Marcos Borato Viana

Malnutrition as a prognostic factor in lymphoblastic leukaemia: a multivariate analysis.

One hundred and twenty eight Brazilian children with lymphoblastic leukaemia were intensively treated with a Berlin-Frankfurt-Munich based protocol. More children had a white cell count above 50 x 10(9)/l (31%) then observed in developed countries. After a median follow up of 31 months (11-58 months), the estimated probability of relapse free survival was 41% (7%) for the whole group. After adjustment in the Coxs multivariate model, malnutrition was the most significant adverse factor affecting duration of complete remission. Age above 8 years and high peripheral white cell count were also significant adverse factors. Among the nutritional indices, the height for age and weight for age z scores were both significant, whether the cut off points of z-2 or z = -1.28 were chosen to define malnutrition. A strong statistical association between the two indices was found; the contribution of height for age z score to the prediction of relapse free survival was more significant. Children with height for age z score < -2 had a relapse risk of 8.2 (95% confidence interval 3.1 to 21.9) relative to children with z score > -2. The results of this study suggest that socioeconomic and nutritional factors should be considered in the prognostic evaluation of children with leukaemia in developing countries.

Benefits of the Intermittent Use of 6-Mercaptopurine and Methotrexate in Maintenance Treatment for Low-Risk Acute Lymphoblastic Leukemia in Children: Randomized Trial From the Brazilian Childhood Cooperative Group—Protocol ALL-99

PURPOSE To describe event-free survival (EFS) and toxicities in children with low-risk acute lymphoblastic leukemia (ALL) assigned to receive either continuous 6-mercaptopurine (6-MP) and weekly methotrexate (MTX) or intermittent 6-MP with intermediate-dose MTX, as maintenance treatment. PATIENTS AND METHODS Between October 1, 2000, and December 31, 2007, 635 patients with low-risk ALL were enrolled onto Brazilian Childhood Cooperative Group for ALL Treatment (GBTLI) ALL-99 protocol. Eligible children (n = 544) were randomly allocated to receive either continuous 6-MP/MTX (group 1, n = 272) or intermittent 6-MP (100 mg/m(2)/d for 10 days, with 11 days resting) and MTX (200 mg/m(2) every 3 weeks; group 2, n = 272). RESULTS The 5-year overall survival (OS) and EFS were 92.5% +/- 1.5% SE and 83.6% +/- 2.1% SE, respectively. According to maintenance regimen, the OS was 91.4% +/- 2.2% SE (group 1) and 93.6% +/- 2.1% SE (group 2; P = .28) and EFS 80.9% +/- 3.2% SE (group 1) and 86.5% +/- 2.8% SE (group 2; P = .089). Remarkably, the intermittent regimen led to significantly higher EFS among boys (85.7% v 74.9% SE; P = .027), while no difference was seen for girls (87.0% v 88.8% SE; P = .78). Toxic episodes were recorded in 226 and 237 children, respectively. Grade 3 to 4 toxic events for groups 1 and 2 were, respectively, 273 and 166 for hepatic dysfunction (P = .002), and 772 and 636 for hematologic episodes (P = .005). Deaths on maintenance were: seven (group 1) and one (group 2). CONCLUSION The intermittent use of 6-MP and MTX in maintenance is a less toxic regimen, with a trend toward better long-term EFS. Boys treated with the intermittent schedule had significantly better EFS.

Clinical and laboratory evaluation of compliance in acute lymphoblastic leukaemia

Aim: To evaluate compliance in children with acute lymphoblastic leukaemia (ALL). Methods: Compliance was assessed through specific interviews, annotations from medical charts, and erythrocytic determination of 6-mercaptopurine metabolites. Results: A total of 39 patients who had concluded maintenance phase of chemotherapy were included in the study. Mothers were responsible for delivering 6-MP in 87% of cases. Thirty five interviewees said that medical prescription was well understood and that the main reason for non-compliance was forgetfulness. Non-compliance was detected through interviews (33.3% of the cases), reports from medical charts (30.7%), and drug determination (16.6%); 53.8% of children were found to be non-compliant. Non-compliance was significantly associated with chronic undernourishment. Although not statistically significant, there was a trend for the group of non-compliant children to be associated with low per capita family income. No significant associations of non-compliance with age at diagnosis, gender, parents’ schooling level, number of family members, power consumption, and medians of absolute leucocyte or neutrophil blood counts were detected. A short follow up period precluded valid analysis on outcome. In the non-compliant group (n = 21), seven children relapsed, contrasting with three relapses in the compliant group (n = 18). Conclusions: Results suggest that non-compliance is one of the mechanisms which underlies the adverse influence of socioeconomic factors on the outcome of children with ALL. Additional studies are necessary to confirm this hypothesis. Comprehensive approaches to the problem of non-compliance are urgently needed.

Growth Deficits in Children with Sickle Cell Disease

BACKGROUND Growth deficits are common in children with sickle cell disease. Few prospective studies are available and the pathophysiologic basis for the impaired growth is not clearly understood. Our objectives were to collect data on anthropomorphic measurements of children with sickle cell disease prospectively followed for 1 year and to correlate them with hematologic data. METHODS One hundred children <8 years of age (73 with homozygous SS sickle cell anemia [HbSS] and 27 with hemoglobinopathy SC [HbSC]) were included. Standardized Z scores of weight for age (waz), height for age (haz), and weight for height (whz) were compared to the National Center for Health Statistics (NCHS) reference population. RESULTS At study entry, the means (standard deviation [SD]) of waz, haz, and whz were -0.69 (1.06), -0.65 (1.11), and -0.32 (1.00), respectively. After 1 year of study, children with HbSS presented a significant decrease in waz (p = 0.01) and whz (p = 0.02); the decrease in haz was not statistically significant (p = 0.48). The effect was similar for children older or younger than 24 months of age. The decrease in waz and whz was significant for boys but not for girls. After 1 year of follow-up, lower mean waz scores were observed among patients with lower hemoglobin concentration and higher reticulocyte count (p = 0.03 and p = 0.08). Hemoglobin concentration was higher in girls. The anthropomorphic measurements did not deteriorate significantly in children with HbSC. CONCLUSIONS Growth deficits may be demonstrable in children with HbSS, even during a short period of observation. Fast red blood cell turnover may be partially responsible for the observed effect.

Mortalidade de crianças com doença falciforme: um estudo de base populacional

OBJETIVO: Caracterizar os obitos das criancas com doenca falciforme (DF) triadas no estado de Minas Gerais e acompanhadas na Fundacao Hemominas. METODOS: Coorte de criancas diagnosticadas pelo Programa de Triagem Neonatal de Minas Gerais (marco/1998 - fevereiro/2005). Os obitos foram identificados pela busca ativa das criancas ausentes nas consultas agendadas nos hemocentros. Dados clinicos e epidemiologicos foram coletados dos documentos de obito, banco de dados da triagem neonatal, prontuarios medicos e em entrevistas com as familias. RESULTADOS: Foram triadas 1.833.030 criancas no periodo, sendo 1.396 com DF (1:1.300). Ocorreram 78 obitos: 63 em criancas com genotipo SS, 12 em criancas com genotipo SC e tres em criancas com genotipo S/β+ talassemia. Cinquenta e seis criancas (71,8%) morreram antes dos 2 anos de idade; 59 morreram em hospitais e 18 no domicilio ou trânsito. Causas de obito pelo atestado (n = 78): 38,5% infeccao; 16,6% sequestro esplenico agudo; 9% outras causas; 15,4% sem assistencia medica; e 20,5% indeterminada. Segundo as entrevistas (n = 52), o sequestro esplenico foi responsavel por quase 1/3 dos obitos, contrastando com a porcentagem de apenas 14% registrada nos atestados de obito. As probabilidades de sobrevida aos 5 anos (erro padrao da media) para criancas SS, SC e Sβ+ talassemia foram: 89,4 (1,4), 97,7 (0,7) e 94,7% (3,0), respectivamente (SS versus SC, p < 0,0001). CONCLUSOES: Mesmo em um programa de triagem neonatal com rigoroso controle do tratamento, a probabilidade de obito em criancas com genotipo SS ainda e elevada. Os obitos com causa indeterminada indicam dificuldades no reconhecimento da DF e das suas complicacoes. Esforcos educativos dirigidos a profissionais da saude e familiares devem ser incrementados para diminuir a mortalidade pela DF.

A simplified minimal residual disease polymerase chain reaction method at early treatment points can stratify children with acute lymphoblastic leukemia into good and poor outcome groups

This paper describes a simplified PCR strategy for minimal residual disease (MRD) monitoring in children with acute lymphoblastic leukemia. Since this method is cheaper and simpler than standard methods, it may be particularly suitable for countries with limited economic resources. See related perspective article on page 748. Background Minimal residual disease is an important independent prognostic factor in childhood acute lymphoblastic leukemia. The classical detection methods such as multiparameter flow cytometry and real-time quantitative polymerase chain reaction analysis are expensive, time-consuming and complex, and require considerable technical expertise. Design and Methods We analyzed 229 consecutive children with acute lymphoblastic leukemia treated according to the GBTLI-99 protocol at three different Brazilian centers. Minimal residual disease was analyzed in bone marrow samples at diagnosis and on days 14 and 28 by conventional homo/heteroduplex polymerase chain reaction using a simplified approach with consensus primers for IG and TCR gene rearrangements. Results At least one marker was detected by polymerase chain reaction in 96.4% of the patients. By combining the minimal residual disease results obtained on days 14 and 28, three different prognostic groups were identified: minimal residual disease negative on days 14 and 28, positive on day 14/negative on day 28, and positive on both. Five-year event-free survival rates were 85%, 75.6%, and 27.8%, respectively (p<0.0001). The same pattern of stratification held true for the group of intensively treated children. When analyzed in other subgroups of patients such as those at standard and high risk at diagnosis, those with positive B-derived CD10, patients positive for the TEL/AML1 transcript, and patients in morphological remission on a day 28 marrow, the event-free survival rate was found to be significantly lower in patients with positive minimal residual disease on day 28. Multivariate analysis demonstrated that the detection of minimal residual disease on day 28 is the most significant prognostic factor. Conclusions This simplified strategy for detection of minimal residual disease was feasible, reproducible, cheaper and simpler when compared with other methods, and allowed powerful discrimination between children with acute lymphoblastic leukemia with a good and poor outcome.

Low socioeconomic status is a strong independent predictor of relapse in childhood acute lymphoblastic leukemia

The results of the treatment of acute lymphoblastic leukemia (ALL) in children depend not only on the biologic diversity of the leukemia cell, the multi‐drug treatment schedule and the individual variability of drug metabolism, but also on the socioeconomic and cultural background of the leukemic child. Social and cultural disparity is very marked in underdeveloped countries and has been increasing in industrialized nations. The prognostic influences of these factors are poorly documented and sometimes mistakenly attributed to differences in ethnic origin. We have investigated in Brazil the relative impact of malnutrition and socioeconomic status on the outcome of ALL, adjusting for the known influence of biologic factors. Children with ALL (n = 167) treated with a Berlin‐Frankfurt‐Munster‐based protocol were studied prospectively. At a median follow‐up of 1623 days, the estimated probability of disease‐free survival was 43 ± 4%. The main cause for interruption of remission was bone‐marrow relapse. Socioeconomic indicators of poverty (poor housing conditions, low per capita income and energy consumption) were significantly associated with a greater risk of relapse in univariate analysis. They were consolidated in a single index, socioeconomic status (SES), defined by the product of monthly per capita income times mean familial daily energy consumption. Other unfavorable findings included age, z score for the height for age at diagnosis (HAZ) below −1.28 and the z score for weight for age below −1.28. After adjustment in Coxs multivariate model, only HAZ and poor SES remained as predictive factors for relapse. Poor prognosis for leukemic children of low SES is just another indicator of social inequality. Int. J. Cancer Supplement 11:56–61, 1998.

β-globin gene cluster haplotypes in a cohort of 221 children with sickle cell anemia or Sβ⁰-thalassemia and their association with clinical and hematological features.

Background/Aims: βS-Haplotype prevalence and its associations with clinical and hematological characteristics were assessed in Brazilian children with sickle cell anemia or Sβ⁰-thalassemia. Methods: A retrospective randomized cohort study was undertaken with 208 SS and 13 Sβ⁰-thalassemia children derived from the Newborn Screening Program of the state of Minas Gerais. βS-Haplotypes were determined by PCR-RFLP. Results: Thirty-nine percent of the SS subjects had the CAR/CAR genotype, 33% had CAR/Ben, 24% had Ben/Ben, 1% had CAR/Atp, 1% had Ben/Atp, and 1% had Arab-Indian/Ben; 1% could not be characterized. Of the Sβ⁰-thalassemia children, 5 were CAR/undefined, 2 were Ben/undefined, and 1 was CAM/undefined. There was no significant association between βS-haplotypes and the total Hb, Hb F, MCV, MCH, WBC, and reticulocyte count among the SS children. Likewise, no significant association was detected between βS-haplotypes and the frequency of acute chest syndrome episodes, blood transfusions, splenic sequestration, or cerebrovascular disease (high-risk/conditional transcranial Doppler ultrasonography or clinical stroke). A limited number of Sβ⁰-thalassemia children precluded valid analyses. Conclusions: The prevalence of βS-haplotypes in this study is in agreement with the historical records of African slaves brought to the state of Minas Gerais. Furthermore, βS-haplotypes CAR and Ben were not associated with any analyzed feature of children with sickle cell anemia.

High reticulocyte count is an independent risk factor for cerebrovascular disease in children with sickle cell anemia

Transcranial Doppler ultrasonography (TCD) is an important way of detecting risk of ischemic stroke in children with sickle cell anemia.

Height deficit during and many years after treatment for acute lymphoblastic leukemia in children: A review

There are conflicting data on the incidence and severity of height deficits in children with acute lymphoblastic leukemia (ALL). This is probably due to: (1) collection of data in different phases of treatment; (2) differences in chemotherapeutic regimens; (3) inclusion or not of children who had received cranial irradiation (CRT); (4) limited numbers of patients; (5) relative numbers of prepubertal and pubertal children; (6) different ways of measuring growth deficits. Twenty‐five papers published between 1987 and 2006 were reviewed. These reveal that (1) chemotherapy always causes some height reduction during treatment regardless of whether additional CRT is given; (2) catch‐up growth occurs immediately after cessation of treatment; (3) intensive chemotherapy alone significantly decreases height in the long‐term but to a lesser extent than with additional CRT; (4) young children develop more severe height loss; (5) girls are reported to have greater height deficits but confounding factors have not been adequately considered; (6) late growth hormone (GH) deficiency has been detected in many children, mostly in those who had CRT; (7) GH replacement therapy seems to be effective. ALL relapse in GH‐treated children is not more common than in those not treated with GH. Pediatr Blood Cancer 2008;50:509–516.