Avaliação da eficácia e segurança de pegaspargase, em comparação à L-asparaginase, e sua viabilidade econômica no tratamento de leucemia linfoblástica aguda / Evaluation of the efficacy and safety of pegaspargase, compared to L-asparaginase, and its economic viability in the treatment of acute lymphoblastic leucemia

Introdução: O tratamento da leucemia linfoblástica aguda (LLA) é relacionado a eventos adversos (EA) e mortalidade por toxicidade dos medicamentos utilizados. Protocolos com L-asparaginase (L-Asp) têm demonstrado melhor prognóstico, porém podem causar hipersensibilidade e desenvolvimento de anticorpos neutralizantes por ser produzida a partir da Escherichia coli. A conjugação de E. coli L-Asp com monometoxipolietilenoglicol resulta na PEG-Asp, com menor imunogenicidade e maior meia-vida. Objetivo: Avaliar eficácia e segurança da PEG-Asp, em comparação à L-Asp, no tratamento de LLA, e sua viabilidade econômica para subsidiar a tomada de decisão quanto à sua incorporação. Material e Métodos: Estudo descritivo de síntese de evidências e avaliação econômica. Busca de evidências foi realizada no MEDLINE, Cochrane Library, Embase, Epistemonikos, e agências de avaliação de tecnologias em saúde. Foram considerados elegíveis revisões sistemáticas, ensaios clínicos e estudos observacionais, publicados em inglês, espanhol e português, independente da data. Viabilidade econômica foi calculada a partir do custo do uso da PEG-Asp no protocolo GRAALL ­ 2003 frente ao valor faturado via Autorização de Procedimentos de Alta Complexidade. Resultados: As evidências demonstraram eficácia semelhante entre PEG-Asp e L-Asp para maioria dos desfechos de interesse, com superioridade na prevenção de leucemia no sistema nervoso central em adultos e comodidade posológica. PEG-Asp demonstrou maior frequência de EA em adultos recém diagnosticados, e ausência de diferença na toxicidade e mortalidade nos recidivados. A incorporação da PEG-Asp se mostrou economicamente viável para pacientes adultos, e desvantajosa naqueles com 18 e 19 anos incompletos, considerando superfície corpórea média de 1,7m². Conclusão: Recomendou-se a incorporação de PEG-Asp para tratamento de LLA em pacientes acima de 18 anos e naqueles com 18 a 19 anos incompletos, deve-se avaliar a viabilidade econômica em função da superfície corpórea. Além do perfil de eficácia e segurança da PEG-Asp, não há medicamentos dessa classe terapêutica com registro para adultos na Agência Nacional de Vigilância Sanitária.

Introduction: Treatment of acute lymphoblastic leukemia (ALL) is associated with adverse events (AEs) and mortality due to toxicity of drugs used. Protocols with L-asparaginase (L-Asp) have shown improved prognosis, but can cause hypersensitivity and development of neutralizing antibodies, as L-Asp is produced from Escherichia coli. The conjugation of E. coli L-Asp with monomethoxypolyethylene glycol results in PEG-Asp, with lower immunogenicity and longer half-life. Objective: To evaluate the efficacy and safety of PEG-Asp, compared to L-Asp, in ALL treatment, and its economic viability in order to subsidize decision making regarding its incorporation. Material and Methods: Descriptive study of evidence synthesis and economic evaluation. Evidence was searched in MEDLINE, Cochrane Library, Embase, Epistemonikos, and Health technology assessment agencies. Systematic reviews, clinical trials and observational studies published in English, Spanish and Portuguese, regardless of date, were considered eligible. Economic viability was calculated based on the cost of using PEG-Asp in GRAALL - 2003 protocol compared to the amount billed via High-complexity Procedures Authorization. Results: Evidence showed similar efficacy between PEG-Asp and L-Asp for most of the outcomes of interest, with superiority in prevention of Central Nervous System leukemia in adults and in dosage convenience. PEG-Asp showed a higher frequency of AEs in newly diagnosed adults, and no difference in toxicity and mortality in relapsed adults. The incorporation of PEG-Asp proved to be economically viable for adult patients, and disadvantageous for patients between 18 and 19 years of age, considering a mean body surface area of 1.7m². Conclusion: Incorporation of PEG-Asp for the treatment of ALL in patients over 18 years was recommended, and in those aged 18 to 19 years incomplete, the economic viability should be assessed according to body surface area. In addition to the efficacy and safety profile of PEG-Asp, there are no drugs in this therapeutic class for adults registered within ANVISA.

COVID-19 infection during blinatumomab therapy: Is safety a dilemma?

Patients with acute lymphoblastic leukemia may be particularly vulnerable to SARS-CoV-2 infection and severe illness. The mainstay of current treatment is the use of blinatumomab in patients with refractory or relapsed B-cell precursor acute lymphoblastic leukemia. We discuss the case of a patient with relapsed acute lymphoblastic leukemia who became positive for SARS-CoV-2 during blinatumomab therapy. There are no formal recommendations on the decision to continue, withhold, or delay blinatumomab treatment in these patients. More studies exploring this issue are warranted, as SARS-CoV-2 is expected to be here to stay.

Cytopathological diagnosis of herpes simplex virus infection causing oral aphthous ulcers in a patient with acute lymphocytic leukemia: case report / Diagnóstico citopatológico de infecção pelo vírus herpes simples causando úlceras aftosas orais em paciente com leucemia linfocítica aguda: relato de caso

Aim:This paper aims to report an atypical oral HSV infection diagnosed by cytopathological examination in a patient with acute lymphocytic leukemia. Case report: A nine-year-old white female was admitted with acute lymphocytic leukemia, presenting ulcers covered with pseudomembrane and spontaneous bleeding on the left soft palate, measuring approximately 2 cm, as well as other ulcers measuring 1 cm on the left lateral border of the tongue. Exfoliative cytopathology revealed neutrophils and cytopathic effects of HSV in the keratinocytes in a fibrin background. Based on the exfoliative examination, the diagnosis of HSV infection was obtained. Conclusion: Oral HSV infection can be atypical in immunocompromised patients and can cause high morbidity and mortality. Healthcare professionals, especially those working in a hospital environment, should be aware of the possibility of HSV infection in atypical lesions in these patients and evaluate the need to include antiviral prophylactic therapy.

Objetivo:Este trabalho tem como objetivo relatar uma infecção oral atípica por HSV diagnosticada por exame citopatológico em um paciente com leucemia linfocítica aguda. Relato de caso:Paciente do sexo feminino, nove anos, branca, portadora de leucemia linfocítica aguda, apresentando úlceras recobertas por pseudomembrana e sangramento espontâneo em palato mole esquerdo medindo aproximadamente 2 cm, além de outras úlceras medindo 1 cm na borda lateral esquerda da língua. A citopatologia esfoliativa revelou neutrófilos e efeitos citopáticos do HSV nos ceratinócitos em um fundo de fibrina. Com base no exame esfoliativo, foi obtido o diagnóstico de infecção por HSV. Conclusão: A infecção oral por HSV pode ser atípica em pacientes imunocomprometidos e pode causar alta morbidade e mortalidade. Os profissionais de saúde, principalmente os que atuam em ambiente hospitalar, devem estar atentos à possibilidade de infecção pelo HSV em lesões atípicas nesses pacientes e avaliar a necessidade de inclusão de terapia antiviral profilática.

Predictive Factors and Outcomes after Allogeneic Stem Cell Transplantation for Adults with Acute Lymphoblastic Leukemia in Brazil.

Allogeneic stem cell transplantation (HSCT) remains a potentially curative approach for acute lymphoblastic leukemia (ALL), especially for high-risk patients and those with relapsed/refractory disease, although its efficacy is offset by a not-negligible toxicity. Adult patients with ALL fare worse in developing countries, with little data about the HSCT in this setting. In this study, we aimed to describe outcomes and examine risk factors for overall survival (OS), leukemia-free survival (LFS), cumulative incidence of relapse (CIR), nonrelapse mortality (NRM), and graft-versus-host disease (GVHD) after HSCT for ALL in Brazilian centers. This retrospective registry study included patients with ALL or ambiguous lineage leukemia age >16 years who underwent a first HSCT at 5 Brazilian centers between January 2007 and December 2017. A total of 275 patients were included, with a median age of 31 years (range, 16 to 65 years). Thirty-five percent were Philadelphia chromosome-positive. A matched sibling donor was used in 53%, a matched unrelated donor (MUD) in 19%, a mismatched unrelated donor in 9%, a haploidentical donor in 19%, and umbilical cord blood in 5%. The engraftment failure rate was 1.5%. The 5-year cumulative incidence of acute grade II-IV was 54.2%, and that of chronic GVHD was 26.2%. Five-year CIR and NRM were 28.1% and 34.1%, respectively. Central nervous system involvement at diagnosis (hazard ratio [HR], 2.2) and disease status (HR, 1.8 for second or later complete response and 7.9 for refractory) were associated with increased relapse incidence, whereas the use of peripheral blood graft (HR, .51) and a haploidentical donor (HR, .4) significantly decreased relapse incidence. Five-year OS and LFS were 40.7% (95% confidence interval [CI], 35.1-47.1) and 37.8% (95% CI, 32.3-44.1), respectively. Patient age, donor age, and disease status were independently associated with OS and LFS. Pre-HSCT positivity of minimal residual disease (>.01%) was associated with worse LFS (HR, 1.47) in available cases. This is the largest series of adults with ALL undergoing HSCT from Brazil reported to date. Although OS and LFS were similar to data reported in the literature, NRM was higher. Patient age and donor age outweighed donor type or graft source in our analysis. Interestingly, haploidentical HSCT was associated with lower CIR, whereas the use of MUDs was associated with higher NRM and GVHD rates. These results impact donor selection strategy in Brazil with the aim of offering timely HSCT for high-risk ALL patients in our setting.

Induction-related mortality in adolescents and young adults with acute lymphoblastic leukemia in a resource-limited setting: do treatment-related complications create more impact than disease biology?

BACKGROUND: Acute lymphoblastic leukemia (ALL) is a malignant clonal bone marrow disorder with a high mortality rate during the initial therapy. This retrospective study aimed to describe and analyze the risk factors and causes of induction-related mortality (IRM) in an adolescent and adult ALL population treated in a low- and middle-income country. METHODS: From 2009 to 2016, a total of 167 patients were included, of which 50.9% were male with a median age of 28 years. B-immunophenotype represented 97.6%, and high-risk cytogenetics were present in 23.3%. During induction therapy, 91% had at least 1 complication, most of which were infectious, with an IRM of 12%. RESULTS: Factors associated with increased mortality rate were central nervous system (CNS) status [CNS-3: hazard ratio (HR) 3.029; 95% confidence interval (CI), 0.79‒11.49; P =0.103 and CNS-2: HR, 9.98; 95% CI, 2.65‒37.65; P =0.001] and dialysis requirement (HR, 9.15; 95% CI, 2.44‒34.34; P =0.001). CONCLUSION: Our study confirms that ALL patients treated in resource-constrained settings have high rates of IRM, mainly attributed to advanced disease and high tumor burden at diagnosis.

Quimioterapia intensiva asociada a imatinib en leucemia linfoblástica aguda del adulto, Philadelphia positivo. Experiencia en un hospital público / Intensive chemotherapy with tyrosine kinase inhibitors in philadelphia-positive acute lymphoblastic leukemia

Background: Before the advent of tyrosine kinase inhibitors (TKIs), patients with Philadelphia-positive Acute Lymphoblastic Leukemia (Ph+ALL) had a poor prognosis. The association of TKIs to intensive chemotherapy (CT) improved outcome. Aim: To evaluate results of an intensive CT protocol including TKI in a public hospital in Santiago, Chile. Material and Methods: All patients with Ph+ALL diagnosed between January 2010 and February 2019, and who met inclusion criteria for intensive CT, received the Ph+ALL national protocol in association with imatinib and were included in this analysis. Results: Thirty-five patients aged 15 to 59 years received treatment. Complete response (CR) was obtained in 97%. Measurable residual disease (MRD) was negative in 61% (19/31 evaluable cases) during follow-up, and 55% (16/29) were MRD (-) before three months. Relapse was observed in 13 cases. Three patients underwent allogeneic hematopoietic stem cell transplant (HSCT), two in CR1. The overall survival (OS) and event-free survival (EFS) at three years were 52 and 34%, respectively. In patients who achieved MRD negativity before three months, no statistically significant differences in OS (64 and 42% respectively, p = 0.15) or EFS (35 and 32% respectively, p = 0.37) were observed. Conclusions: The prognosis of Ph+ALL improved with the association of imatinib to intensive CT. MRD-negative status before three months in this series was not significantly associated with better outcomes. Our series suggests that the Ph+ALL national protocol associated to TKI is a therapeutic alternative with high CR and aceptable MRD (-) rates.

Adipokines in young survivors of childhood acute lymphocytic leukemia revisited: beyond fat mass.

PURPOSE: This cross-sectional study evaluated the relationship between adipokines (leptin, adiponectin, visfatin, and resistin) and adiposity indexes regarding sex and cranial radiotherapy exposure among young acute lymphocytic leukemia survivors. METHODS: A multivariate analysis of covariance (MANCOVA) was used to evaluate the joint effect of sex, cranial radiotherapy, and body mass index (BMI) z-score (model 1) or fat mass index (FMI) (model 2) on adipokines. RESULTS: This study included 55 survivors of childhood acute lymphocytic leukemia between 15 and 23 years of age from both sexes (56.4% female); 43.6% of the sample had undergone cranial radiotherapy (18-24 Gy). The BMI z-score, the FMI, and sex (P<0.050 for all) influenced at least one adipokine, while cranial radiotherapy exposure was marginal in model 2. Parameter estimates from the MANCOVA's final model showed that the BMI z-score (ß=-0.437, P=0.010) and the FMI (ß=-0.209, P=0.004) negatively influenced adiponectin, while the FMI positively affected resistin (ß=0.142, P=0.020). The relationship between leptin, visfatin, and the adiposity ndexes could not be established. In model 1, females presented with increased adiponectin (ß=-1.014, P=0.011) and resistin (ß=-1.067, P=0.002) levels; in model 2, female sex positively affected adiponectin (ß=-1.515, P=0.001) and marginally influenced resistin (ß=-0.707, P=0.054) levels. Cranial radiotherapy negatively determined visfatin levels in both final models (P<0.050). CONCLUSION: Changes in body fat may be associated with adipose tissue dysfunction and should be carefully evaluated in survivors of acute lymphocytic leukemia, considering both sex and cranial radiotherapy exposure, to treat disorders that may possibly aggravate their risk for early cardiovascular disease.

Frecuencias genotípicas en Niños con Leucemia Linfoblástica Aguda en dos centros Oncológicos / Genotypic frequencies in Children with Acute Lymphoblastic Leukemia in two Oncology centers

Introducción: La leucemia linfoblásticaaguda (LLA) es una de las oncopatologías más frecuentes a nivel infantil, ocupando el primer lugar de los cincos tipos de cáncer con mayor incidencia en Ecuador. El objetivodel estudio fue determinar las frecuencias genotípicas y alélicas delos polimorfismos genéticos de MTHFR 677C>T (rs1801133) y MTHFR 1298A>C(rs1801131) en niños con leucemia linfoblástica aguda de SOLCA ­Loja y SOLCA ­Cuenca. Métodos:Es un estudio transversal, donde se evaluó a 160 pacientes pediátricosdiagnosticados con LLA. La detección de lospolimorfismos MTHFR 677C>T y 1298A>C se realizó mediante la técnica PCR entiempo real. El análisis estadístico descriptivo se desarrolló a través del software IBM SPSS (versión 22) y el programa bioinformático SNPStats. Resultados: Se determinóque las frecuencias genotípicas para el SNP MTHFR 677C>T fueron 25% C/C y 75%C/T con una frecuencia alélica del 38% para el alelo mutado (T). Para el SNP MTHFR1298 A>C se encontró una frecuencia genotípica de 2% A/A, 16% A/C y 82% C/C, entanto que su frecuencia alélica fue del 90% para el alelo mutado (C). No se encontróasociación genotípica ni alélica con ninguna de las variables intervinientes (p>0.05),así como tampoco se manifestó una correlación estadísticamente significativa de lospolimorfismos en mención y el tipo de riesgo de LLA. Conclusión:En la población estudiada con LLA, se evidenció para el SNP de MTHFR 677C>T una frecuencia genotípica del 75% para el heterocigoto C/T. Para el SNP MTHFR 1298A>C se encontró una frecuencia genotípica del 82% para el homocigoto mutado C/C. La distribución de la frecuencia alélica se mostró de la siguiente manera: para MTHFR 677C>T se obtuvo 38% para el alelo mutado T y en cuanto a MTHFR 1298 A>C, 90% correspondió para el alelo mutado C. En el análisis estadístico no se encontró asociación genotípica ni alélica con las variablesdemográficas y clínicas

Introduction:Acute lymphoblastic leukemia (ALL) is one of the most frequent oncopathologiesin childhood, occupying the first place of the five types of cancer with the highest incidence in Ecuador. The objective of the study was to determine the genotypic and allelic frequencies of the genetic polymorphisms of MTHFR 677C> T (rs1801133) and MTHFR 1298A> C (rs1801131) in children with acute lymphoblastic leukemia from SOLCA -Loja and SOLCA -Cuenca. Methods: It is a cross-sectional study, where 160 pediatric patients diagnosed with ALL were evaluated. The detection of MTHFR 677C> T and 1298A> C polymorphisms was performed using the real-time PCR technique. The descriptive statistical analysis was developed using the IBM SPSS software (version 22) and the SNPStats bioinformatics program. Results: It was determined that the genotype frequencies for the SNP MTHFR 677C> T were 25% C / C and 75% C / T with an allele frequency of 38% for the mutated allele (T). For the SNP MTHFR 1298 A> C, a genotype frequency of 2% A / A, 16% A / C and 82% C / C was found, while its allelic frequency was 90% for the mutated allele (C). No genotypic or allelic association was found with any of the intervening variables (p> 0.05), as well as no statistically significant correlation of the mentioned polymorphisms and the type of risk of ALL. Conclusion: In the population studied with ALL, a genotypic frequency of 75% was evidenced for the MTHFR 677C> T SNP for the heterozygous C / T. For the SNP MTHFR 1298A> C, a genotypic frequency of 82% was found for the homozygous mutated C / C. The allelic frequency distribution was shown as follows: for MTHFR 677C> T, 38% was obtained for the mutated allele T and for MTHFR 1298 A> C, 90% corresponded to the mutated allele C. In the statistical analysis No genotypic or allelic association was found with demographic and clinical variables

Outpatient low toxic regimen with bortezomib in relapsed/refractory acute lymphoblastic leukemia in pediatrics and AYA patients: Single-center Mexican experience.

Relapsed or refractory acute lymphoblastic leukemia represents a major challenge in low- and middle-income countries where new therapies are not easily accessible. Combinations of cost-effective drugs should be considered as a bridge for hematopoietic stem cell transplantation. We retrospectively analyzed pediatric and adolescent and young adult patients who received reinduction with a protocol based on l-asparaginase, doxorubicin, vincristine, dexamethasone, and bortezomib (BZ). Fifteen patients were included. Total complete response (CR) was achieved by nine of 15 patients (60%); five patients achieved CR with negative minimal residual disease, two achieved complete morphological response (CR), and two complete morphological response without platelet recovery. Eleven patients (73%) were not hospitalized and 10 (66%) did not require any blood component transfusions. There were no cases of serious toxicity or mortality. Nine patients (60%) underwent transplant. Five-year overall survival was 40%. This BZ-based protocol is effective and safe when administered as an outpatient regimen and feasible in a low resource setting.

Brainstem auditory pathway of children with acute lymphoid leukemia on chemotherapy with methotrexate / Via auditiva em tronco encefálico de crianças com leucemia linfoide aguda em quimioterapia com metotrexato

Abstract Objective: Investigate the auditory pathway in the brainstem of children with acute lymphoblastic leukemia submitted to chemotherapy (by intravenous or intrathecal infusion). Methods: Fourteen children aged between 2 and 12 years with diagnosis of acute lymphoid leukemia were evaluated. The following procedures were used: meatoscopy, acoustic immitance measurements, tonal audiometry, vocal audiometry, transient otoacoustic emissions, and auditory brainstem response. Results: From the 14 children with normal auditory thresholds, 35.71% showed an alteration in auditory brainstem response, with a predominance of hearing impairment in the lower brainstem. It was found that 80% of the children with alteration had used intrathecal methotrexate less than 30 days and that 40% had the highest cumulative intravenous methotrexate doses. Conclusion: Children with acute lymphoblastic leukemia submitted to chemotherapy, present auditory pathway impairment in the brainstem, with a predominance of a low brainstem.

Resumo Objetivo: Investigar a via auditiva em tronco encefálico de crianças com leucemia linfoide aguda submetidas à quimioterapia (por infusão intravenosa ou por via intratecal). Métodos: Foram avaliadas 14 crianças com idade entre 2 e 12 anos, com diagnóstico de leucemia linfoide aguda. Foram utilizados os seguintes procedimentos: meatoscopia, medidas de imitância acústica, audiometria tonal, audiometria vocal, emissões otoacústicas transientes e potencial evocado auditivo de tronco encefálico. Resultados: Das 14 crianças com limiares auditivos normais, 35,71% demonstraram alteração no Potencial Evocado Auditivo de Tronco Encefálico, com predomínio de comprometimento de via auditiva em tronco encefálico baixo. Verificou-se que 80% das crianças com alteração haviam feito uso do metotrexato via intratecal a menos de 30 dias e que 40% tinham as maiores doses acumulativas de metotrexato por via endovenosa. Conclusão: Crianças com leucemia linfoide aguda submetidas à quimioterapia apresentam comprometimento na via auditiva em tronco encefálico, com predomínio em tronco encefálico baixo.

Exposição a agrotóxicos e a leucemia linfocítica aguda em criança: uma revisão de escopo / Exposición a pesticidas y leucemia linfocítica aguda en niños: una revisión del alcance / Pesticide exposure and acute lymphocytic leukemia in children: a scope review

RESUMO Introdução: A Leucemia Linfocítica Aguda (LLA) é um tipo de câncer que acomete o processo hematopoiético e está diretamente relacionada a fatores genéticos e ambientais. Objetivo: Identificar na literatura a existência de associação entre a exposição à agrotóxicos e o desenvolvimento de Leucemia Linfocítica Aguda em crianças no cenário nacional e internacional. Métodos: Realizou-se uma revisão de escopo nas bases de dados LILACS, IBECS, MEDLINE, BDENF, CINAHL e bibliotecas Cochrane e Scielo e Google Scholar. Incluíram-se produções relacionadas à exposição por agrotóxicos e o desenvolvimento de Leucemia Linfocítica Aguda em crianças. Resultados: A revisão abrangeu 22 estudos publicados de 2008 a 2017. A associação da exposição a pesticidas com o desenvolvimento de LLA infantil deu-se na exposição materna aos pesticidas domésticos no período pré-concepção, gestacional e exposição da própria criança à pesticidas domésticos na primeira infância. Conclusão: Os resultados permitiram identificar as publicações sobre a associação entre o uso de agrotóxicos e o desenvolvimento de Leucemia Linfocítica Aguda em crianças. Entretanto, há a necessidade de novos estudos sobre a exposição de crianças à pesticidas domésticos, conhecimento sobre sua toxicidade e danos à saúde humana, assim como medidas para redução do uso.

RESUMEN Introducción: la Leucemia Linfocítica Aguda (LLA) es un tipo de cáncer que acomete el proceso hematopoyético y está directamente relacionada a factores genéticos y ambientales. Objetivo: identificar en la literatura la existencia de asociación entre la exposición a pesticidas y el desarrollo de Leucemia Linfocítica Aguda en niños ene les cenario nacional e internacional. Métodos: se realizó una revisión del alcance en las bases de datos LILACS, IBECS, MEDLINE, BDENF, CINAHL y bibliotecas Cochrane y Scielo y Google Scholar. Se incluyeron producciones relacionadas a la exposición por pesticidas yel desarrollo de Leucemia Linfocítica Aguda en niños. Resultados: la revisión abarcó 22 estudios publicados de 2008 a 2017. La asociación de la exposición a pesticidas con el desarrollo de LLA infantil ocurrióen la exposición materna a los pesticidas domésticos en el período preconcepción, gestacional y exposición del proprioniño a pesticidas domésticos en la primera infancia. Conclusión: los resultados permitieron identificar las publicaciones sobre la asociación entre el uso de pesticidas y el desarrollo de Leucemia Linfocítica Aguda en niños. Pero, hay la necesidad de nuevos estudios sobre la exposición de niños a pesticidas domésticos, conocimiento sobre su toxicidad ylos daños a la salud humana, así como medidas para la reducción del uso.

ABSTRACT Introduction: Acute Lymphocytic Leukemia (ALL) is a type of cancer that affects the hematopoietic process and is directly related to genetic and environmental factors. Objective: To identify in the literature the existence of an association between exposure to pesticides and the development of Acute Lymphocytic Leukemia in children in the national and international scenario. Methods: A scoping review was carried out in the LILACS, IBECS, MEDLINE, BDENF, CINAHL databases, and Cochrane and Scielo and Google Scholar libraries. Production related to pesticide exposure and the development of Acute Lymphocytic Leukemia in children were included. Results: The review had 22 studies published from 2008 to 2017. The association of pesticide exposure with the development of childhood ALL was due to maternal exposure to domestic pesticides in the pre-conception, gestational period, and the child's exposure to domestic pesticides in early childhood. Conclusion: The results allowed us to identify publications on the association between the use of pesticides and the development of Acute Lymphocytic Leukemia in children. However, there is a need for further studies on children's exposure to domestic pesticides, knowledge of their toxicity, and damage to human health, as well as measures to reduce its use.

Acute lymphocytic leukemia associated with toxoplasmosis: case report / Leucemia linfoblástica aguda associada à toxoplasmose: relato de caso

ABSTRACT Rare clinical case of acute lymphocytic leukemia (ALL) associated with toxoplasmosis affecting a 23-year-old male patient with progressive dyspnea. Chest computed tomography revealed expansive lesions indicating right supraclavicular fossa lymph node enlargement and right pleural effusion. Toxoplasmosis serology was performed: positive for immunoglobulin G [(IgG) 180.6] and positive for immunoglobulin M [(IgM) 0.98]. Therefore, treatment for the infection was initiated and immunohistochemistry of left cervical lymph node revealed ALL. Consequently, chemotherapy treatment was introduced at an oncology center. The diagnosis of toxoplasmosis allowed treatment to be administered, preventing the worsening of the condition caused by chemotherapy-induced immunosuppression.

RESUMEN Reportamos un caso clínico raro de leucemia linfocítica aguda (LLA) asociada a toxoplasmosis en un paciente masculino de 23 años con cuadro de disnea progresiva. La tomografía de tórax reveló lesiones expansivas, indicando agrandamiento de los ganglios linfáticos en fosa supraclavicular derecha y derrame pleural a la derecha. Examen serológico para toxoplasmosis: inmunoglobulinas G (IgG) e inmunoglobulinas M (IgM) positivas - 180,6 y 0,98, respectivamente. Se inició el tratamiento de la infección; la inmunohistoquímica de ganglio linfático cervical izquierdo reveló LLA. Se llevó a cabo la quimioterapia en un hospital oncológico. El diagnóstico de toxoplasmosis permitió hacer el tratamiento, impidiendo que la inmunosupresión inducida por la quimioterapia agravara el cuadro clínico.

RESUMO Relatamos um caso clínico raro de leucemia linfoblástica aguda (LLA) associada à toxoplasmose em um paciente do sexo masculino, 23 anos, com quadro de dispneia progressiva. A tomografia de tórax revelou lesões expansivas, indicando linfonodomegalias em fossa supraclavicular direita e derrame pleural à direita. Sorologia realizada para toxoplasmose: imunoglobulinas da classe G (IgG) e da classe M (IgM) positivas - 180,6 e 0,98, respectivamente. Tratamento para a infecção foi iniciado; estudo imuno-histoquímico de linfonodo cervical esquerdo foi realizado, revelando LLA. Institui-se tratamento quimioterápico em centro oncológico. O diagnóstico de toxoplasmose permitiu que o tratamento fosse feito, impedindo que a imunossupressão induzida pela quimioterapia agravasse o quadro clínico.

Candida on oral cavity of pediatric individuals with ALL and its susceptibility to nystatin and amphotericin B / Candida na cavidade oral de indivíduos pediátricos com LLA e sua susceptibilidade à nistatina e à anfotericina B

ABSTRACT Objective: The aim of this study was to evaluate the prevalence of Candida colonizationon oral cavity of pediatric individuals with acute lymphocytic leukemia (ALL) and its susceptibility/resistance to nystatin and amphotericin B. Methods: This was a cross sectional study with observational, descriptive and analytic approach. Saliva was collected from40 individuals diagnosed with ALL and from40 healthy subjects, as a comparative group, matched by age and gender with ALL group. The mean age for both groups were 8 years-old. The isolation and identification of the Candidaspecies were performed using the CHROMagarCandidaTM and confirmed by polymerase chain reaction. The samples were subjected to antifungal susceptibility by microdilution assay for nystatin and amphotericin B. Salivary alterations and chemotherapy-induced oralmucositis were evaluated using modifiedOral Assessment Guide. Results: The positivity to Candida was higher inALL individuals (32.5%,13/40)than in a comparative group(2.5%, 1/40) (p<0.001). Candida albicans was the most prevalent strain (86.6%). The mucositis was directly associated with positive Candidacolonization (p=0.017) in the ALL group but not related with salivary alterations (p= 0.479). Six strains of C. albicans (54.5%), on ALL group, were resistant to nystatin and all strains were not susceptible to amphotericin B. Conclusion: Candida colonization was associated with ALL condition and with oral mucositis in these individuals. C. albicans was the prevalent strain and most samples were resistant to antifungal agents tested, nystatin and amphotericin B.

RESUMO Objetivo: o objetivo deste estudo foi avaliar a prevalência e colonização de Candida na cavidade oral de indivíduos pediátricos com leucemia linfocítica aguda (LLA) e sua susceptibilidade/resistência à nistatina e à anfotericina B. Métodos: estudo transversal observacional com abordagem descritiva e analítica. A saliva foi coletada de 40 indivíduos diagnosticados com LLA e de 40 indivíduos saudáveis, como grupo comparativo, combinados por idade e sexo com o grupo LLA. A idade média para ambos os grupos foi de 8 anos de idade. O isolamento e a identificação das espécies de Candida foram realizados utilizando o CHROMagarCandidaTM e confirmados pela reação em cadeia da polimerase. As amostras foram submetidas a susceptibilidade antifúngica por meio de ensaio de microdiluição para nistatina e anfotericina B. As alterações salivares e a mucosite oral induzida por quimioterapia foram avaliadas utilizando o Guia de avaliação modificada. Resultados: A positividade para Candida foi superior aos indivíduos in situ (32,5%, 13/40) do que em um grupo comparativo (2,5%, 1/40) (p <0,001). Candida albicans foi a cepa mais prevalente (86,6%). A mucosite foi diretamente associada à colonização positive por Candida (p = 0,017) no grupo LLA, mas não relacionada com alterações salivares (p = 0,479). Seis estirpes de C. albicans (54,5%), no grupo LLA, eram resistentes à nistatina e todas as cepas não eram suscetíveis à anfotericina B. Conclusão: A colonização por Candida foi associada à condição LLA e à mucosite oral nesses indivíduos. C. albicans era a cepa predominante e a maioria das amostras eram resistentes aos agentes antifúngicos testados, nistatina e anfotericina B.

Efecto de la metformina en la etapa de inducción en pacientes con leucemia aguda linfoblástica y su impacto clínico en la supervivencia / Effect of metformin added to chemotherapy on the survival of patients with acute lymphoblastic leukemia

Background: Metformin has antineoplastic and cancer protective effects in vitro, sensitizing leukemia cells to chemotherapeutic agents, inducing apoptosis and cell cycle arrest. Aim: To assess the effect of metformin on the induction stage in patients with ALL and its impact on overall survival and relapse. Material and Methods. We included 123 patients treated with metformin and without metformin. The dose used was 850 mg PO at 8 h intervals. The survival analysis was used by Kaplan-Meier method, the difference between the distinct groups was performed using the log Rank test. Results. The overall survival at a median follow up of 700 days of follow-up was 43%, with a disease-free survival of 47%. Regarding the treatment groups, patients with metformin had a lower rate of relapse compared to the group receiving only chemotherapy (6.5% vs 17.1%, p = 0.006). Conclusions. The addition of metformin to the conventional treatment of ALL was associated with an improvement in survival, this association being independent of the type of biological risk at diagnosis.

Oral diseases in children with acute lymphoblastic leukemia with chemotherapy treatment / Alteraciones bucodentales en niños con leucemia linfoblástica aguda bajo tratamiento con quimioterapia

Background: Pediatric patients with acute lymphoblastic leukemia (ALL) usually develop oral manifestations due to the disease itself, as well as side effects of chemotherapy that severely affect their health and quality of life. The aim of this paperis to determine the prevalence of oral diseases in pediatric all patients with and without chemotherapy and its relation to the different phases of chemotherapy. Methods: A cross-sectional observational study was conducted in 103 pediatric patients with all between 3-15 years. They were classified into groups: without chemotherapy and with chemotherapy at phase of consolidation, enhancement, maintenance and monitoring. Clinical diagnosis was performed and gingival inflammation index (IMPA) and caries criteria (dmf and DMF) were applied. Results: The prevalence oral manifestations in the chemotherapy group were mucositis (98%), ulcers (90%), gingivitis (86%) and candidiasis (78%). The induction phase related with mucositis: RM = 7.6, 95%CI: 4.4-13, p = 0.0001; candidiasis: OR = 103, 95%CI: 13.0-818, p = 0.0001; gingivitis: OR = 16.2, 95%CI: 5.5-47, p = 0.0001; ulcers OR = 61.5, 95%CI: 8.7-432, p = 0.0001. Conclusions: The frequency and severity of oral diseases was hight and associated with the induction phase of chemotherapy, altering the overall nutrition and health of children.

Introducción: los pacientes pediátricos con leucemia linfoblástica aguda habitualmente desarrollan manifestaciones bucales debidas a la propia enfermedad, así como por efectos secundarios de la quimioterapia (QT) que afectan severamente su salud y calidad de vida. El objetivo de este trabajo fue determinar la prevalencia de patologías bucales en pacientes pediátricos con leucemia linfoblástica aguda (LLA) con y sin tratamiento QT, así como su relación con las fases del tratamiento QT. Métodos: se realizó un estudio transversal, observacional y analítico en pacientes pediátricos con LLA de 3 a 15 años. Se clasificaron en varios grupos: sin tratamiento, con tratamiento QT en fase de inducción, consolidación, intensificación, mantenimiento y vigilancia. Se realizó un examen clínico de los tejidos bucales y se aplicaron los índices de inflamación gingival (IPMA) y caries (ceod y CPOD). Resultados: el grupo bajo QT presentó mucositis (98%), úlceras (90%), gingivitis (86%) y candidiasis (78%). La fase de inducción se asoció con la presencia de mucositis: RM = 7.6, IC95%: 4.4-13, p = 0.0001; candidiasis: RM = 103, IC95%: 13.0-818, p = 0.0001; gingivitis: RM = 16.2, IC95%: 5.5-47, p = 0.0001; úlceras RM = 61.5, IC95%: 8.7-432, p = 0.0001. Conclusiones: la mayor frecuencia y severidad de las patologías bucodentales se asociaron a la fase de inducción, alterando la alimentación y la salud integral de los niños.

In Situ Leukemia as Manifestation of Relapse After Allogeneic Transplantation of Bone Marrow of ALL B: A Case Report.

Acute lymphoid leukemia (ALL) is a malignant proliferation of abnormal lymphoid precursors in the bone marrow. It is the most common acute leukemia in childhood, accounting for only 20% of acute leukemia in adults. The clinical presentation is heterogeneous including pallor, fatigue and weakness. Diagnosis is performed through myelogram, bone marrow biopsy and immunophenotyping. Chemotherapy and, in some cases, bone marrow transplantation (BMT) are used to treat the disease. However, the efficacy of treatment in adult patients is still below expected and therapeutic innovations have not increased disease-free survival. In addition, about 20% of patients have relapse, usually generalized, of the disease. This article aims to report the case of a patient previously treated for ALL B presenting localized medullar relapse or in situ leukemia.

O conhecimento dos familiares sobre cuidados à criança com leucemia linfocítica aguda no isolamento protetor / Family knowledge on child care with acute lymphocytic leukemia in protective isolation / El conocimiento de la familia sobre los cuidados a los niños con leucemia linfoblástica aguda en aislamiento protector

Objetivo: descrever o conhecimento dos familiares sobre os cuidados à criança com leucemia linfocítica aguda em isolamento protetor. Método: estudo de natureza qualitativa e descritiva, realizado no isolamento do centro de Referência para doenças onco-hematológicas da Região Norte, em Manaus, por meio de entrevista semiestruturada com 11 familiares, entre janeiro e março de 2016. Os dados foram analisados através da Análise Temática. Resultados: nas categorias: "Isolamento Protetor como prevenção de infecção: ainda um bicho de sete cabeças?" e "Cuidados no Isolamento Protetor: é preciso que todos tenham informações"; observou-se que o isolamento possui várias facetas: de proteção, prevenção, separação, que foram vivenciados pelos familiares nesse ambiente cuja rotina é diferenciada para cuidar da criança leucêmica. Conclusão: permeados de dúvidas e ansiedade, os familiares conhecem pouco sobre os cuidados a criança no isolamento; mostraram-se dispostos a aprender e sugerem a construção de um material educativo para facilitar o empoderamento do conteúdo.

Aim: to describe family members' knowledge about child care with acute lymphocytic leukemia in protective isolation. Method: this was a qualitative and descriptive study, carried out in the isolation of the Reference center for oncohematological diseases of the Northern Region, in Manaus, through a semi-structured interview with 11 relatives, from January to March 2016. Data were analyzed through Thematic Analysis. Results: from the categories: "Protective Isolation as infection prevention: is it still a seven-headed animal?" and "Protective Isolation Care: everyone needs information" it was possible to observe that the isolation has several facets. For instance, protection, prevention and the separation experienced by the family in this environment (whose routine is differentiated in order to care for the leukemic child). Conclusion: family members know little about child care in isolation and are permeated with doubts and anxiety. They have been willing to learn and suggest the construction of an educational material to facilitate the empowerment of content.

Objetivo: describir el conocimiento familiar sobre el cuidado a los niños con leucemia linfoblástica aguda en aislamiento protector. Método: estudio descriptivo cualitativo, en un centro de referencia de aislamiento para enfermedades oncohematológicas de la Región Norte, en Manaus, por medio entrevistas semiestructuradas con 11 familiares, entre enero y marzo de 2016. Los datos fueron analizados a través de análisis temático. Resultados: en las categorías: "Aislamiento con blindaje como prevención a la infección: un trabajo complejo" y "Cuidado en el blindaje de aislamiento: todos deben tener información"; se observó que el aislamiento tiene múltiples facetas: protección, prevención, separación que fueron vividas por la familia en un espacio en el cual la rutina es diferenciada para cuidar del niño con leucemia. Conclusión: con muchas dudas y ansiedad, la familia sabe poco sobre la atención de aislamiento, pero quiere aprender y sugiere el desarrollo de un material educativo para facilitar el empoderamiento del contenido.

Visfatin is a positive predictor of bone mineral density in young survivors of acute lymphocytic leukemia.

Bone mass acquisition may be compromised in survivors of childhood acute lymphocytic leukemia due to various factors, including adiposity. Fat accumulation can affect bone through the direct effect of adipokines or indirectly through the state of chronic inflammation. The aim of this study was to evaluate the effect of body composition and adipokines on bone mass in survivors of acute lymphocytic leukemia. This was a cross-sectional study of 56 survivors aged between 15 and 24 years, 44.6 % of whom received cranial radiotherapy (18-24 Gy), assessed according to body fat, lean mass, and bone mineral density (dual energy X-ray absorptiometry), computed tomography scan-derived abdominal adipose tissue, and adipokines by a multiple regression analysis. Both lumbar spine L1-L4 (trabecular bone) and total body (cortical bone) bone mineral density were positively correlated with visfatin (p < 0.050). Lean mass index was positively correlated, while waist-to-height ratio was negatively correlated with cortical bone (p < 0.010). Low bone mineral density for chronological age was detected in 5.4 % of patients in total body, and 8.9 % at the lumbar spine. In survivors of acute lymphocytic leukemia, visfatin may play an important role in the complex relationship between body composition and bone. At present, visfatin may represent a model for further study of bone metabolism, and could possibly explain the unknown mechanisms linking bone metabolism and cancer.

Ajuste de intensidad para el trasplante hematopoyético alogénico en leucemia aguda / Intensity adjustment of hematopoietic alogeneic transplantation in acute leukemia

Background: The intensity of conditioning chemotherapy and radiotherapy in hematopoietic stem cell transplantation (HSCT) varies according to several factors including the patient’s age, pre-existing conditions and performance status. Myeloablative conditioning (MA) increases transplant related mortality and reduces survival in older patients. Reduced intensity conditioning (RIC) is a good option for these patients. Aim: To report our experience with HSCT in patients of different ages with acute leukemia. Material and Methods: Retrospective analysis of 115 allogeneic HSCT performed in patients with acute myeloid or lymphoblastic leukemia. Results: We analyzed the cohort of patients in groups according to age at transplantation: younger than 40 years (n = 74), 41 to 50 years (n = 25) and older than 51 years of age (n = 16). Overall survival (OS), Disease free survival (DFS) and relapse at five years were similar in both groups of patients younger than 50 years (OS 40 and 44% respectively, DFS 38 and 42% respectively and relapse 40% and 34% respectively, p = NS). Patients over 51 years had a five years OS of 12%. However when we analyzed those patients by date and conditioning we found that patients who were treated with MA regimens in the first decade of the transplant program (before 2000) had lower OS compared to those treated after 2000 with RIC (five years OS 49% and 12% respectively, p < 0.01). No significant differences in terms of OS, recurrence or incidence of graft-versus-host disease were found when comparing groups under 40 years, between 41 and 50 years and older than 51 years treated only with RIC. Conclusions: RIC provides the possibility of HSCT in older patients with rates comparable to those obtained in younger patients successfully treated with MA conditioning.

Outcome of children and adolescents with lymphoblastic lymphoma / Evolução de crianças e adolescentes com linfoma linfoblástico

SUMMARY Introduction: lymphoblastic lymphoma (LBL) is the second most common subtype of non-Hodgkin lymphoma in children. The aim of this study was to characterize the clinical course of children and adolescents with LBL treated at a tertiary center. Methods: this is a retrospective cohort study of 27 patients aged 16 years or less with LBL admitted between January 1981 and December 2013. Patients received intensive chemotherapy regimen derived from acute lymphoblastic leukemia (ALL) therapy. Diagnosis was based on biopsy of tumor and/or cytological examination of pleural effusions. The overall survival was analyzed using the Kaplan-Meier method. Results: the median age at diagnosis was 11.6 years (interquartile range, 4.6-13.8). LBL had T cell origin in 16 patients (59%). The most common primary manifestation in T-cell LBL was mediastinum involvement in 9 patients (56%). Intra-abdominal tumor was the major site of involvement in patients with pB-LBL. Most patients had advanced disease (18 patients - 67%) at diagnosis. Twenty-four patients (89%) achieved complete clinical remission. After a median follow-up of 43 months (interquartile range, 6.4-95), 22 patients (81%) were alive in first complete remission. Five children (18.5%) died, three of them soon after admission and two after relapsing. The probability of survival at five years for 20 patients with de novo LBL was 78% (SD 9.4). Conclusion: our findings confirm the favorable prognosis of children with LBL with an intensive chemotherapy regimen derived from ALL therapy.

RESUMO Objetivos: linfoma linfoblástico (LL) é o segundo subtipo mais comum de linfoma não Hodgkin em crianças. O objetivo deste estudo foi caracterizar a evolução clínica de crianças e adolescentes com LL em um centro terciário. Métodos: estudo de coorte retrospectivo de 27 pacientes com idade de até 16 anos com LL admitidos entre janeiro de 1981 e dezembro de 2013. Os pacientes foram tratados de acordo com o protocolo de tratamento para leucemia linfoblástica aguda (LLA). O diagnóstico foi baseado em biópsia do tumor e/ou no exame citológico de derrame pleural. A sobrevida global foi analisada pelo método de Kaplan-Meier. Resultados: a média de idade ao diagnóstico foi de 11,6 anos (variação interquartil, 4,6-13,8). LL de células T foi identificado em 16 pacientes (59%) e a manifestação primária mais comum foi o acometimento mediastinal em 9 pacientes (56%). Tumor intra-abdominal foi a manifestação clínica principal nos pacientes com LL de células pré-B. A maioria dos pacientes apresentava doença avançada (18 pacientes - 67%) ao diagnóstico. Vinte e quatro pacientes (89%) alcançaram remissão clínica completa. Após um período de acompanhamento médio de 43 meses (intervalo interquartil, 6,4-95), 22 pacientes (81%) continuam vivos em primeira remissão clínica completa. Cinco crianças (18,5%) morreram, três delas logo após a admissão e duas após recidiva. A probabilidade de sobrevida em cinco anos para 20 pacientes com LL de novo foi de 78% (SD 9.4). Conclusão: nossos resultados confirmam o prognóstico favorável de crianças com LL tratadas com regime de quimioterapia intensiva derivado da terapia de LLA.