ABSTRACT The long-term outcome of acute lymphoblastic leukemia has improved dramatically due to the development of more effective treatment strategies. L-asparaginase (ASNase) is one of the main drugs used and causes death of leukemic cells by systematically depleting the non-essential amino acid asparagine. Three main types of ASNase have been used so far: native ASNase derived from Escherichia coli, an enzyme isolated from Erwinia chrysanthemi and a pegylated form of the native E. coli ASNase, the ASNase PEG. Hypersensitivity reactions are the main complication related to this drug. Although clinical allergies may be important, a major concern is that antibodies produced in response to ASNase may cause rapid inactivation of ASNase, leading to a worse prognosis. This reaction is commonly referred to as "silent hypersensitivity" or "silent inactivation". We are able to analyze hypersensitivity and inactivation processes by the measurement of the ASNase activity. The ability to individualize the ASNase therapy in patients, adjusting the dose or switching patients with silent inactivation to an alternate ASNase preparation may help improve outcomes in those patients. This review article aims to describe the pathophysiology of the inactivation process, how to diagnose it and finally how to manage it.

ABSTRACT In the present paper we summarize the suggestions of a multidisciplinary group including experts in pediatric oncology and infectious diseases who reviewed the medical literature to elaborate a consensus document (CD) for the diagnosis and clinical management of invasive fungal diseases (IFDs) in children with hematologic cancer and those who underwent hematopoietic stem-cell transplantation. All major multicenter studies designed to characterize the epidemiology of IFDs in children with cancer, as well as all randomized clinical trials addressing empirical and targeted antifungal therapy were reviewed. In the absence of randomized clinical trials, the best evidence available to support the recommendations were selected. Algorithms for early diagnosis and best clinical management of IFDs are also presented. This document summarizes practical recommendations that will certainly help pediatricians to best treat their patients suffering of invasive fungal diseases.

ABSTRACT Background: Peripheral blood stem cell concentrations are traditionally adjusted to 20–40 × 106 leukocytes/mL prior to freezing. This low cell concentration at cryopreservation implies larger volumes with more dimethyl sulfoxide being used, and higher cost and toxicity at the time of transplant. Higher cell concentrations have been reported but this is not widely accepted. Moreover, the influence of cell concentration on engraftment has not been well documented. Therefore, this study retrospectively analyzed the influence of peripheral blood stem cell concentration at freezing on engraftment after autologous hematopoietic stem cell transplantation. Method: Leukapheresis products were plasma-depleted and cryopreserved with 5% dimethyl sulfoxide, 6% hydroxyethylamide solution and 4% albumin in a −80 °C freezer. Individual patient data from hospital records were reviewed. Results: Fifty consecutive patients with oncological diseases underwent 88 leukaphereses. Median age was six years (range: 1–32 years) and median weight was 19 kg (range: 8–94 kg). Median leukocyte concentration was 109 × 106/mL at collection and 359 × 106 (range: 58–676 × 106) at freezing with 78% viability (range: 53–95%); leukocyte recovery after thawing was 95% (range: 70–100%). In multivariate analysis, cell concentration (p-value = 0.001) had a negative impact on engraftment. Patients infused with bags frozen with <200 × 106 leukocytes/mL engrafted after a median of nine days (range: 8–12 days), 200–400 × 106 leukocytes/mL after 11 days (range: 9–20 days); 400–600 × 106 leukocytes/mL after 12 days (range: 8–19 days) and with cell concentrations >600 × 106 leukocytes/mL, engraftment was after 14 days (range: 13–22 days). Conclusion: In patients with adequate CD34 cell collections, total leukocyte concentrations of 282 × 106/mL, freezing with 5% dimethyl sulfoxide and 6% hydroxyethylamide solution without a controlled-rate freezer, and storing cells at −80 ºC yielded excellent engraftment. Further increases in cell concentration may delay engraftment, without affecting safety.

RESUMO Objetivo: Avaliar o impacto da terapia sobre a densidade mineral óssea (DMO) e composição corporal em sobreviventes da leucemia linfoide aguda (LLA), tratados de acordo com os protocolos brasileiros do Grupo Cooperativo Brasileiro de Tratamento de Leucemia Linfoide Aguda na Infância (GBTLI), LLA-93 e LLA-99. Métodos: Em estudo transversal com 101 pacientes, avaliaram-se a composição corporal e a DMO por meio da densitometria óssea, interpretando-a conforme a faixa etária e a população de referência. Foi considerado grupo de risco para baixa DMO valores de z-escore entre -1,1 e -1,9 no grupo dos menores de 20 anos. Compararam-se os valores da DMO com características clínicas, tratamento recebido e composição corporal. Foram utilizados os testes qui-quadrado, exato de Fisher, razão de verossimilhança e t de Student, com nível de significância de 5%. Resultados: Foram encontradas 2% de fraturas, 2% de osteonecrose e 2,9% de baixa DMO. No grupo de pacientes com menos de 20 anos, três apresentaram baixa DMO. Os 16 pacientes com risco para baixa DMO exibiram menores valores em vértebras lombares L1-L4 (p=0,01), corpo total (p=0,005) e valores mais baixos de massa magra (p=0,03). No grupo de 22 pacientes com mais de 20 anos, dez demonstraram osteopenia. Conclusões: O baixo impacto do tratamento sobre a DMO neste estudo ratifica o conceito de que o ganho de massa óssea ocorre com o aumento da idade e que o tratamento não influencia tal processo. A população de risco para baixa DMO demonstrou valores menores de massa óssea, podendo beneficiar-se de um acompanhamento em longo prazo para uma possível toxicidade óssea.

ABSTRACT Objective: To evaluate the impact of therapy on bone mineral density (BMD) and body composition in survivors of acute lymphoblastic leukemia (ALL) treated in accordance with Brazilian protocols by the Brazilian Cooperative Group of Treatment of Lymphoblastic Leukemia in Childhood (GBTLI) LLA-93 and LLA-99. Methods: A cross-sectional study with 101 patients was performed. BMD and body composition were evaluated using bone densitometry and were interpreted according to the age group and the reference population. Values between -1.1 and -1.9 in the group of children under 20 years were considered as risk group for low BMD z-scores. BMD values were compared to clinical characteristics, treatment received and body composition. A chi-square test, Fisher’s exact test, likelihood ratio and Student’s t-test were applied, with a 5% significance level. Results: The patients presented a frequency of fractures of 2%, of osteonecrosis, 2%, and of low BMD, 2.9%. In the group of 79 patients under 20 years of age, three had low BMD. The 16 that presented risk for low BMD, demonstrated lower valutes in lumbar vertebrae L1-L4 (p=0.01) and whole body (p=0.005), and smaller values of lean body mass (p=0.03). In the group of 22 patients over 20 years of age, ten had osteopenia. Conclusions: The low impact of treatment on BMD of this study confirms the concept that the bone mass gain occurs with increasing age and that the treatment does not influence the process. The population at risk for low BMD values presented lower bone mass values and could benefit from a long-term monitoring for possible bone toxicity.

BACKGROUND: The empirical use of antibiotic treatments is widely accepted as a means to treat cancer patients in chemotherapy who have fever and neutropenia. Intravenous monotherapy, with broad spectrum antibiotics, of patients with a high risk of complications is a possible alternative. METHODS: We conducted a prospective open-label, randomized study of patients with lymphoma or leukemia who had fever and neutropenia during chemotherapy. Patients received either monotherapy with ticarcillin/clavulanic acid (T) or ceftriaxone plus amikacin (C+A). RESULTS: Seventy patients who presented 136 episodes were evaluated, 68 in each arm of the study. The mean neutrophil counts at admission were 217cells/mm³ (T) and 201cells/mm³ (C+A). The mean duration of neutropenia was 8.7 days (T) and 7.6 days (C+A). Treatment was successful without the need for modifications in 71% of the episodes in the T group and 81% in the C+A group (p=0.23). Treatment was considered to have failed because of death in two episodes (3%) in the T group and three episodes (4%) in the C+A group, and because of a change in the drug applied in one episode in the T group and two episodes in the C+A group. Overall success was 96% (T) and 93% (C+A). Adverse events that occurred in group T were not related to the drugs used in this study. CONCLUSION: In pediatric and adolescent patients with leukemia or lymphoma, who presented with fever and neutropenia, during chemotherapy, ticarcillin/clavulanic acid was as successful as the combination of ceftriaxone plus amikacin. It should be considered an appropriate option for this group of patients at high risk for infections.

Objetivo: estudar a prevalência e as características clínicas e laboratoriais dos pacientes com manifestações músculo-esqueléticas na apresentação inicial das leucemias agudas. Métodos: estudo de casos prevalentes, retrospectivo, descritivo, no qual foram avaliados pacientes com diagnóstico de leucemia aguda, atendidos no Instituto de Oncologia Pediátrica da UNIFESP, de novembro de 1999 a fevereiro de 2000. As queixas músculo-esqueléticas foram investigadas através de um questionário. Os dados referentes ao exame físico e provas laboratoriais, no início da doença, foram obtidos através da revisão de prontuários. Resultados: sessenta e uma crianças foram incluídas neste estudo, sendo que 93% apresentavam leucemia linfóide aguda, e 7% leucemia mielóide aguda. Trinta e oito crianças (62%) apresentaram dor músculo-esquelética no início da doença. Artrite foi observada em 8 casos (13%). A média de articulações acometidas foi 2,5 (variando de 1 a 6), sendo as mais acometidas os joelhos, os tornozelos e os cotovelos. Três pacientes (4,9%) apresentavam hemograma normal, 54 (88%) hemoglobina baixa (em 6 pacientes foi a única alteração), leucopenia em 14 (22%), leucocitose em 26 (42%), e plaquetopenia em 46 (75%) pacientes. Oito pacientes (13%) mostravam blastos em sangue periférico. Conclusão: as queixas músculo-esqueléticas são manifestações iniciais freqüentes das leucemias agudas, e devem ser consideradas no diagnóstico diferencial da dor em membros e das artrites agudas ou crônicas da infância. Os exames laboratoriais podem ser inicialmente normais, tornando ainda mais difícil esta diferenciação.

Objective: to study the frequency, the clinical features and laboratory exams of patients with musculoskeletal symptoms at the onset of acute leukemia. Methods: retrospective, descriptive study including patients diagnosed with acute leukemia, and treated at the Institute of Pediatric Oncology of UNIFESP, carried out from November 1999 to February 2000. The data on musculoskeletal complaints were obtained from a questionnaire. The medical records were revised in order to get data on the clinical examination and laboratory tests at the beginning of the illness. Results: sixty-one children were included in this trial, 93% with acute lymphoid leukemia, and 7% with acute myeloid leukemia. Thirty-eight patients (62%) had musculoskeletal pain at the onset. Arthritis was observed in 8 patients. The mean number of involved joints was 2.5 (1 - 6). The most frequently involved joints were the knees, ankles and elbows. Three patients (4.9%) had normal blood count. Low hemoglobin was reported in 54 patients (88%) (in six patients it was the only hematological abnormality), leukopenia in 14 (22%), leukocytosis in 26 (42%) and low platelet count in 46 (75%). Conclusions: the musculoskeletal symptoms are common at the onset of acute leukemia so, malignancy should always be ruled out in patients presenting chronic or acute arthritis or benign limb pain. The laboratory tests may be normal at the onset of the illness, making differential diagnosis more difficult.