Cytogenetics of Hispanics and Whites with Childhood Acute Lymphoblastic Leukemia in California.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4536-4536
Author(s):  
Melinda C. Aldrich ◽  
Luoping Zhang ◽  
Joseph L. Wiemels ◽  
Xiaomei Ma ◽  
Mignon Loh ◽  
...  
Keyword(s):  
Risk Factors ◽  
Childhood Leukemia ◽  
Lymphoblastic Leukemia ◽  
Population Based ◽  
Epidemiologic Studies ◽  
Disease Etiology ◽  
Genetic Characteristics ◽  
Mechanistic Basis ◽  
B Lineage

Abstract Epidemiologic studies of childhood leukemia have made limited use of tumor genetic characteristics, which may be related to disease etiology. We characterized the cytogenetics of 543 childhood leukemia patients (0–14 years of age) enrolled in the Northern California Childhood Leukemia Study, an approximately population-based study comprised primarily of Hispanics (42%) and non-Hispanic whites (41%), and compared the cytogenetic profiles between these two ethnic groups. Subjects were classified by immunophenotypes, conventional cytogenetic characteristics, and fluorescence in situ hybridization findings. The abnormalities most frequently observed among all patients were pseudodiploidy and high hyperdiploidy (51–67 chromosomes) (27% and 25%, respectively). No ethnic differences in the frequency of 11q23/MLL rearrangements were observed between Hispanics and non-Hispanic whites. Among B lineage ALL patients without 11q23/MLL rearrangements, the percentage of TEL-AML1 translocations was significantly lower in Hispanics (13%) than in non-Hispanic whites (24%; P = 0.01). This is the first large study to compare frequencies of cytogenetic events of primarily Hispanic and non-Hispanic white childhood leukemia patients. Our data suggest some cytogenetic characteristics likely differ between non-Hispanic whites and Hispanics. The mechanistic basis for the two-fold variation in frequency of TEL-AML1 may be due to ethnic-specific risk factors or genetics and should be explored further. Owing to the heterogeneity of leukemia in children, it is possible that cytogenetic subgroups may have distinct etiologies and risk factors which otherwise would be overlooked with the broad leukemia subtypes (e.g. ALL, AML) presently used in epidemiologic analyses.

scholarly journals Acute leukemia of childhood: A single institution's experience

2005 ◽  
Vol 57 (1) ◽  
pp. 11-17 ◽  
Author(s):  
Bojana Slavkovic ◽  
Marija Guc-Scekic ◽  
Gordana Bunjevacki ◽  
S. Djuricic ◽  
Aleksandra Krstic ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Acute Leukemia ◽  
Childhood Leukemia ◽  
Lymphoblastic Leukemia ◽  
Chromosomal Rearrangements ◽  
Age Distribution ◽  
Normal Karyotype ◽  
Mediterranean Countries ◽  
B Lineage ◽  
Childhood Acute Leukemia

The aim of this study was to investigate distribution of immunophenotypic and cytogenetic features of childhood acute leukemia (AL) in the cohort of 239 newly diagnosed patients registered at the leading pediatric oncohematology center in the country during a six-year period (1996-2002). With approximately 60-70% of all childhood AL cases in Serbia and Montenegro being diagnosed and treated in this institution the used data represent a valid research sample to draw conclusions for entire country. On the basis of five phenotypic markers, the distribution of immunological subtypes was as follows: 169 (70.7%) expressed B-cell marker CD19 (137 were CD10 positive and 32 CD10 negative), 37 (15.5%) belonged to T-lineage acute lymphoblastic leukemia (T-ALL) (cyCD3 positive), and 33 (13.8%) were acute myeloblastic leukemia (AML) (CD13 positive and/or CD33 positive in the absence of lymphoid-associated antigens). The ratio of males and females was 1.5:1. Most of the cases were between the ages of 2 and 4, and were predominantly B-lineage acute lymphoblastic leukemia (B-ALL) cases. Another peak of age distribution was observed at the age of 7. The frequency of T-ALL (18% of ALL) was similar to that reported for Mediterranean countries: France (19.4%), Greece (28.1%), Southern Italy (28.3%), and Bulgaria (28.0%). Cytogenetic analyses were performed in 193 patients: 164 ALL and 29 AML. Normal karyotype was found in 57% of ALL and in 55% of AML patients, while cytogenetic abnormalities including structural, numerical, and complex chromosomal rearrangements were found in 43% of ALL and in 45% of AML patients. Our results represent a contribution to epidemiological aspects of childhood leukemia studies.

scholarly journals Venous thromboembolism in patients with acute leukemia: incidence, risk factors, and effect on survival

Blood ◽  
2009 ◽  
Vol 113 (17) ◽  
pp. 3911-3917 ◽  
Author(s):  
Grace H. Ku ◽  
Richard H. White ◽  
Helen K. Chew ◽  
Danielle J. Harvey ◽  
Hong Zhou ◽  
...  
Keyword(s):  
Risk Factors ◽  
Venous Thromboembolism ◽  
Acute Leukemia ◽  
Lymphoblastic Leukemia ◽  
Venous Catheter ◽  
Population Based ◽  
Older Age ◽  
Myelogenous Leukemia ◽  
Vein Thrombosis ◽  
Chronic Comorbidities

Abstract A population-based cohort was used to determine the incidence and risk factors associated with development of venous thromboembolism (VTE) among Californians diagnosed with acute leukemia between 1993 to 1999. Principal outcomes were deep vein thrombosis in both the lower and upper extremities, pulmonary embolism, and mortality. Among 5394 cases with acute myelogenous leukemia (AML), the 2-year cumulative incidence of VTE was 281 (5.2%). Sixty-four percent of the VTE events occurred within 3 months of AML diagnosis. In AML patients, female sex, older age, number of chronic comorbidities, and presence of a catheter were significant predictors of development of VTE within 1 year. A diagnosis of VTE was not associated with reduced survival in AML patients. Among 2482 cases with acute lymphoblastic leukemia (ALL), the 2-year incidence of VTE in ALL was 4.5%. Risk factors for VTE were presence of a central venous catheter, older age, and number of chronic comorbidities. In the patients with ALL, development of VTE was associated with a 40% increase in the risk of dying within 1 year. The incidence of VTE in acute leukemia is appreciable, and is comparable with the incidence in many solid tumors.

scholarly journals Changes in Oxidant Defense, Apoptosis, and Cognitive Abilities During Treatment for Childhood Leukemia

2018 ◽  
Vol 20 (4) ◽  
pp. 393-402 ◽  
Author(s):  
Ida M. (Ki) Moore ◽  
Kari M. Koerner ◽  
Patricia M. Gundy ◽  
David W. Montgomery ◽  
Kathleen C. Insel ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cognitive Abilities ◽  
Childhood Leukemia ◽  
Short Term Memory ◽  
Lymphoblastic Leukemia ◽  
Intrathecal Chemotherapy ◽  
Early Event ◽  
Neurologic Injury ◽  
Chemotherapy Administration ◽  
Cognitive Problems

Aggressive central nervous system (CNS)-directed treatment for acute lymphoblastic leukemia (ALL), the most prevalent cancer among children and adolescents, prevents metastasis of leukemia cells into the brain. Up to 60% of survivors experience cognitive problems, but knowledge about risk factors for and mechanisms of neurologic injury is lacking. Objectives of the present study were to (1) quantify changes in oxidant defense and apoptosis over the course of ALL therapy and (2) elucidate risk factors for long-term cognitive problems. The sample included 71 children with ALL. Cerebrospinal fluid (CSF) samples were collected at diagnosis and during intrathecal chemotherapy administration. Oxidant defense was measured by reduced glutathione (GSH), oxidized glutathione (GSSG), and the ratio of GSH:GSSG. Apoptosis was measured by activity of several cysteine-dependent aspartate-specific protease (abbreviated as caspase) enzymes that initiate (caspases 8 and 9) or execute (caspases 3/7) apoptosis. Cognitive abilities were assessed by standardized measures of short-term memory, visual-motor integration, and attention 3 years after ALL diagnosis. GSH and GSSG concentration increased significantly during ALL therapy, and a low GSH:GSSG ratio was indicative of an oxidized extracellular environment. Caspase enzyme activity increased significantly, and caspases 3/7 activity was significantly and negatively associated with performance on measures of cognitive abilities. Younger age at time of ALL diagnosis was associated with some measures of attention. Efflux of glutathione into CSF maintains oxidant defense by scavenging free radicals and other reactive oxygen species and is an early event in apoptosis. These mechanisms may be involved in neurologic injury associated with CNS-directed treatment and subsequent cognitive problems.

scholarly journals Venous Thromboembolism and Its Risk Factors in Children with Acute Lymphoblastic Leukemia in Israel: A Population-Based Study

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2759
Author(s):  
Shlomit Barzilai-Birenboim ◽  
Ronit Nirel ◽  
Nira Arad-Cohen ◽  
Galia Avrahami ◽  
Miri Ben Harush ◽  
...  
Keyword(s):  
Risk Factors ◽  
Venous Thromboembolism ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Univariate Analysis ◽  
Population Based ◽  
Population Based Study ◽  
Inherited Thrombophilia ◽  
Severe Hypertriglyceridemia

Venous thromboembolism (VTE) is a serious complication of acute lymphoblastic leukemia (ALL) therapy. The aim of this population-based study was to evaluate the rate, risk factors, and long-term sequelae of VTE in children treated for ALL. The cohort included 1191 children aged 1–19 years diagnosed with ALL between 2003–2018, prospectively enrolled in two consecutive protocols: ALL-IC BFM 2002 and AIEOP-BFM ALL 2009. VTEs occurred in 89 patients (7.5%). Long-term sequelae were uncommon. By univariate analysis, we identified four significant risk factors for VTEs: Severe hypertriglyceridemia (p = 0.005), inherited thrombophilia (p < 0.001), age >10 years (p = 0.015), and high-risk ALL group (p = 0.039). In addition, the incidence of VTE was significantly higher in patients enrolled in AIEOP-BFM ALL 2009 than in those enrolled in ALL-IC BFM 2002 (p = 0.001). Severe VTE occurred in 24 children (2%), all of whom had at least one risk factor. Elevated triglyceride levels at diagnosis did not predict hypertriglyceridemia during therapy. In a multivariate analysis of 388 children, severe hypertriglyceridemia and inherited thrombophilia were independent risk factors for VTE. Routine evaluation for these risk factors in children treated for ALL may help identify candidates for intervention.

Antileukemic Activity of the HSP70 Inhibitor Pifithrin-μ

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3306-3306
Author(s):  
Martin Kaiser ◽  
Andrea Kuehnl ◽  
Jutta Ortiz-Tanchez ◽  
Ouidad Benlasfer ◽  
Cornelia Schlee ◽  
...  
Keyword(s):  
Cell Viability ◽  
Cell Lines ◽  
Combination Treatment ◽  
Caspase 3 ◽  
Lymphoblastic Leukemia ◽  
Active Form ◽  
Combination Therapies ◽  
Acute Leukemias ◽  
Genetic Characteristics ◽  
B Lineage

Abstract Abstract 3306 Introduction: Heat shock protein (HSP) 70 is aberrantly expressed in acute leukemias and other hematologic and solid malignancies, promoting tumor cell survival and therapy resistance. Recently, the small molecule pifithrin-μ (2-phenylethynesulfonamide) has been identified as a direct inhibitor of inducible HSP70, showing antiproliferative activity in different cell lines of solid tumors. Here, we analysed the in vitro antileukemic effect of pifithrin-μ in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) cell lines, as well as in primary AML blasts. In addition, incubations of pifithrin-μ with cytarabine, the histone deacetylase inhibitor SAHA, the HSP90 inhibitor 17-AAG, and the multikinase inhibitor sorafenib were performed to evaluate the potential use of combination therapies with pifithrin-μ in acute leukemias. Methods: Leukemic cell lines KG-1a (AML), K562 (CML in blast crisis), K562r (cytarabine-resistant K562), NALM-6 (B-lineage ALL), TOM-1 (B-lineage ALL, BCR-ABL pos.), Jurkat (T-lineage ALL), BE-13 (T-lineage ALL) and 9 bone marrow cell samples from newly diagnosed or relapsed AML patients were exposed to pifithrin-μ. Cell viability of all cell lines listed above was quantified by WST-1 assay. Subsequent functional analyses were performed on KG-1a and NALM-6 cells. Apoptosis was determined by annexin-V/7-AAD staining and subsequent flow cytometric analysis. Activated caspase-3 was detected by flow cytometry. Levels of the cell signaling kinase Akt were measured by intracellular staining and FACS analysis. Coincubations of pifithrin-μ with cytarabine, SAHA, 17-AAG or sorafenib were performed in KG-1a, NALM-6 and TOM-1, using WST-1 assays to analyse cytotoxic effects of combination therapies. Results: Pifithrin-μ at low micromolar concentrantions significantly inhibited viability of all acute leukemia cell lines tested, with IC50 values ranging from 2.5 to 12.7 μM independent of the differentiation lineage. Importantly, viability of both cytarabine-sensitive and -resistant K562 cells was effectively inhibited by pifithrin-μ. The median IC50 of primary AML blasts was 8.8 μM, ranging from 5.7 to 11.8 μM with no obvious differences regarding patients' clinical or genetic characteristics. Apoptosis was induced in a time- and dose-dependent fashion with a rate of specific apoptosis of 46% at 4 μM pifithrin-μ for NALM-6 and 36% at 40 μM pifithrin-μ for KG1a. In NALM-6, treatment with 3 μM pifithrin-μ for 24 hours resulted in a significant increase in the cleaved, active form of caspase-3, whereas in KG1a no increase in active caspase-3 was detected. Intracellular concentrations of Akt were markedly reduced after 12 hours incubation of NALM-6 with pifithrin-μ. In NALM-6, KG-1a, and TOM-1 combination treatment of pifithrin-μ at concentrations below the IC50 with either SAHA, 17-AAG or sorafenib resulted in a significant decrease of cell viability compared to corresponding monotherapy. Thus in NALM-6 combination of 2 μM pifithrin-μ with 0.6 μM SAHA inhibited viability by 73%, compared to 22% and 0% inhibition for either drug alone (p<0.05). Combination of 2 μM pifithrin-μ with 2 μM 17-AAG led to 58% inhibition, in contrast the monotherapy inhibited cell viability only in 31% for either drug alone. In NALM-6 and TOM-1, the combination of pifithrin-μ with cytarabine decreased viability significantly (47% and 55%, respectively), whereas the single agents were less effective (22% for 2 μM pifithrin-μ, 24% for 9 nM cytarabine in NALM-6; 26% for 3.5 μM pifithrin-μ and 41% for 40 nM cytarabine in TOM-1). Conclusion: This is, to our knowledge, the first report of the antileukemic effects of the HSP70 inhibitor pifithrin-μ. The inhibitor is highly active against all AML and ALL cell lines tested, including cytarabine resistant cell lines as well as primary leukemic cells. Effectivity of pifithrin-μ could even be increased in combination treatment with other antileukemic agents. Targeting HSP70 might be a promising new therapeutic approach for the treatment of acute leukemias to overcome drug resistance. Thus, our data might build a framework for future clinical trials. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Risk Factors for Childhood Leukemia: Radiation and Beyond

2021 ◽  
Vol 9 ◽  
Author(s):  
Janine-Alison Schmidt ◽  
Sabine Hornhardt ◽  
Friederike Erdmann ◽  
Isidro Sánchez-García ◽  
Ute Fischer ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Lymphoblastic Leukemia ◽  
Mouse Models ◽  
Environmental Risk ◽  
Childhood Leukemia ◽  
Background Radiation ◽  
Lymphoblastic Leukemia ◽  
International Workshop ◽  
Experimental Studies ◽  
The Impact

Childhood leukemia (CL) is undoubtedly caused by a multifactorial process with genetic as well as environmental factors playing a role. But in spite of several efforts in a variety of scientific fields, the causes of the disease and the interplay of possible risk factors are still poorly understood. To push forward the research on the causes of CL, the German Federal Office for Radiation Protection has been organizing recurring international workshops since 2008 every two to three years. In November 2019 the 6th International Workshop on the Causes of CL was held in Freising and brought together experts from diverse disciplines. The workshop was divided into two main parts focusing on genetic and environmental risk factors, respectively. Two additional special sessions addressed the influence of natural background radiation on the risk of CL and the progress in the development of mouse models used for experimental studies on acute lymphoblastic leukemia, the most common form of leukemia worldwide. The workshop presentations highlighted the role of infections as environmental risk factor for CL, specifically for acute lymphoblastic leukemia. Major support comes from two mouse models, the Pax5+/− and Sca1-ETV6-RUNX1 mouse model, one of the major achievements made in the last years. Mice of both predisposed models only develop leukemia when exposed to common infections. These results emphasize the impact of gene-environment-interactions on the development of CL and warrant further investigation of such interactions — especially because genetic predisposition is detected with increasing frequency in CL. This article summarizes the workshop presentations and discusses the results in the context of the international literature.

Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) In Adults With Philadelphia Chromosome (Ph)-Negative Acute Lymphoblastic Leukemia (ALL): Results From The Group For Research On Adult ALL (GRAALL)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 552-552 ◽  
Author(s):  
Nathalie Dhédin ◽  
Anne Huynh ◽  
Sébastien Maury ◽  
Reza Tabrizi ◽  
Xavier Thomas ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
White Blood Count ◽  
Prognostic Impact ◽  
Allogeneic Hsct ◽  
Post Transplant ◽  
Unrelated Donors ◽  
B Lineage

Abstract Purpose The pediatric-inspired intensified GRAALL protocol yielded a marked improvement in the outcome of adults with Ph-negative acute lymphoblastic leukemia (ALL) (Huguet et al,JCO 2009), raising the issue of the place of allogeneic HSCT in this new context. We report here the results associated with HSCT in first complete remission (CR) in younger adults treated in the GRAALL-2003/2005 trials. Patients and methods In these trials, HSCT was offered in first CR to patients aged 15-55 years with ALL at higher risk of relapse. High-risk factors included white blood count >30 x 109/L for B-lineage ALL, central nervous system (CNS) involvement, t(4;11)/MLL anomalies, t(1;19), low hypodiploidy/near triploidy, complex karyotype, early resistance to the steroid prephase (CsR), early resistance to chemotherapy (ChR) as assessed by poor bone marrow blast clearance at day 8, and late CR. Per protocol, HSC donor should be a matched sibling or an unrelated donor (10/10 or eventually 9/10 HLA matched) and conditioning regimen should include single fraction 10-Gy or fractionated 12-Gy total body irradiation (TBI) and high-dose cyclophosphamide. The role of HSCT was evaluated by HSCT versus no-HSCT cohort comparison (Mantel-Byar time-dependent analysis). Results Among the 522 high-risk patients eligible, 283 (54%) actually received HSCT in first CR (185 B-lineage and 98 T-lineage ALL; median age, 31 years). There were no significant differences in baseline characteristics and early response between HSCT and no-HSCT cohorts, except more HSCT patients with t(4;11)/MLL anomalies. Among the 283 HSCT patients, 46 had t(4;11)/MLL anomalies, 13 had CNS disease, 116 had CsR and 176 had ChR ALL. Origin of HSC was 140 sibling and 143 unrelated donors, including 47 unrelated donors with 1 HLA mismatch. The following HSCT protocol violations were observed: a) conditioning did not include TBI in 17 patients; b) 10 patients received reduced-intensity conditioning (RIC); and c) 13 patients received cord blood HSCT. These patients remained in the HSCT cohort for the analysis. With a median post-transplant follow-up of 3.5 years, post-HSCT cumulative incidence of relapse (CIR), non-relapse mortality (NRM) and relapse-free survival (RFS) were estimated respectively at 19% (95% CI, 15-25), 16% (95% CI, 12-21) and 64% (95% CI, 58-70) at 3 years, without any RFS difference between sibling and unrelated donors. A marked trend for a higher NRM was observed in patients aged 45 years or more (26% versus 13% at 3 years; HR, 1.6; p=0.059), while post-transplant CIR was similar in older and younger patients. Mantel-Byar RFS estimations showed no significant difference between both HSCT and no-HSCT cohorts (HR, 0.80; p=0.13), meaning that the risk factors used in these protocols failed to identify patients who could significantly benefit from HSCT in first CR. As minimal residual disease (MRD) had a major prognostic impact, we retrospectively analyzed the effect of HSCT in the 278/522 patients evaluated for 6-week Ig/TCR MRD level (154 HSCT and 124 no-HSCT patients, including 92 and 62 patients with MRD >=10-4, respectively). Mantel-Byar RFS estimations showed that HSCT did not benefit to patients with MRD <10-4 (HR, 1.2; p=0.67) as opposed to those with MRD >=10-4 (HR, 0.6; p=0.02), with a positive HSCT-by-MRD interaction (p=0.04) (Figure 1). Conclusion In adult patients with high-risk ALL in first CR treated in the GRAALL-2003/2005 trials, myeloablative allogeneic HSCT from sibling and unrelated donors was associated with a 64% RFS at 3 years. The 26% NRM observed at 3 years in patients aged 45 years or more suggests considering RIC-HSCT in these patients. MRD response appears to be a powerful tool to select patients who might benefit from HSCT. This selection tool will be prospectively evaluated in the next GRAALL-2013 trial. ND and AH contributed equally to the work. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Maternal Residential Proximity to Major Roadways and the Risk of Childhood Acute Leukemia: A Population-Based Case-Control Study in Texas, 1995–2011

2019 ◽  
Vol 16 (11) ◽  
pp. 2029 ◽  
Author(s):  
Erin C. Peckham-Gregory ◽  
Minh Ton ◽  
Karen R. Rabin ◽  
Heather E. Danysh ◽  
Michael E. Scheurer ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Early Life ◽  
Childhood Leukemia ◽  
Lymphoblastic Leukemia ◽  
Birth Certificate ◽  
Population Based ◽  
Residential Proximity ◽  
Early Life Exposure ◽  
Proximity Measures ◽  
Childhood Acute Leukemia

Acute leukemia is the most common pediatric malignancy. Some studies suggest early-life exposures to air pollution increase risk of childhood leukemia. Therefore, we explored the association between maternal residential proximity to major roadways and risk of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Information on cases with acute leukemia (n = 2030) was obtained for the period 1995–2011 from the Texas Cancer Registry. Birth certificate controls were frequency matched (10:1) on birth year (n = 20,300). Three residential proximity measures were assessed: (1) distance to nearest major roadway, (2) residence within 500 meters of a major roadway, and (3) roadway density. Multivariate logistic regression was used to generate adjusted odds ratios (aOR) and 95% confidence intervals (CI). Mothers who lived ≤500 meters to a major roadway were not more likely to have a child who developed ALL (OR = 1.03; 95% CI: 0.91–1.16) or AML (OR = 0.84; 95% CI: 0.64–1.11). Mothers who lived in areas characterized by high roadway density were not more likely to have children who developed ALL (OR = 1.06, 95% CI: 0.93–1.20) or AML (OR = 0.83, 95% CI: 0.61–1.13). Our results do not support the hypothesis that maternal proximity to major roadways is strongly associated with childhood acute leukemia. Future assessments evaluating the role of early-life exposure to environmental factors on acute leukemia risk should explore novel methods for directly measuring exposures during relevant periods of development.

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