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The treatment of acute lymphoblastic leukemia (ALL) has evolved in recent decades, reaching an overall survival rate close to 90%. Currently, approximately 4% of patients with ALL die from secondary complications of chemotherapy. Among these complications, the most frequent is febrile neutropenia (FN). The treatment of acute myeloid leukemias (AMLs) is even more aggressive, being consequently related to a considerable amount of treatment-related toxicity with a high risk of severe infection and death.In order to reduce the infection-related risks in these groups of patients, systemic antibacterial prophylaxis has emerged as a possible approach.Antibiotic prophylaxis during neutropenia periods in those undergoing chemotherapy have .already been proven in adults with acute leukemias (ALs). Among the possible available therapeutic options for bacterial prophylaxis in children with cancer, fluoroquinolones emerged with the most amount of evidence. Within this class, levofloxacin became the best choice.Therefore, the use of levofloxacin seems to be indicated in very specific situations: in children who are known to be neutropenic for a long time, secondary to intensive chemotherapy; in children with AL undergoing chemotherapy to induce remission; or in children undergoing hematopoietic stem cell transplantation (HSCT). This article aims to describe recent evidence focusing on antibiotic prophylaxis in children with ALs.

Objective This study aims to describe the epidemiological characteristics and survival rates of children with acute myeloid leukemia treated in hospitals in southern Brazil and compare them with international data. Methods A multicenter cohort study was conducted with retrospective data collection of all new patients with acute myeloid leukemia under 18 treated at five referral centers in pediatric hematology-oncology in southern Brazil between January 2005 and December 2015. Results Of the 149 patients with acute myeloid leukemia, 63.0% (n = 94) were male. The median age at diagnosis was 10.5 years (range 0–18 years) and 40.3% (n = 60) had a white blood cell count below 50,000/mm2. The most common Franco-American-British (FAB) subtype was M3 (n = 43, 28.9%). Nine (6.0%) patients had central nervous system disease. In M3 patients, overall survival (OS) was 69.2% and 3-year event-free survival was 67.7%; in non-M3 patients, these rates were 45.3% and 36.7%, respectively. In non-M3 patients, OS was significantly different between transplanted (61.8%) and non-transplanted (38.2%) patients (p = 0.031). Conclusions These results show a higher prevalence of the Franco-American-British M3 subtype than that reported in the international literature, as well as a decreased OS compared with that of developed countries. Further multicenter Brazilian studies with a larger sample size are encouraged to better understand the characteristics of acute myeloid leukemia, and to improve the treatment and prognosis in this population.

Severe aplastic anemia (SAA) is a life-threatening disease that can be cured with allogeneic cell transplantation (HCT). Haploidentical donor transplantation with post-transplantation cyclophosphamide (haplo-PTCy) is an option for patients lacking an HLA-matched donor. We analyzed 87 patients who underwent haplo-PTCy between 2010 and 2019. The median patient age was 14 years (range, 1 to 69 years), most were heavily transfused, and all received previous immunosuppression (25% without antithymocyte globulin). Almost two-thirds (63%) received standard fludarabine (Flu)/cyclophosphamide (Cy) 29/total body irradiation (TBI) 200 cGy conditioning, and the remaining patients received an augmented conditioning: Flu/Cy29/TBI 300-400 (16%), Flu/Cy50/TBI 200 (10%), or Flu/Cy50/TBI 400 (10%). All patients received PTCy-based graft-versus-host disease (GVHD) prophylaxis. Most grafts (93%) were bone marrow (BM). The median duration of follow-up was 2 years and 2 months. The median time to neutrophil recovery was 17 days. Primary graft failure occurred in 15% of the patients, and secondary or poor graft function occurred in 5%. The incidences of grade II-IV acute GVHD was 14%, and that of chronic GVHD was 9%. Two-year overall survival and event-free survival (EFS) were 79% and 70%, respectively. EFS was higher for patients who received augmented Flu/Cy/TBI (hazard ratio [HR], .28; P = .02), and those who received higher BM CD34 cell doses (3.2 × 10E6/kg) (HR, .29; P = .004). The presence of donor-specific antibodies before HSCT was associated with lower EFS (HR, 3.92; P = .01). Graft failure (HR, 7.20; P.0001) was associated with an elevated risk of death. Cytomegalovirus reactivation was frequent (62%). Haploidentical HCT for SAA is a feasible procedure; outcomes are improved with augmented conditioning regimens and BM grafts with higher CD34 cell doses.

Allogeneic hematopoietic stem cell transplantation (HCT) can cure primary immunodeficiency diseases (PID). When a HLA-matched donor is not available, a haploidentical family donor may be considered. The use of T cell-replete haploidentical HCT with post-transplantation cyclophosphamide (haplo-PTCy) in children with PID has been reported in few case series. A donor is usually readily available, and haplo-PTCy can be used in urgent cases. We studied the outcomes of 73 patients with PID who underwent haplo-PTCy, including 55 patients who did so as a first transplantation and 18 who did so as a salvage transplantation after graft failure of previous HCT. The median patient age was 1.6 years. Most of the children were male (n = 54) and had active infection at the time of transplantation (n = 50); 10 children had severe organ damage. The diagnosis was severe combined immunodeficiency (SCID) in 34 patients and non-SCID in 39 (Wiskott-Aldrich syndrome; n = 14; chronic granulomatous disease, n = 10; other PID, n = 15). The median duration of follow-up of survivors was 2 years. The cumulative incidence of neutrophil recovery was 88% in the SCID group and 84% in non-SCID group and was 81% for first transplantations and 83% after a salvage graft. At 100 days, the cumulative incidence of acute GVHD grade II-IV and III-IV was 33% and 14%, respectively. The majority of patients reached 200/μL CD4+ and 1000/μL CD3+ cell counts between 3 and 6 months. The estimated 2-year overall survival was 66%; it was 64% for SCID patients and 65% for non-SCID patients and 63% for first HCT and 77% for salvage transplantations. Twenty-five patients died, most of them due to infection early after transplantation (before 100 days). In conclusion, haplo-PTCy is a feasible procedure, can cure two-thirds of children with PID, and can be used as rescue treatment for previous graft failure. © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Background: Despite high cure rates, treatment-related mortality in children with acute lymphoblastic leukemia (ALL) remains significant. About 4% of patients die during remission induction therapy and approximately two-thirds of treatment-related deaths are due to infectious complications. Methods: From May 2021 to June 2022, children aged one through 18 years, with a recent diagnosis of ALL, admitted to three pediatric oncology centers in Brazil, were enrolled in this multicenter, open-label, randomized, phase 3 clinical trial. Eligible patients were randomly divided into two groups, based on a 1:1 allocation ratio, to receive, or not, levofloxacin as a prophylactic agent during the induction phase. All patients were treated according to the IC-BFM 2009 chemotherapy protocol. Primary endpoints were carbapenemase-producing Enterobacteriaceae (CPE) colonization, Clostridioides difficile diarrhea, and other adverse events related to the use of levofloxacin. The secondary endpoint was febrile neutropenia during induction. The median follow-up was 289 days. Results: Twenty patients were included in this trial, 10 in each group (control and levofloxacin). Mild adverse reactions related to levofloxacin were observed in three patients (30%). Three patients had Clostridioides difficile diarrhea, two in the levofloxacin group and one in the control group (p > 0.99). Only one patient presented colonization by CPE. This patient belonged to the levofloxacin group (p > 0.99). Nine patients presented febrile neutropenia, five in the control group and four in the levofloxacin intervention group (p > 0.99), one patient died due to febrile neutropenia. Conclusion: The use of levofloxacin was shown to be safe in the induction phase in children with de novo ALL. The use of this medication did not increase the rate of colonization by CPE nor the rate of diarrhea by C. difficile. All adverse reactions were mild and remitted either spontaneously or after switching medicine administration from oral to intravenous route.

This work aimed to better understand the impact of pandemics of respiratory viruses on children with hemoglobinopathies through a comprehensive review of the literature. MEDLINE, SCIELO, LILACS, and PUBMED were used as data sources to find articles without time period restrictions. Previous observations suggest that patients with hemoglobinopathies are a group especially susceptible to the complications of viral respiratory infections, with greater morbidity and mortality related to them. Within this context, this review found that, during the 2009 H1N1 pandemic, the risk of hospitalization in children and adults increased, especially in patients with a history of complications such as acute chest syndrome. In addition, the Coronavirus Disease 2019 (COVID-19) pandemic appears to have less repercussion among children with hemoglobinopathies compared to adults, similar to what is seen in the general population. In the H1N1 pandemic, patients with hemoglobinopathies behaved as a group more susceptible to complications, with increased morbidity and mortality. However, for COVID-19, the existing data to date on these patients do not show the same clinical impact. Thus, although these children deserve attention in case of infection due to their potential risks, they seem to have a favorable evolution. Highlights Children with hemoglobinopathies have less severe conditions with Coronavirus 2019 Disease (COVID-19) compared to adults, which is similar to that observed in the general population In the H1N1 pandemic, patients with hemoglobinopathies behaved as the group most susceptible to complications, with increased morbidity and mortality

In recent years, there has been an expansion in the use of flow cytometry (FC) immunophenotyping in the diagnosis and monitoring of childhood solid neoplasms. Neuroblastoma (NB), in turn, is the most common extracranial solid tumor in childhood. In the present study, we sought to compare FC and anatomopathological examination (PA) / immunohistochemistry (IHC) of children diagnosed or suspected with NB. The median age was 59 months (minimum 0; maximum 325 months), of these 12 were male (57.1%, 12/21). Forty-eight samples (27 bone marrow (BM), 10 peripheral blood (PB), 8 primary tumors (PT) and 2 liver nodules (HN) and 1 rib fragment (RF)) from 21 patients were evaluated. Twenty-nine samples were from patients with clinical suspicion while 19 samples were from patients with previously confirmed diagnosis. Thirteen samples (7 BM, 5 PT and 1 HN) presented NB when analyzed in FC while 8 (3 BM and 5 PT) samples were positive for NB in the PA/IHC. They were concordant in 88.9% of the cases. No NB cells were identified in any PB. Considering the PA as the gold standard, the FC obtained a sensitivity of 100%, a specificity of 86%, a positive predictive value of 67% and a negative predictive value of 100%. This study demonstrates that FC can be used as a methodology for diagnosis and assessment of NB involvement. In addition, FC has the advantage of allowing a quick diagnosis and accurate classification of the disease, and can also assist in monitoring the treatment.

Busulfan (Bu) is a key component of conditioning regimens used before hematopoietic stem cell transplantation (SCT) in children. Different predictive methods have been used to calculate the first dose of Bu. To evaluate the necessity of further improvements, we retrospectively analyzed the currently available weight- and age-based guidelines to calculate the first doses in 101 children who underwent allogenic SCT in CHU Sainte-Justine, Montreal, after an intravenous Bu-containing conditioning regimen according to genetic and clinical factors. The measured areas under the curve (AUCs) were within target (900 to 1500 µM/min) in 38.7% of patients after the administration of the first dose calculated based on age and weight, as locally recommended. GSTA1 diplotypes linked to poor Bu metabolism (G3) and fludarabine-containing regimens were the only factors associated with AUC within target (OR, 4.7 [95% CI, 1.1 to 19.8, P = .04]; and OR, 9.9 [95% CI, 1.6 to 61.7, P = .01], respectively). From the 11 methods selected for dose calculation, the percentage of AUCs within the target varied between 16% and 74%. In some models G3 was associated with AUCs within the therapeutic and the toxic range, whereas rapid metabolizers (G1) were correlated with subtherapeutic AUCs when different methods were used. These associations were confirmed by clearance-prediction analysis, in which GSTA1 diplotypes consistently influenced the prediction errors of the methods. These findings suggest that these factors should be considered in Bu dose prediction in addition to the anthropometric data from patients. Furthermore, our data indicated that GSTA1 diplotypes was a factor that should be included in future population pharmacokinetic models, including similar conditioning regiments, to improve the prediction of Bu exposure after its initial dose.

Background: Our research group recently showed that the only ASNase formulation available in Brazil from 2017 to 2018 when used at the same dose and frequency as the formulation provided previously did not reach, in most cases, the serum activity considered therapeutic. Based on these data, our goal was to assess the impact of these facts on the prognosis of children with ALL at 10 different pediatric oncology centers in our country. Methods: a multicenter retrospective observational study followed by prospective follow-up. Patients aged >1 and

High levels of fetal hemoglobin (HbF) reduce sickle cell anemia (SCA) morbidity and mortality. HbF levels vary considerably and there is a strong genetic component that influences HbF production. Genetic polymorphisms at three quantitative trait loci (QTL): Xmn1-HBG2, HMIP-2 and BCL11A, have been shown to influence HbF levels and disease severity in SCA. Hydroxyurea (HU) is a drug that increases HbF. We investigated the influence of single nucleotide polymorphisms (SNPs) at the Xmn1-HBG2 (rs7482144); BCL11A (rs1427407, rs4671393 and rs11886868); and HMIP-2 (rs9399137 and rs9402686) loci on baseline and HU-induced HbF levels in 111 HbSS patients. We found that both BCL11A and HMIP-2 were associated with increased endogenous levels of HbF. Interestingly, we also found that BCL11A was associated with higher induction of HbF with HU. This effect was independent of the effect of BCL11A on baseline HbF levels. Additional studies will be needed to validate these findings and explain the ample inter-individual variations in HbF levels at baseline and HU-induced in patients with SCA.

Introduction Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for several primary immunodeficiencies. In the absence of a matched sibling or a well matched unrelated donor, the use of an haploidentical family donor can be considered. Historically, most part of haploidentical HSCT were performed with in vitro T-cell depletion techniques that aren't worldwide available, especially in middle or low income countries. The use of T-cell replete haploidentical HSCT with PTCy in children with PID has been described in only a few case-series. Objectives To report the outcomes of haploidentical HSCT with PTCy for children with severe PID Methods Retrospective chart review of 73 patients with PID who underwent haploidentical HSCT with PTCy from July 2012 to May 2019 at 9 centers in Brazil. Results Fifty-five patients received first allogeneic transplants, and 18 were rescued after graft failure of a previous transplant. Median age was 1.6 years (2 months to 19 years). Most patients were male (n=54) and had active infection at the time of transplant (n=50). Diagnoses were: severe combined immunodeficiency (n=34), Wiskott-Aldrich Syndrome (n=14), chronic granulomatous disease (n=10) and other PID (n=15). Donors were father (N=46), mother (N=24), or siblings (N=3); and cell source was predominantly bone marrow (94% of patients). Conditioning regimen was non-myeloablative (fludarabine 150mg/m2 + cyclophosphamide 29mg/Kg + TBI 200cGy) in 35 patients; and myeloblative in 38 patients (most part receiving: bussulfan + fludarabine 160mg/m2 + ATG 4-7,5 mg/Kg or alemtuzumab 0,5-1mg/Kg). GVHD prophylaxis was PT-Cy, CsA or Tacrolimus and MMF. The median follow-up of surviving patients was 24 months. Four patients died before 28 days and were not evaluable for engraftment. Sixty-one patients engrafted in a median of 15 days. The 100-day incidence of acute GVHD grades II–IV was 33% and grades III–IV, 14%. The incidence of Chronic GVHD at 1 year was 16%. Twenty-two patients died, most of them due to infection (n=15). The two-year overall survival was 66%. There was no difference in OS between patients receiving first allogeneic or rescue transplants, suggesting survival bias. Patients transplanted for WAS or SCID had a better OS compared to those transplanted for CGD (p=0,02). Conclusion In conclusion, 66% of Brazilian children with severe PID and no matched donor could be cured with haploidentical HSCT with PTCy. The high proportion of patients in our cohort transplanted with an active infection (70%) may have had a major impact in our results. The optimal conditioning regimen for these patients and long term follow up data are the objective of our ongoing studies.

Severe aplastic anemia is a life-threatening disease usually treated with immunosuppression or HSCT. This is a multicenter retrospective study that included 78 patients who have undergone haploidentical HSCT with PTCy for severe aplastic anemia in Brazil between 2010 and 2019. Median age was 14 y/o (range: 1-69), and most patients had been heavily transfused. Conditioning regimen was FluCyTBI-based, and GVHD prophylaxis consisted of PTCy, MMF, and tacrolimus (13%) or cyclosporine (87%). Most grafts (92%) were bone marrow. One-year OS was 81%, and it was lower in females (HR=4.6; P=0.007) and in those who had graft failure or poor graft function (HR=10.3; P 30 y/o and lower TNC dose. In conclusion, we have shown that haploidentical transplantation for SAA is feasible. The incidence of graft failure/poor graft function was high, and increasing the TBI dose to 300-400 cGy or Cy to 50 mg/kg in the conditioning regimen may overcome graft failure, but not the addition of ATG. Patients who had not been previously exposed to ATG or alemtuzumab might be at high risk of graft failure. High cellular bone marrow grafts should be pursued.

Early lymphocyte recovery after allogeneic hematopoietic stem cell transplantation (HSCT) is related to the prevention of serious infections and the clearing of residual tumor cells.We analyzed the absolute lymphocyte count at 20 (D+20) and 30 (D+30) days after HSCT in 100 patients with malignant hematologic diseases and correlated with the risk of transplant-related mortality, overall survival (OS), disease-free survival (DFS), nonrelapsed mortality (NRM), and risk of infection.Patients presenting with lymphocyte counts of300 × 103/μL on D+30 have a 3.76 times greater risk of death in100 days. Over a medium follow-up of 20 months OS, DFS, and NRM were similar between the groups.In our group of patients delayed lymphocyte recovery after HSCT was a predictor of early death post-HSCT.

β2-Microglobulin is the major prognostic factor in multiple myeloma, a known comorbidity of Gaucher disease. We evaluated herein serum β2-microglobulin levels of 31 type 1 Gaucher patients; for 8/31 patients, pre- and post-treatment comparisons were made. Thirteen patients (on treatment = 6) had high levels of β2-microglobulin, and showed higher chitotriosidase activity and Severity Score Index, and lower concentration of platelets, than patients with normal levels. Levels of β2-microglobulin correlated with chitotriosidase activity (ρ = 0.65; p

A Sociedade Brasileira de Transplante de Medula (SBTMO) promoveu o I Encontro de Diretrizes do Transplante de Medula Ossea em 2009. Para revisao das indicacoes de transplante em Pediatria baseadas em evidencias foi constituido grupo de trabalho com oncologistas e hematologistas com experiencia em pediatria. Os artigos cientificos foram cuidadosamente avaliados e, para cada doenca, foram definidas as evidencias para recomendacao dos transplantes (de A a C) e a qualidade destas evidencias (de 1 a 3). As recomendacoes incluem doencas hematologicas malignas e nao malignas, tumores solidos, imunodeficiencias e doencas de deposito tratadas com transplantes de celulas-tronco hematopoeticas, quer autologos, alogenicos de irmao HLA compativel ou nao aparentados (doadores adultos ou sangue de cordao umbilical). Como nao existem recomendacoes uniformemente aceitas em pediatria, nao foram incluidas recomendacoes para transplantes de intensidade reduzida, com manipulacao do enxerto e nem parcialmente compativeis. E importante ressaltar que todas as indicacoes sao baseadas no conhecimento atual e podem modificar-se com o tempo. Assim, esta revisao nao deve ser utilizada para aplicacao direta no cuidado do paciente sem levar em conta caracteristicas da doenca, do doador e fatores de risco do proprio paciente. Este trabalho nao deve ainda ser utilizado como documento que limite o acesso do paciente ao transplante adequadamente indicado. Ressaltamos ainda, nesta revisao, diferencas entre transplantes em criancas e em adultos, com algumas recomendacoes especificas para os transplantes em pediatria.

We studied 58 childhood B-lineage acute lymphoblastic leukemia (B-ALL) in Brazilian sample patients at the time of diagnosis to investigate the prevalence of the cryptic t(12;21)(p13;q22). All bone marrow specimens were G-band karyotyped, and commercial dual-color DNA probes were used to search for fusion signals in nuclei. The karyotype analysis showed hyperdiploidy as the most frequent abnormality. The frequency of patients with TEL/AML1 gene fusion was 19% (11 out of 58 cases). Six of the positive samples had normal karyotypes. Deletion of the wild-type TEL allele was observed in 27.3% of TEL/AML1 fusion–positive cases, but it was also identified in 4.2% of the negative cases. Three cases presented two fusion signals, indicating possible duplication of the der(21). The mean age of the patients with TEL/AML1 fusion was 4.8 years and the mean amount of peripheral leukocytes was 44,270×10 6 /L. The higher frequency of females with B-ALL (33/58 cases) observed in our sample was probably due to the selection mode of the study cases. The prevalence of TEL/AML1 fusion in Brazilian children in our study is similar to that found in other populations.

CO RR EC TE D P RO OF the juvenile forms by age of onset, rate of disease progression and age of death. There are no approved treatments for gangliosidoses. Biomarkers for evaluating disease phenotype, disease progression, and response to therapies would serve to facilitate the design and development of potential treatment of these diseases, but such biomarkers have not been identified. Increasing evidence from animal models and human cadavers suggests inflammatory mediators in the CNS play a role in disease pathology and progression. Hypothesis: The more rapid disease progression and more severe clinical phenotype of the infantile GM1and GM2-gangliosidosis relative to juvenile forms will coincide with levels of disease specific inflammatory mediators in the CNS. Methods: CSF and serum inflammatory markers were quantified by immunoassay in 8 children with infantile forms of gangliosidoses (including patients with Tay–Sachs disease, Sandhoff disease and GM1 gangliosidosis). Findings were compared to values from 4 patients with more slowly progressing forms of gangliosidoses (i.e., late-infantile, juvenile forms) and to values of 9 children with mucopolysaccharidosis (MPS) diseases. Results: Of 188 analytes assayed, elevated inflammatory markers occurredmore often in the CSF of infantile gangliosidosis patients when compared to the more slowly progressing forms of juvenile gangliosidosis and MPS disease. Five candidate biomarkers were distinguished by persistent elevation in the CSF of patients with the severe infantile phenotype: ENA-78, MCP-1, MIP-1α, MIP-1β, TNFR2. Additional candidates for CNS and serum inflammatory markers for infantile and juvenile phenotypes were found. Conclusion: This study identified candidate biomarkers of CNS inflammatory disease in infantile and juvenile gangliosidoses that are promising as markers for evaluating CNS disease progression, distinguishing infantile and juvenile phenotypes and monitoring response to future therapeutic interventions in the gangliosidoses. (Supported by Lysosomal Disease Network, NIH U54NS065768 and Pharmacotherapy for InheritedMetabolic Diseases Fellowship training program, GenzymeSanofi.)

Nos últimos vinte anos, nosso serviço recebeu os pacientes com a suspeita de Leucemia Mielóide Aguda (LMA) provenientes de todas as regiões do estado. Entre março de 1980 e dezembro de 1999 analisamos 195 pacientes com idades superior a 12 e inferior a 70 anos, apresentando LMA "de novo" excetuando o subtipo M3. Na década de 80 foram registrados 102 pacientes: 47 homens e 55 mulheres. Destes, 84 receberam quimioterapia de indução com Citarabina e Daunorrubicina (esquema "7+3"), resultando no índice de remissão de 51% (43/84). As médias de sobrevidas livre de doença e global foram dez meses em 35% e 12 meses em 13% respectivamente. De jan/90 a dez/93 houve 41 novos diagnósticos e todos foram submetidos à quimioterapia com esquema "7+3" atingindo a taxa de 66% de remissão. As sobrevidas livre de doença e global foram estatisticamente (p