Early Mortality in Children and Adolescents with Acute Promyelocytic Leukemia: Experience of the Boldrini Children's Center.

INTRODUCTION: Acute promyelocytic leukemia (APL) is currently considered a highly curable disease. However, an early death (ED) remains one of the main causes of APL treatment failure. PATIENTS AND METHODS: In this retrospective study, we aimed to analyze the clinical characteristics of 91 children and adolescents with APL, who were consecutively registered at the (name of institution removed) Children's Center from January 1, 1998 to December 31, 2017. Data were assessed for age, sex, ethnicity, body mass index percentile, initial white blood cell count, peripheral blood blast count, and platelet count, hemoglobin value, partial thromboplastin time, prothrombin time, fibrinogen level, serum creatinine level, APL morphology subtype (classic vs. hypogranular variant M3v), and FLT3 gene mutations. RESULTS: ED occurred in 12 of 91 (13.1%) patients and was mainly related to cerebral thromboembolism. Overall 66% of deaths occurred in the second week after diagnosis. ED was associated with white blood cell ≥10×10 cells/L (odds ratio of 8.44; 95% confidence interval [CI]=1.48-48.26; P=0.0016), initial promyelocytes ≥20×10/L (odds ratio of 9.29; 95% CI=2.45-35.8; P=0.001), morphologic subtype M3v (odds ratio of 3.63; 95% CI=1.04-12.64; P=0.043), and creatinine serum levels >0.7 mg/dL (odds ratio of 6.78; 95% CI=1.83-25.13; P=0.004). In multivariate analyses, ED was associated with initial peripheral promyelocytes ≥20×10 blasts/L and creatinine serum levels >0.7 mg/dL. CONCLUSIONS: EDs were mainly caused by thrombohemorrhagic events and occurred within the second week after diagnosis. High peripheral promyelocytes and creatinine levels were predictors of ED in APL.

A novel der(12)t(7;12)(p15;q24.3) in a patient with childhood T-cell acute lymphoblastic leukemia.

Approximately 35% of T-cell acute lymphoblastic leukemia (T-ALL) cases have chromosomal translocations as evaluated by conventional cytogenetic methods (G-banding). Some chromosomal translocations are associated with morphologically and immunophenotypically distinct leukemia subtypes and define patients with different clinical outcomes. Chromosomal translocations may deregulate gene expression, thus contributing to the development of neoplasia, either by placing a putative oncogene under the control of strong regulatory elements or by generating chimeric genes and oncogenic fusion proteins. We report here a novel der(12)t(7;12)(p15;q24.3) in a child with T-ALL. Cloning and characterization of the breakpoint region may contribute to the discovery of new genes that are important in T-ALL.

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.

Prognostic significance of WT1 gene expression in pediatric acute myeloid leukemia.

BACKGROUND: The Wilms Tumor gene (WT1) encodes a transcription factor involved in kidney development and malignancy. WT1 expression in a subpopulation of early CD34+ cells has suggested its involvement in hematopoiesis. WT1 is aberrantly expressed in leukemias. High expression of WT1 at diagnosis has been associated with unfavorable prognosis in adult acute myeloid leukemia (AML). The prognostic relevance of WT1 expression in pediatric AML was evaluated in only one study, including 47 patients, which showed that very low levels of WT1 at presentation were associated with an excellent outcome. To test the validity of these findings we measured levels of WT1 in 41 newly diagnosed pediatric AML of the non-M3 FAB subtype. PROCEDURE: Patients were treated according to an AML-BFM 83-based protocol in a single institution. Mononucleated cells obtained from presentation BM aspirates were cryopreserved and later thawed and used for total RNA extraction and cDNA synthesis. The quantitative assessment of WT1 transcripts was made by real-time PCR (RQ-PCR). WT1 transcripts values were normalized with respect to the number of ABL transcripts. RESULTS: WT1 levels were significantly higher in patients bearing favorable chromosome abnormalities, t(8;21) and inv(16) (P = 0.002). Higher levels of WT1 expression were unexpectedly associated with a higher probability of overall survival by Cox regression analysis (P = 0.002). Multivariate regression analysis could not discriminate between the effects of WT1 and cytogenetics on survival. CONCLUSIONS: Higher WT1 expression was associated with favorable cytogenetics subtypes and accordingly with better outcome in children with AML in this study.