed information was gathered retrospectively from each center. Descriptive statistics were used to describe G-CSF use and Cox regression to assess the association between G-CSF and risk of relapse. RESULTS: G-CSF as supportive care was given to 128 (35%) patients after 268 (39%) courses, with a large variation between centers (0-93%). The use decreased with time-the country-adjusted odds ratio was 0.8/diagnostic year (95% confidence interval [CI] 0.7-0.9). The median daily dose was 5 µg/kg (range 3-12 µg/kg) and the median cumulative dose was 75 µg/kg (range 7-1460 µg/kg). Filgrastim was used in 82% of G-CSF administrations and infection was the indication in 44% of G-CSF administrations. G-CSF was associated with increased risk of relapse-the adjusted hazard ratio was 1.5 (95% CI 1.1-2.2). CONCLUSIONS: G-CSF as supportive care was used in a third of patients, and use decreased with time. Our results indicate that the use of G-CSF may be associated with an increased risk of relapse.
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Factor Estimulante de Colonias de Granulocitos/efectos adversos , Leucemia Mieloide Aguda/tratamiento farmacológico , Recurrencia Local de Neoplasia/etiología , Cuidados Paliativos/estadística & datos numéricos , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Niño , Preescolar , Ensayos Clínicos como Asunto , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Lactante , Leucemia Mieloide Aguda/patología , Masculino , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/epidemiología , Pronóstico , Factores de Riesgo , Países Escandinavos y Nórdicos/epidemiologíaRESUMEN
BACKGROUND: A previous study based on Norwegian Cancer Registry data suggested regional differences in overall survival (OS) after treatment for medulloblastoma (MB) and supratentorial primitive neuroectodermal tumor (CNS-PNET) in Norway. The purpose of the present study was to confirm in an extended cohort whether there were regional differences in outcome or not, and if so try to identify possible explanations. MATERIAL AND METHODS: Data from patients aged 0-20 years diagnosed with and treated for MB/CNS-PNET at all four university hospitals in Norway from 1974 to 2013 were collected and compared. RESULTS: Of 266 identified patients, 251 fulfilled inclusion criteria. MB was diagnosed in 200 and CNS-PNET in 51 patients. Five-year OS and event-free survival (EFS) were 59% and 52%, respectively. There was a significant difference in five-year OS and EFS between MB and CNS-PNET patients; 62% versus 47% (P = 0.007) and 57% versus 35% (P < 0.001). In multivariable analysis, two factors were found to significantly contribute to improved five-year OS and EFS, whereas one factor contributed to improved five-year OS only. Gross total resection (GTR) versus non-GTR (hazard ratio [HR] 0.53, P = 0.003; HR 0.46, P < 0.001) and cerebrospinal irradiation (CSI) versus non-CSI (HR 0.24, P < 0.001; HR 0.28, P < 0.001) for both, and treatment outside Oslo University Hospital for OS only (HR 0.64, P = 0.048). CONCLUSION: Survival was comparable with data from other population-based studies, and the importance of GTR and CSI was confirmed. The cause for regional survival differences could not be identified.
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Neoplasias Cerebelosas/mortalidad , Meduloblastoma/mortalidad , Tumores Neuroectodérmicos Primitivos/mortalidad , Neoplasias Supratentoriales/mortalidad , Adolescente , Neoplasias Cerebelosas/terapia , Niño , Preescolar , Terapia Combinada/métodos , Supervivencia sin Enfermedad , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Meduloblastoma/terapia , Tumores Neuroectodérmicos Primitivos/terapia , Noruega/epidemiología , Estudios Retrospectivos , Neoplasias Supratentoriales/terapia , Análisis de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
The t(7;12)(q36;p13) (MNX1/ETV6) is not included in the WHO classification but has been described in up to 30% of acute myeloid leukemia (AML) in children <2 years and associated with a poor prognosis. We present the clinical and cytogenetics characteristics of AML cases with t(7;12)(p36;p13). A literature review identified 35 patients with this translocation, published between 2000 and 2015. Outcome data were available in 22 cases. The NOPHO-AML (Nordic Society for Pediatric Hematology and Oncology) database contained 651 patients with AML from 1993 to 2014 and seven (1.1%) had the translocation. The t(7;12) was only present in patients <2 years of age (median age 6 months) but none was diagnosed as newborn. These patients constituted 4.3% of the patients <2 years of age. There was a strong association with trisomy 19 (literature: 86%, NOPHO: 100%) and +8 (literature: 19%, NOPHO: 14%). Seventeen of 22 patients from the literature with t(7;12) and four of seven patients from the NOPHO database suffered from relapse. The patients with t(7;12) had a 3-year event free survival of 24% (literature) vs. 43% (NOPHO) and a 3-year overall survival of 42% (literature) vs. 100% (NOPHO). None of the NOPHO patients was treated with hematopoietic stem cell transplantation (HSCT) in first complete remission. Relapse was frequent but the salvage rate using HSCT was high. We conclude that t(7;12)(q36;13) is a unique subgroup of childhood AML with presentation before 2 years of age with most cases being associated with +19.
Asunto(s)
Cromosomas Humanos Par 12 , Cromosomas Humanos Par 19 , Cromosomas Humanos Par 7 , Leucemia Mieloide Aguda/genética , Translocación Genética , Trisomía , Femenino , Humanos , Lactante , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Masculino , Recurrencia , Análisis de SupervivenciaRESUMEN
Data on occurrence, genetic characteristics and prognostic impact of complex and monosomal karyotype (CK/MK) in children with acute myeloid leukaemia (AML) are scarce. We studied CK and MK in a large unselected cohort of childhood AML patients diagnosed and treated according to Nordic Society for Paediatric Haematology and Oncology (NOPHO)-AML protocols 1993-2015. In total, 800 patients with de novo AML were included. CK was found in 122 (15%) and MK in 41 (5%) patients. CK and MK patients were young (median age 2·1 and 3·3 years, respectively) and frequently had FAB M7 morphology (24% and 22%, respectively). Refractory disease was more common in MK patients (15% vs. 4%) and stem cell transplantation in first complete remission was more frequent (32% vs. 19%) compared with non-CK/non-MK patients. CK showed no association with refractory disease but was an independent predictor of an inferior event-free survival (EFS; hazard ratio [HR] 1·43, P = 0·03) and overall survival (OS; HR 1·48, P = 0·01). MK was associated with a poor EFS (HR 1·57, P = 0·03) but did not show an inferior OS compared to non-MK patients (HR 1·14, P = 0·62). In a large paediatric cohort, we characterized AML with non-recurrent abnormal karyotype and unravelled the adverse impact of CK and MK on prognosis.
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Cariotipo Anormal , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Adolescente , Aloinjertos , Niño , Preescolar , Citogenética , Supervivencia sin Enfermedad , Femenino , Humanos , Lactante , Recién Nacido , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/terapia , Masculino , Tasa de SupervivenciaRESUMEN
BACKGROUND: Children with acute myeloid leukemia (AML) treated similarly show different toxicity and leukemic responses. We investigated associations between neutrophil recovery time after the first induction course, infection and relapse in children treated according to NOPHO-AML 2004 and DB AML-01. PROCEDURE: Newly diagnosed patients with AML with bone marrow blast <5% between day 15 after the start of the treatment and the start of second induction course, and in complete remission after the second induction course were included (n = 279). Neutrophil recovery time was defined as the time from the start of the course to the last day with absolute neutrophil count <0.5 × 109 /l. Linear and Cox regressions were used to investigate associations. RESULTS: Neutrophil recovery time after the first induction course was positively associated with neutrophil recovery time after the remaining courses, and longer neutrophil recovery time (≥25 days) was associated with increased risk of grade 3-4 infections (hazard ratio 1.4, 95% confidence interval [CI], 1.1-1.8). Longer neutrophil recovery time after the first induction (>30 days) was associated with the increased risk of relapse (5-year cumulative incidence: 48% vs. 42%, hazard ratio 1.7, 95% CI, 1.1-2.6) for cases not treated with hematopoietic stem cell transplantation in first complete remission. CONCLUSION: Longer neutrophil recovery time after the first induction course was associated with grade 3-4 infections and relapse. If confirmed, this knowledge could be incorporated into risk stratification strategies in pediatric AML.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Neutrófilos/fisiología , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Niño , Preescolar , Femenino , Humanos , Lactante , Infecciones/epidemiología , Infecciones/etiología , Leucemia Mieloide Aguda/inmunología , Masculino , Neutropenia/inducido químicamente , Modelos de Riesgos Proporcionales , Recurrencia , Inducción de Remisión , Factores de Tiempo , Resultado del TratamientoRESUMEN
Hyperleucocytosis in paediatric acute myeloid leukaemia (AML) is associated with increased morbidity and mortality. We studied hyperleucocytosis in 890 patients with AML aged 0-18 years registered in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) registry, with special focus on very high white blood cell counts (WBC >200 × 10/l). Eighty-six patients (10%) had WBC 100-199 × 109 /l and 57 (6%) had WBC ≥200 × 109 /l. Patients with WBC ≥200 × 109 /l had a high frequency of t(9;11) and a paucity of trisomy 8. Due to the high frequency of deaths within the first 2 weeks (30% vs. 1% for all others), overall survival in this group was inferior to patients with WBC <200 × 109 /l (39% vs. 61%). Main cause of early death was intracranial haemorrhage and leucostasis. Twenty-six per cent of these patients never started antileukaemic protocol therapy. Leukapheresis or exchange transfusion was used in 24% of patients with hyperleucocytosis without impact on survival. Patients with hyperleucocytosis surviving the first week had identical survival as patients with lower WBC. We conclude that death within the first days after diagnosis is the major challenge in patients with high WBC and advocate rapid initiation of intensive chemotherapy.
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Leucemia Mieloide Aguda/complicaciones , Leucocitosis/etiología , Adolescente , Niño , Preescolar , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 9/genética , Bases de Datos Factuales , Femenino , Hong Kong/epidemiología , Humanos , Lactante , Recién Nacido , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/sangre , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Recuento de Leucocitos , Leucocitosis/sangre , Leucocitosis/genética , Leucocitosis/mortalidad , Masculino , Pronóstico , Sistema de Registros , Países Escandinavos y Nórdicos/epidemiología , TrisomíaRESUMEN
Given that 30-40% of children with acute myeloid leukaemia (AML) relapse after primary therapy it is important to define prognostic factors and identify optimal therapy. From 1993 to 2012, 543 children from the Nordic countries were treated according to two consecutive protocols: 208 children relapsed. The influence of disease characteristics, first line treatment, relapse therapy and duration of first remission on outcome was analysed. Second complete remission (CR2) was achieved in 146 (70%) patients. Estimated 5-year overall survival (OS5y ) was 39 ± 4% for the whole group and 43 ± 4% for the 190 patients given re-induction therapy, of whom 76% received regimens that included fludarabine, cytarabine (FLA) ± anthracyclines, 18% received Nordic Society for Paediatric Haematology and Oncology (NOPHO) upfront blocks and 5% received other regimens. Late relapse ≥1 year from diagnosis, no allogeneic stem cell transplantation (SCT) in first remission and core binding factor AML were independent favourable prognostic factors for survival. For the 128 children (124 in CR2) that received SCT as consolidation therapy after relapse, OS5y was 61 ± 5%. Four of 19 children (21%) survived without receiving SCT as part of relapse therapy. Our data show that intensive re-induction followed by SCT can give cure rates of 40% in children with relapsed AML.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/terapia , Trasplante de Células Madre/métodos , Adolescente , Biomarcadores de Tumor/sangre , Niño , Preescolar , Aberraciones Cromosómicas , Factores de Unión al Sitio Principal/sangre , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Infiltración Leucémica , Masculino , Pronóstico , Recurrencia , Inducción de Remisión , Factores de Riesgo , Análisis de Supervivencia , Resultado del TratamientoAsunto(s)
Biomarcadores , Histiocitosis de Células de Langerhans/líquido cefalorraquídeo , Histiocitosis de Células de Langerhans/tratamiento farmacológico , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Inhibidores de Proteínas Quinasas/uso terapéutico , Preescolar , Susceptibilidad a Enfermedades , Femenino , Histiocitosis de Células de Langerhans/diagnóstico , Histiocitosis de Células de Langerhans/etiología , Humanos , Lactante , Masculino , Mutación , Pronóstico , Inhibidores de Proteínas Quinasas/farmacología , Resultado del TratamientoRESUMEN
BACKGROUND: The prognostic significance of extramedullary leukemia (EML) in childhood acute myeloid leukemia is not clarified. PROCEDURE: This population-based study included 315 children from the NOPHO-AML 2004 trial. RESULTS: At diagnosis, 73 (23%) patients had EML: 39 (12%) had myeloid sarcoma, 22 (7%) had central nervous system disease, and 12 (4%) had both. EML was associated with young age (median age: 2.6 years), a high white blood cell count (median: 40 × 109 /l), M5 morphology (40%), and 11q23/MLL (KMT2A) rearrangements (34%). No patient received involved field radiotherapy. Five-year event-free survival did not differ significantly between the EML and the non-EML patients (54% vs. 45%, P = 0.57), whereas 5-year overall survival (OS) was significantly lower in the EML group (64% vs. 73%, P = 0.04). The risk of induction death was significantly higher for EML patients (8% vs. 1%, P = 0.002). There was a trend toward a lower risk of relapse for EML patients (5-year cumulative incidence of relapse 33% vs. 49%, P = 0.16). Traumatic lumbar puncture did not adversely affect survival in this cohort. CONCLUSIONS: EML was associated with increased risk of induction death impacting the OS. No patients relapsed at the primary site of the myeloid sarcoma despite management without radiotherapy.
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Leucemia Mieloide Aguda/patología , Adolescente , Recuento de Células , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Lactante , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Masculino , Pronóstico , Recurrencia , Punción Espinal , Resultado del TratamientoRESUMEN
Trisomy 8 (+8) is a common cytogenetic aberration in acute myeloid leukemia (AML); however, the impact of +8 in pediatric AML is largely unknown. We retrospectively investigated 609 patients from the NOPHO-AML database to determine the clinical and cytogenetic characteristics of +8 in pediatric AML and to investigate its prognostic impact. Complete cytogenetic data were available in 596 patients (98%) aged 0-18 years, diagnosed from 1993 to 2012, and treated according to the NOPHO-AML 1993 and 2004 protocols in the Nordic countries and Hong Kong. We identified 86 patients (14%) with +8. Trisomy 8 was combined with other cytogenetic aberrations in 68 patients (11%) (+8 other) and in 18 patients (3%), it was the sole abnormality (+8 alone). Trisomy 8 was associated with FAB M5 (36%) but otherwise clinically comparable with non-trisomy 8 patients. Trisomy 8 was favorable in patients of young age and with t(9;11). Trisomy 8 alone was associated with older age (median age 10.1 years), FAB M2 (33%), and FLT3-ITD mutations (58%). The 5-year event-free survival for patients with +8 alone was 50% and 5-year overall survival was 75%. In conclusion, +8 is one of the most common cytogenetic aberrations in pediatric AML. Trisomy 8 positive AML is a heterogeneous group and the majority of cases have additional cytogenetic aberrations. Patients with +8 alone differed from patients with +8 other and were associated with older age, FAB M2, and FLT3-ITD aberrations. There were no differences in survival despite the more frequent occurrence of FLT3-ITD in +8 alone. © 2016 Wiley Periodicals, Inc.
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Aberraciones Cromosómicas , Leucemia Mieloide Aguda/genética , Secuencias Repetidas en Tándem/genética , Trisomía/genética , Tirosina Quinasa 3 Similar a fms/genética , Adolescente , Estudios de Casos y Controles , Niño , Preescolar , Cromosomas Humanos Par 8/genética , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Masculino , Estadificación de Neoplasias , Pronóstico , Tasa de SupervivenciaRESUMEN
Treatment for pediatric acute myeloid leukemia is very toxic and the association between outcome and age and Body Mass Index is unclear. We investigated effect of age and Body Mass Index on toxicity and survival in pediatric acute myeloid leukemia. We studied all patients who completed first induction course of NOPHO-AML 2004 (n=318). Toxicity following induction and consolidation courses (n=6) was analyzed. The probabilities of toxicity and death were determined using time-to-event analyses with Cox multivariate proportional hazard regression for comparative analyses. Age 10-17 years was associated with sepsis with hypotension [hazard ratio 2.3 (95% confidence interval 1.1-4.6)]. Being overweight (>1 standard deviation) was associated with requiring supplemental oxygen [1.9 (1.0-3.5)]. The 5-year event-free and overall survival were 47% and 71%. Children aged 10-17 years showed a trend for inferior 5-year overall survival compared to children aged 2-9 (64% vs. 76%; P=0.07). Infants showed a trend for superior 5-year event-free survival (66% vs. 43%; P=0.06). Overweight children aged 10-17 years showed a trend for superior survival [5-year event-free survival 59% vs. 40% (P=0.09) and 5-year overall survival 78% vs. 56% (P=0.06)] compared to healthy weight children aged 10-17 years. In conclusion, children aged 10-17 years and overweight children had a higher risk of grade 3-4 toxicity. Children aged 10-17 years showed inferior survival, but, unexpectedly, in this age group overweight children tended to have increased survival. This suggests different pharmacokinetics of chemotherapeutic drugs in adolescents and warrants further studies.
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Antineoplásicos/toxicidad , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/mortalidad , Adolescente , Factores de Edad , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Peso Corporal , Niño , Preescolar , Quimioterapia de Consolidación/efectos adversos , Humanos , Quimioterapia de Inducción/efectos adversos , Lactante , Leucemia Mieloide Aguda/tratamiento farmacológico , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: There is a concern regarding long-term cognitive late effects after treatment for acute lymphoblastic leukemia (ALL). The present study assessed neuropsychological function in very long-term childhood ALL survivors treated with chemotherapy only. We also investigated associations between neurocognitive performance and individual treatment load. PROCEDURE: One-hundred and twelve adult ALL survivors, diagnosed 1970-2002 before age 16 and treated with chemotherapy only, and 100 comparison peers underwent neuropsychological tests covering processing speed, executive functions, working memory, and verbal learning and memory. Individual cumulative doses of cytostatic agents were extracted from the medical records for each patient. RESULTS: Mean age at diagnosis for survivors was 6.3 years and mean follow-up time was 22.6 years. There was no difference in general intellectual ability between survivors and comparison peers. However, survivors performed significantly more poorly in the neurocognitive domains' processing speed (P = 0.003, Cohen's d 0.48), executive functions, and working memory (both P < 0.001, Cohen's d 0.81-0.95). Among survivors, the rates of poor neurocognitive performance (>1.5 SD below control mean) for processing speed was 22%, executive functions 31%, working memory 34%, and verbal learning and memory 16%. Comparing survivors with poor versus normal neurocognitive performance, we found no difference with respect to cumulative doses of any of the cytostatic agents, age at diagnosis, or gender. CONCLUSIONS: Very long-term survivors of childhood ALL treated exclusively with chemotherapy showed no impairment in general intellectual ability, but significantly poorer performance in several neurocognitive domains than comparison peers. However, no associations emerged between neurocognitive impairment and treatment burden.
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Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/fisiopatología , Adolescente , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Niño , Función Ejecutiva/fisiología , Femenino , Humanos , Masculino , Memoria a Corto Plazo/fisiología , Pruebas Neuropsicológicas , Resultado del Tratamiento , Aprendizaje Verbal/fisiología , Adulto JovenRESUMEN
BACKGROUND: Studies on adolescents and young adults with acute lymphoblastic leukemia suggest better results when using pediatric protocols for adult patients, while corresponding data for acute myeloid leukemia (AML) are limited. PROCEDURE: We investigated disease characteristics and outcome for de novo AML patients 10-30 years old treated in pediatric or adult departments. We included 166 patients 10-18 years of age with AML treated according to the pediatric NOPHO-protocols (1993-2009) compared with 253 patients aged 15-30 years treated in hematology departments (1996-2009) in the Nordic countries. RESULTS: The incidence of AML was 4.9/million/year for the age group 10-14 years, 6.5 for 15-18 years, and 6.9 for 19-30 years. Acute promyelocytic leukemia (APL) was more frequent in adults and in females of all ages. Pediatric patients with APL had similar overall survival as pediatric patients without APL. Overall survival at 5 years was 60% (52-68%) for pediatric patients compared to 65% (58-70%) for adult patients. Cytogenetics and presenting white blood cell count were the only independent prognostic factors for overall survival. Age was not an independent prognostic factor. CONCLUSIONS: No difference was found in outcome for AML patients age 10-30 years treated according to pediatric as compared to adult protocols.
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Departamentos de Hospitales , Leucemia Mieloide Aguda/terapia , Adolescente , Adulto , Niño , Femenino , Hematología , Humanos , Leucemia Mieloide Aguda/mortalidad , Masculino , Pediatría , Pronóstico , Países Escandinavos y Nórdicos , Adulto JovenRESUMEN
The World Health Organization (WHO) classification of myeloid leukaemia was revised in 2008. It incorporates newly recognized entities and emphasizes the pivotal role of cytogenetic abnormalities. The aim of this study was to evaluate the usability of the WHO classification when applied to a large population-based paediatric acute myeloid leukaemia (AML) cohort. We included children diagnosed with de novo AML, 0-18 years of age from the Nordic countries and Hong Kong from 1993 to 2012. Data were retrieved from the Nordic Society for Paediatric Haematology and Oncology AML database and patients classified according to the WHO 2008 classification. A successful karyotype was available in 97% of the cases. AML with recurrent genetic abnormalities were present in 262 (41%) and 94 (15%) were classified as AML with myelodysplasia-related changes (AML-MDS). WHO classifies patients with monosomy 7 and del(7q) into one group. We found that -7 (n = 14) had significantly poorer outcome than del(7q) (n = 11); 5-year event-free survival 26% vs. 67%, (P = 0·02), and 5-year overall survival 51% vs. 90%, (P = 0·04). The largest group was the highly heterogeneous AML not otherwise specified (NOS) (n = 280) (44%). In conclusion, the WHO classification allocated 15% to AML-MDS, 44% to NOS and grouped together entities with clearly different outcome, therefore limiting the applicability of the current WHO classification in children with AML.