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.

Invasive fungal disease (IFD) shows distinct regional incidence patterns and epidemiological features depending on the geographic region.We conducted a prospective survey in eight centres in Brazil from May 2007 to July 2009. All haematopoietic cell transplant (HCT) recipients and patients with acute myeloid leukaemia (AML) or myelodysplasia (MDS) were followed from admission until 1 year (HCT) or end of consolidation therapy (AML/MDS). The 12-month cumulative incidence (CI) of proven or probable IFD was calculated, and curves were compared using the Grey test. Among 237 AML/MDS patients and 700 HCT recipients (378 allogeneic, 322 autologous), the 1-year CI of IFD in AML/MDS, allogeneic HCT and autologous HCT was 18.7%, 11.3% and 1.9% (p <0.001), respectively. Fusariosis (23 episodes), aspergillosis (20 episodes) and candidiasis (11 episodes) were the most frequent IFD. The 1-year CI of aspergillosis and fusariosis in AML/MDS, allogeneic HCT and autologous HCT were 13.4%, 2.3% and 0% (p <0.001), and 5.2%, 3.8% and 0.6% (p 0.01), respectively. The 6-week probability of survival was 53%, and was lower in cases of fusariosis (41%). We observed a high burden of IFD and a high incidence and mortality for fusariosis in this first multicentre epidemiological study of IFD in haematological patients in Brazil.

The present data suggest a low participation of the drug efflux genes in treatment failure in patients with childhood ALL. However, the low expression of some of these genes may be associated with a higher death risk related to treatment toxicity.

AimMaintenance therapy is an important phase of the childhood ALL treatment, requiring 2-year long therapy adherence of the patients and families. Weekly methotrexate with daily 6-mercaptopurine (6MP) constitutes the backbone of maintenance therapy. Reduction in the maintenance therapy could overweight problems related with poverty of children with ALL living in limited-income countries (LIC).ObjectiveTo compare, prospectively, the EFS rates of children with ALL treated according to two maintenance regimens: 18 vs. 24 months duration.Materials and methodsFrom October 1993 to September 1999, 867 consecutive untreated ALL patients <18 years of age were treated according to the Brazilian Cooperative Group for Childhood ALL Treatment (GBTLI) ALL-93 protocol. Risk classification was based exclusively on patient’s age and leukocyte count (NCI risk group) and clinical extra medullary involvement of the disease. Data were analyzed by the intention-to-treat approach.ResultsFourteen patients (1.6%) were excluded: wrong diagnosis (n = 7) and previous corticosteroid (n = 7). Of the 853 eligible patients, 421 were randomly allocated, at study enrollment, to receive 18-month (group 1) and 432 to receive 24-month (group 2) maintenance therapy. Complete remission rate was achieved in 96% of the patients (817/853). Twenty-eight patients (3.4%) died during the induction phase. Thirty-four patients (4.0%) were lost to follow-up. The overall EFS was 66.1 ± 1.7% at 15 years. No difference was seen according to maintenance: EFS15y was 65.8 ± 2.3% (group 1) and 66.3 ± 2.3% (group 2; p = 0.79). No difference between regimens was detected after stratifying the analyses according to factors associated with adverse prognosis in this study (age group <1 year or >10 years and high WBC at diagnosis). Overall death in remission rate was 6.85% (56 patients). Deaths during maintenance were 13 in group 1 and 12 in group 2, all due to infection. Over 15 years of follow-up, two patients both from group 2 presented a second malignancy (Hodgkin’s disease and thyroid carcinoma) after 8.3 and 11 years off therapy, respectively.ConclusionSix-month reduction of maintenance therapy in ALL children treated according to the GBTLI ALL-93 protocol provided the same overall outcome as 2-year duration regimen.

No abstract

Resistance to anti-leukemic agents in childhood ALL has been strongly associated with prognosis. The aim of this study was to analyze the expression profile of genes related to resistance/sensibility of 4 anti-leukemic agents and their correlations with age, diagnosis WBC count, risk group classification, molecular cytogenetics, induction treatment response and event-free survival (EFS) in ALL children. Were analyzed the expression profile of 19 genes related to resistance/sensibility to vincristine (RPRP2, CD44, TCF5, KCNN1, TIF1), prednisolo ne (F8A, CDK2AP1, BLVRB, CD69), daunorubicin (MAP3K12, SHOCK2, PDCH9, EGF1, KCNN4) and L-asparaginase (GPR56, MAN1, SCGF, IGFBP7, GATA3) by real-time quantitative PCR, using SYBR Green approach and melting curve analysis, with GUSB as housekeeping gene. Relative quantification was done using the 2-DDCT method (efficiencies from 1.9 to 2.1 to all the analyzed genes). These genes were chosen according to those described on microarray analysis by Holleman et al. (NEJM, 351:533, 2004). From 154 consecutive children admitted to ALL treatment in the 3 participating institutions, 139 had the gene expression profile analyzed. Sixteen were excluded due to lack of good quality RNA/cDNA. The follow up ranges from 36–60 months. All patients were classified and treated according the Brazilian ALL treatment protocol (GBTLI-99). Association among the variables analyzed and the gene expression levels was evaluated by Mann-Whitney and chi-square tests. EFS analysis was performed using Kaplan-Meier and log-rank test and multivariate analysis by the Cox proportional model to define independent prognostic factors. Correlation between the genes was analyzed by Spearman test. The 4-years EFS was 75,5% to all patients analyzed (81,4% to standard risk and 68,7% to high risk). Statistical correlation was observed among the genes of resistance of daunorrubicin, L-asp and vincristine (P<0,001). There is a significant association (p<0,05) between the levels of expression of the genes TIF1A, BLVRB, CD44, SCFBP1, TCFL5 and risk group; CD44, MAP3K12, SHOCK2 and CD10 antigen and GPR56, SHOCK2 with favorable event. The overexpression of SHOCK2 and GPR56 genes were also associated to better 4y-EFS in univariate (86,3% x 68,7% (p:0,04) and 86,2% x 72,2% (p:0,03) respectively) and multivariate analysis (p:0,03 and 0,09 respectively). No significant differences were observed in the other variables analyzed. The present data suggest that the expression of some analyzed genes have influence in the resistence/sensibility to the treatment and outcome in childhood ALL; especially over-expression of the SHOCK2 and GPR15 genes were associated with higher sensibility to daunorrubicin and L-asp respectively.