IKZF1 deletions associate with CRLF2 overexpression leading to a poor prognosis in B-cell precursor acute lymphoblastic leukaemia.

Cytokine Receptor-Like Factor 2 (CRLF2) overexpression occurs in 5-15% of B-cell precursor acute lymphoblastic leukaemia (B-ALL). In ∼50% of these cases, the mechanisms underlying this dysregulation are unknown. IKAROS Family Zinc Finger 1 (IKZF1) is a possible candidate to play a role in this dysregulation since it binds to the CRLF2 promoter region and suppresses its expression. We hypothesised that IKZF1 loss of function, caused by deletions or its short isoforms expression, could be associated with CRLF2 overexpression in B-ALL. A total of 131 paediatric and adult patients and 7 B-ALL cell lines were analysed to investigate the presence of IKZF1 deletions and its splicing isoforms expression levels, the presence of CRLF2 rearrangements or mutations, CRLF2 expression and JAK2 mutations. Overall survival analyses were performed according to the CRLF2 and IKZF1 subgroups. Our analyses showed that 25.2% of patients exhibited CRLF2 overexpression (CRLF2-high). CRLF2-high was associated with the presence of IKZF1 deletions (IKZF1del, p = 0.001), particularly with those resulting in dominant-negative isoforms (p = 0.006). Moreover, CRLF2 expression was higher in paediatric samples with high loads of the short isoform IK4 (p = 0.011). It was also associated with the occurrence of the IKZF1 plus subgroup (p = 0.004). Furthermore, patients with CRLF2-high/IKZF1del had a poorer prognosis in the RELLA05 protocol (p = 0.067, 36.1 months, 95%CI 0.0-85.9) and adult cohort (p = 0.094, 29.7 months, 95%CI 11.8-47.5). In this study, we show that IKZF1 status is associated with CRLF2-high and dismal outcomes in B-ALL patients regardless of age.

IKZF1 deletion and co-occurrence with other aberrations in a child with chronic myeloid leukemia progressing to acute lymphoblastic leukemia.

Chronic myeloid leukemia (CML) is a rare disease in children. Different from that in adults, childhood CML involves transformative events occurring over a short time period. CML transformation to lymphoid blast phase (BP) is associated with copy number abnormalities, characteristic of BCR-ABL1 positive acute lymphoblastic leukemia, but not of CML in the chronic phase. Here, we present an unusual case of CML progressing to BP in a 1.6-year-old child, harboring IKZF1, PAX5, CDKN2A, and ETV6 deletions at diagnosis. It remains to be addressed whether distinct mechanisms might account for CML pathogenesis in early childhood.

An uncommon t(9;11)(p24;q22) with monoallelic loss of ATM and KMT2A genes in a child with myelodysplastic syndrome/acute myeloid leukemia who evolved from Fanconi anemia.

BACKGROUND: Myelodysplastic syndrome (MDS) is rare in the pediatric age group and it may be associated with inheritable bone marrow failure (BMF) such as Fanconi anemia (FA). FA is a rare multi-system genetic disorder, characterized by congenital malformations and progressive BMF. Patients with FA usually present chromosomal aberrations when evolving to MDS or acute myeloid leukemia (AML). Thus, the cytogenetic studies in the bone marrow (BM) of these patients have an important role in the therapeutic decision, mainly in the indication for hematopoietic stem cell transplantation (HSCT). The most frequent chromosomal alterations in the BM of FA patients are gains of the chromosomal regions 1q and 3q, and partial or complete loss of chromosome 7. However, the significance and the predictive value of such clonal alterations, with respect to malignant progress, are not fully understood and data from molecular cytogenetic studies are very limited. CASE PRESENTATION: A five-year-old boy presented recurrent infections and persistent anemia. The BM biopsy revealed hypocellularity. G-banding was performed on BM cells and showed a normal karyotype. The physical examination showed to be characteristic of FA, being the diagnosis confirmed by DEB test. Five years later, even with supportive treatment, the patient presented severe hypocellularity and BM evolution revealing megakaryocyte dysplasia, intense dyserythropoiesis, and 11% myeloblasts. G-banded analysis showed an abnormal karyotype involving a der(9)t(9;11)(p24;q?22). The FISH analysis showed the monoallelic loss of ATM and KMT2A genes. At this moment the diagnosis was MDS, refractory anemia with excess of blasts (RAEB). Allogeneic HSCT was indicated early in the diagnosis, but no donor was found. Decitabine treatment was initiated and well tolerated, although progression to AML occurred 3 months later. Chemotherapy induction was initiated, but there was no response. The patient died due to disease progression and infection complications. CONCLUSIONS: Molecular cytogenetic analysis showed a yet unreported der(9)t(9;11)(p24;q?22),der(11)t(9;11)(p24;q?22) during the evolution from FA to MDS/AML. The FISH technique was important allowing the identification at the molecular level of the monoallelic deletion involving the KMT2A and ATM genes. Our results suggest that this chromosomal alteration conferred a poor prognosis, being associated with a rapid leukemic transformation and a poor treatment response.

Estado Nutricional de Pacientes Pediátricos Recém-Diagnosticados com Leucemia Linfoblástica Aguda em um Instituto de Referência em Oncologia do Rio de Janeiro / Nutritional Status of Pediatric Patients Newly Diagnosed with Acute Lymphoblastic Leukemia at an Institute of Reference in Oncology of Rio de Janeiro / Estado Nutricional de Pacientes Pediátricos Recién diagnosticados con leucemia linfoblástica Aguda en un Instituto de Referencia en Oncología de Río de Janeiro

Introdução: a leucemia linfoblástica aguda (lla) constitui a neoplasia mais comum em pediatria e a avaliação nutricional é um instrumento essencial para conhecer as condições de saúde dos pacientes. o presente estudo teve como objetivo avaliar e descrever o estado nutricional de pacientes pediátricos recém-diagnosticados com lla e verificar a relação do índice de massa corporal para idade (iMc/i) com as demais medidas antropométricas. Método: estudo observacional, transversal, realizado com pacientes de 1 a 18 anos, recém- -diagnosticados com lla, no período de janeiro/2004 a dezembro/2009. os dados coletados foram idade, peso corporal, estatura, prega cutânea tricipital (Pct), circunferência do braço (cB) e circunferência muscular do braço (cMB). o iMc foi calculado e a classificação iMc/i utilizada na análise. o teste Qui-quadrado de Pearson e exato de Fisher foram utilizados para analisar a associação entre os parâmetros antropométricos. Resultados: Foram incluídos no estudo 54 pacientes. a classificação do "estado nutricional adequado" foi a mais frequente em todos os parâmetros antropométricos. em adição, observou-se que a associação do estado nutricional pela cMB com o iMc/i (p=0,001) demonstra que este último pode ser adequado para classificação dos pacientes pediátricos com lla ao diagnóstico. e a concordância da cB com a cMB (p=0,01) de 43% (p=0,001) também ratifica a utilização da cB frente à cMB, por ser uma medida mais simples. Conclusão: na população estudada, o estado nutricional encontrava-se preservado. assim como a associação da cMB com o iMc/i, a cB demonstrou ser um parâmetro sensível para classificar eutrofia.

Introduction: acute lymphoblastic leukemia (all) is the most common neoplasm in pediatrics, and nutritional assessment is an essential tool for understanding patients' health conditions. The present study aimed to evaluate and describe the nutritional status of pediatric patients newly diagnosed with all and to verify the relation between body mass index for age (BMi-for-age) and other anthropometric measurements. Method: a cross-sectional, observational study was performed with patients from 1 to 18 years of age, newly diagnosed with all, from January 2004 to december 2009. The data collected were age, body weight, height, triceps skinfold (ts), arm circumference (ac) and arm muscle circumference (aMc). The BMi was calculated and the BMi-for-age classification used in the analysis. Pearson's chi-square test and Fisher's exact test were used to analyze the association between anthropometric parameters. Results: 54 patients were included in the study. The classification of "adequate nutritional status" was the most frequent in all anthropometric parameters. in addition, we observed that the association of nutritional status by aMc with BMi-for-age (p=0.001) shows that the BMi-for-age may be adequate for classification of pediatric patients with all at diagnosis. in addition, ac agreement with aMc (p=0.01) of 43% (p=0.001) also confirmed the use of ac versus aMc, as it is a simpler measure. Conclusion: in the studied population the nutritional status was preserved. Just as the association of aMc with BMi-for-age, ac has been shown to be a sensitive parameter for classifying eutrophy

Introducción: la leucemia linfoblástica aguda (lla) constituye la neoplasia más común en pediatría y la evaluación nutricional es un instrumento esencial para conocer las condiciones de salud de los pacientes. el presente estudio tuvo como objetivo evaluar y describir el estado nutricional de pacientes pediátricos recién diagnosticados con lla y verificar la relación del Índice de masa corporal por edad (iMc/i) con las demás medidas antropométricas. Método: estudio observacional, transversal, realizado con pacientes de 1 a 18 años recién diagnosticados con lla en el período de enero / 2004 a diciembre / 2009. los datos recogidos fueron edad, peso corporal, estatura, pliegue cutáneo tricipital (Pct), circunferencia del brazo (cB) y circunferencia muscular del brazo (cMB). el iMc fue calculado y la clasificación iMc/i utilizada en el análisis. la prueba chi-cuadrado de Pearson y exacto de Fisher se utilizaron para analizar la asociación entre los parámetros antropométricos. Resultados: se incluyeron en el estudio 54 pacientes. la clasificación del "estado nutricional adecuado", fue la más frecuente, en todos los parámetros antropométricos. en adición, se observo que la asociación del estado nutricional por la cMB con el iMc/i(p=0,001) demuestra que este último puede ser adecuado para clasificación de los pacientes pediátricos con lla al diagnóstico. Y la concordancia de la cB con la cMB (p=0,01) del 43% (p=0,001), también ratifica la utilización de la cB frente a la cMB, por ser una medida más simple. Conclusión: en la población estudiada el estado nutricional se encontraba preservado. así como la asociación de la cMB con el iMc/i, la cB demostró ser un parámetro sensible para clasificar eutrofia.

Estado nutricional e desfechos clínicos em pacientes pediátricos com leucemia linfoblástica aguda / Nutritional status and clinical outcomes in pediatric patients with acute lymphoblastic leukemia / Estado nutricional y los resultados clínicos en pacientes pediátricos con leucemia linfoblástica aguda

Introdução: A leucemia linfoblástica aguda é a neoplasia mais comum na população pediátrica, e estudos apontam o estado nutricional como um fator prognóstico importante. Objetivo: Avaliar o estado nutricional de uma coorte de crianças e adolescentes durante o tratamento para leucemia linfoblástica aguda, determinar a sua associação com o risco de recaída e com a sobrevida em cinco anos de seguimento. Método: Estudo observacional, retrospectivo, com 54 pacientes de 1 a 18 anos com leucemia linfoblástica aguda, tratados em um hospital de referência em oncologia, entre janeiro de 2004 e dezembro de 2009. Os dados antropométricos foram coletados pela equipe de pesquisadores, nos prontuários, no período de junho a outubro de 2015. Verificaram-se a incidência de recaída e o óbito nos pacientes estudados em cinco anos de seguimento. Resultados: Houve predomínio do sexo masculino (55,6%) e a mediana de idade foi de 7,0 anos no início do seguimento. Observou-se um aumento significativo no escore-z médio do índice de massa corporal para idade durante o tratamento de 0,13±1,19 ao diagnóstico para 0,72±1,07 no início da fase de manutenção (p=0,000). No presente estudo, o estado nutricional ao diagnóstico não foi determinante para o risco de recaída. As curvas de sobrevida não foram diferentes entre os pacientes com ou sem excesso de peso ao diagnóstico. Conclusão: Na população estudada, observou-se um ganho ponderal significativo durante o tratamento, porém não foi encontrada associação entre estado nutricional ao diagnóstico e risco de recaída, e não se verificou influência do excesso de peso na sobrevida.

Introduction: Acute Lymphoblastic Leukemia is the most common neoplasm in the pediatric population, and studies point to nutritional status as an important prognostic factor. Objective: To evaluate the nutritional status of a cohort of children and adolescents during treatment for acute lymphoblastic leukemia, to determine its association with risk of relapse and survival at five years of follow-up Method: Observational retrospective study of 54 patients aged 1 to 18 years old with acute lymphoblastic leukemia treated at an oncology reference hospital, between January 2004 and December 2009. The anthropometric data were collected by the team of researchers from the medical records, from June to October 2015. The incidence of relapse and death was verified in the patients studied at five years of follow-up. Results: There was a predominance of males (55.6%) and the median age was 7.0 years at the beginning of followup. A significant increase was observed in the mean z-score of the Body Mass Index for age during treatment, from 0.13±1.19 at diagnosis to 0.72±1.07 at the beginning of the maintenance phase (p=0.000). In the present study, the nutritional status at diagnosis was not decisive for the risk of relapse. Survival curves did not differ between patients who were and were not overweight at diagnosis. Conclusion: In the studied population, a significant weight gain was observed during treatment, but no association was found between nutritional status at diagnosis and risk of relapse, and no influence of overweight on survival was observed.

Introducción: La leucemia linfoblástica aguda es el cáncer más común en los pacientes pediátricos, y los estudios indican el estado nutricional como un factor pronóstico importante. Objetivo: Evaluar el estado nutricional de una cohorte de niños y adolescentes durante el tratamiento para la leucemia linfoblástica aguda, determinar su asociación con el riesgo de recaídas y la supervivencia a los cinco años de seguimiento. Método: estudio observacional, retrospectivo con 54 pacientes de 1 a 18 años con leucemia linfoblástica aguda tratados en un hospital de referencia en oncología, entre enero de 2004 y diciembre de 2009. Los datos antropométricos fueron recogidos por el equipo de investigadores, en los prontuarios, en el período de junio a octubre de 2015. Se verificó la incidencia de recaída y muerte en los pacientes en cinco años de seguimiento. Resultado: Hubo un predominio del sexo masculino (55,6%) y la edad mediana fue de 7,0 años al inicio del estudio. Se observó un aumento significativo en el escore-z medio del índice de masa corporal para la edad durante el tratamiento, de 0,13±1,19 en el diagnóstico para 0,72±1,07 en el período de mantenimiento (p=0,000). En este estudio, el estado nutricional al momento del diagnóstico no fue decisivo para el riesgo de recaída. Las curvas de supervivencia no fueron diferentes entre los pacientes con o sin exceso de peso al momento del diagnóstico. Conclusión: En la población estudiada, hubo un aumento significativo de peso durante el tratamiento, pero no se encontró asociación entre el estado nutricional al momento del diagnóstico y el riesgo de recaída y no hubo influencia del exceso de peso en la supervivencia.ncia, basándose en los estudios de las necesidades físicas, emocionales, sociales y económicos de este creciente grupo.

Treatment of children with B-cell non-Hodgkin's lymphoma in developing countries: the experience of a single center in Brazil.

PURPOSE: To treat non-Hodgkin's B-cell lymphoma (B-NHL) in children with manageable toxicity-related morbidity and without any decrease in survival. PATIENTS AND METHODS: Between January 1998 and April 2003, 53 consecutive patients (age 16 years or less) from a single institution were enrolled. The patients were stratified by risk factors (stage and LDH level) and treated with a BFM 86/90 (Berlin-Frankfurt-Münster)-based protocol with reduction of the methotrexate dose from 5 mg/m to 2 mg/m. RESULTS: The mean age of the patients was 6 years (range 1-16 years). Seventy-two percent of the patients had lymphomas classified as Burkitt type, 11% as diffuse large cell lymphoma, and 6% as Burkitt-like lymphoma, and 11% were not classified. At a median follow-up of 35 months, 44 patients (83%) survived in complete remission. The event-free survival rate for all patients was 78% (SE = 0.07): 100% (SE = 0.0) for stage I/II patients and 74% (SE = 0.08) for stage III/IV patients. Six patients suffered initial treatment failure and one patient relapsed, all of whom died. There was only one death from sepsis related to treatment. CONCLUSIONS: This strategy was very effective for treating B-NHL in a developing country. The results were comparable to those of the BFM 90 study and other contemporary groups and represented an increase in the cure rates in childhood B-NHL in Brazil.