Pharmacokinetic, Pharmacodynamic and Pharmacogenetic Determinants of Osteonecrosis In Children with Acute Lymphoblastic Leukemia.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1033-1033
Author(s):  
Jitesh D. Kawedia ◽  
Sue Kaste ◽  
Deqing Pei ◽  
John C Panetta ◽  
Xiangjun Cai ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Serum Albumin ◽  
Serum Cholesterol ◽  
Odds Ratio ◽  
Lymphoblastic Leukemia ◽  
Elevated Serum ◽  
Systemic Exposure ◽  
Genomic Variation ◽  
Cholesterol Levels ◽  
Increased Risk

Abstract Abstract 1033 Osteonecrosis is a debilitating corticosteroid-induced toxicity in patients treated for acute lymphoblastic leukemia (ALL). Our goal was to ascertain genetic and non-genetic risk factors for this complication. In St. Jude Total XV protocol for children with newly diagnosed ALL, we prospectively screened 365 patients with magnetic resonance imaging of hips and knees, irrespective of symptoms. We determined whether age, race, sex, ALL treatment arm, body mass index, serum lipids, albumin and cortisol levels, dexamethasone pharmacokinetics and genome-wide germline genetic polymorphisms were associated with symptomatic (grade 2–4) osteonecrosis. Sixty-eight patients developed symptomatic osteonecrosis with a cumulative incidence of 17%. Age greater than 10 years (odds ratio 4.8; 95 % confidence interval [CI], 2.5–9.2; p = 0.00001) and treatment arm (standard/high risk vs. low risk) (odds ratio 2.5; 95% CI 1.2–4.9; p = 0.011) were associated with increased risk of osteonecrosis, and were included as covariates in all other analyses. Lower serum albumin (p = 0.04) and higher serum cholesterol levels (p = 0.02) were associated with symptomatic (grade 2–4) osteonecrosis. In addition, higher dexamethasone plasma exposure (area-under-the-curve) was associated with severe (grade 3–4) osteonecrosis (p = 0.0007). After adjusting for clinical features (age and treatment arm), we identified several single nucleotide polymorphisms (SNPs) associated with the risk of developing osteonecrosis. These include: ACP1 (rs12714403, p = 1.03 × 10-5; odds ratio 4.8; 95% CI 2.4–9.6), a gene involved in regulation of lipids and osteoblast differentiation; and SH3YL1 (rs4241316, p = 5.7 × 10-6; odds ratio 5.0; 95% CI 2.5–10.1). These SNPs were also associated with lower albumin and elevated serum cholesterol levels. In conclusion, older age, lower albumin levels, increased dexamethasone systemic exposure, and higher cholesterol levels were associated with osteonecrosis. Inherited genomic variation that predisposes to osteonecrosis may do so via pleiotropic effects on dexamethasone pharmacokinetics, serum cholesterol and serum albumin. Disclosures: Pui: EUSA Pharma: Honoraria; Enzon: Honoraria; Sanofi-Aventis: Honoraria. Relling:St. Jude Children's Research Hospital: Employment, Patents & Royalties; Enzon Pharmaceuticals: Research Funding.

scholarly journals Pharmacokinetic, pharmacodynamic, and pharmacogenetic determinants of osteonecrosis in children with acute lymphoblastic leukemia

Blood ◽  
2011 ◽  
Vol 117 (8) ◽  
pp. 2340-2347 ◽  
Author(s):  
Jitesh D. Kawedia ◽  
Sue C. Kaste ◽  
Deqing Pei ◽  
John C. Panetta ◽  
Xiangjun Cai ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Confidence Interval ◽  
Odds Ratio ◽  
Lymphoblastic Leukemia ◽  
Genomic Variation ◽  
Lipid Levels ◽  
Genome Wide ◽  
Elevated Cholesterol ◽  
Leukemia Treatment ◽  
Grade 3

Abstract Osteonecrosis is a severe glucocorticoid-induced complication of acute lymphoblastic leukemia treatment. We prospectively screened children (n = 364) with magnetic resonance imaging of hips and knees, regardless of symptoms; the cumulative incidence of any (grade 1-4) versus symptomatic (grade 2-4) osteonecrosis was 71.8% versus 17.6%, respectively. We investigated whether age, race, sex, acute lymphoblastic leukemia treatment arm, body mass, serum lipids, albumin and cortisol levels, dexamethasone pharmacokinetics, and genome-wide germline genetic polymorphisms were associated with symptomatic osteonecrosis. Age more than 10 years (odds ratio, = 4.85; 95% confidence interval, 2.5-9.2; P = .00001) and more intensive treatment (odds ratio = 2.5; 95% confidence interval, 1.2-4.9; P = .011) were risk factors and included as covariates in all analyses. Lower albumin (P = .05) and elevated cholesterol (P = .02) associated with symptomatic osteonecrosis, and severe (grade 3 or 4) osteonecrosis was linked to poor dexamethasone clearance (P = .0005). Adjusting for clinical features, polymorphisms of ACP1 (eg, rs12714403, P = 1.9 × 10−6, odds ratio = 5.6; 95% confidence interval, 2.7-11.3), which regulates lipid levels and osteoblast differentiation, were associated with risk of osteonecrosis as well as with lower albumin and higher cholesterol. Overall, older age, lower albumin, higher lipid levels, and dexamethasone exposure were associated with osteonecrosis and may be linked by inherited genomic variation.

Central Venous Lines in Children With Lesser Risk Acute Lymphoblastic Leukemia: Optimal Type and Timing of Placement

2005 ◽  
Vol 23 (13) ◽  
pp. 3024-3029 ◽  
Author(s):  
Thomas W. McLean ◽  
Christen J. Fisher ◽  
Beverly M. Snively ◽  
Allen R. Chauvenet
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Blood Culture ◽  
Positive Blood Culture ◽  
Odds Ratio ◽  
Pediatric Patients ◽  
Lymphoblastic Leukemia ◽  
Complication Rates ◽  
Central Venous ◽  
Increased Risk ◽  
Optimal Type

Purpose In pediatric patients with acute lymphoblastic leukemia (ALL), the optimal time for central venous line (CVL) insertion and the optimal type of CVL (internal v external) is unclear. This study was undertaken to compare complication rates between early versus late line insertion, and between internal versus external lines in children with lesser risk ALL. Patients and Methods We performed a retrospective analysis of patients enrolled onto Pediatric Oncology Group (POG) protocol 9201. Data regarding demographics, CVL types and insertion dates, blood counts, and complications were reviewed through week 25 of therapy. Results Of 697 patients enrolled onto POG protocol 9201, 362 patients had sufficient data for analysis. When compared to late line placement (> day 15 of induction), early CVL placement (≤ day 15 of induction) was associated with an increased risk of having a positive blood culture (odds ratio, 2.2; 95% CI, 1.0 to 5.0; P = .05). When compared with internal CVLs (“ports”), external CVLs were associated with a positive blood culture (odds ratio, 3.1; 95% CI, 1.3 to 7.5; P = .01), thrombosis (odds ratio, 3.9; 95% CI, 1.5 to 10.3; P = .006), and CVL removal (odds ratio, 5.6; 95% CI, 2.7 to 11.6; P < .001). Conclusion In pediatric patients with lesser risk ALL, internal lines (ports) should be the preferred CVL type due to a lower risk of infectious and thrombotic complications. In addition, CVLs placed early in induction are associated with a higher risk of positive blood culture than those placed later in induction.

Systemic Exposure to Dexamethasone and Asparaginase Affects Risk of Relapse in Children with Acute Lymphoblastic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2550-2550
Author(s):  
Jitesh D. Kawedia ◽  
Chengcheng Liu ◽  
Deqing Pei ◽  
Cheng Cheng ◽  
Christian A Fernandez ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Confidence Interval ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Systemic Exposure ◽  
Hazard Ratio ◽  
Research Hospital ◽  
Cns Relapse ◽  
Increased Risk ◽  
Risk Of Relapse

Abstract Abstract 2550 Dexamethasone and asparaginase are key components of acute lymphoblastic leukemia (ALL) treatment. We previously observed that patients with a higher systemic exposure to asparaginase had a lower clearance and thus a higher systemic exposure to dexamethasone (Yang et al, J Clin Oncol; 26:1932–9, 2008). Whether interpatient dexamethasone pharmacokinetic variability contributes to relapse risk is not known. We determined the prognostic influence of dexamethasone plasma clearance and of anti-asparaginase antibody levels on risk of relapse via multivariate analyses after adjusting for standard clinical and biologic prognostic factors (treatment risk arm, age, race, initial leukocyte count, ALL immunophenotype, minimal residual disease and CNS status) in 410 children with ALL who were treated on a front-line clinical trial (St. Jude Total XV) and were evaluable for the pharmacologic measures through at least 22 weeks from diagnosis. Dexamethasone apparent clearance (average ± standard deviation) was significantly (p = 3 ×10−8) higher in patients with detectable serum levels of anti-asparaginase antibodies (17.7 ± 18.6 L/h/m2) compared to patients with no detectable antibodies (10.6 ± 5·99 L/h/m2), consistent with higher exposure to asparaginase being associated with higher exposure to dexamethasone. In multivariate analysis, higher dexamethasone clearance was associated with a higher risk of any relapse (hematologic, CNS, combined, and other; hazard ratio 1.56, 95% confidence interval, 1.1–2.19; p = 0.01) and of any CNS relapse (CNS and CNS + hematologic; hazard ratio 1.93, 95% confidence interval 1.1–3.37; p = 0.02). CNS relapse was also more frequent in patients with vs. those without anti-asparaginase antibodies (5-year cumulative risk of 4.9% vs. 1.8%; p = 0.02). Classification and regression tree analysis revealed that a dexamethasone clearance greater than 37.5 L/h/m2 might distinguish patients at higher risk of relapse (Figure). In conclusion, the presence of anti-asparaginase antibodies is associated with increased systemic clearance of dexamethasone. Lower exposure to dexamethasone and asparaginase are associated with an increased risk of relapse in children with ALL treated with contemporary therapy. The cumulative incidence of any relapse (A) and CNS relapse (B) was higher in patients with dexamethasone (Dex) clearance (CL) greater than 37.5 L/h/m2 than in those with lower clearance (p values based on log rank test). Disclosures: Evans: St. Jude Children's research Hospital: Employment, Patents & Royalties; NIH & NCI: Research Funding; Aldagen: Membership on an entity's Board of Directors or advisory committees. Relling:Sigma-Tau Pharmaceuticals, Inc: Investigator-initiated research; NIH: Research Funding; St. Jude Children's Research Hospital: Employment, Patents & Royalties.

A SERPINE1 (PAI-1) Single Nucleotide Polymorphism Predicts Osteonecrosis in Children Treated for Acute Lymphoblastic Leukemia: Results of the Children’s Oncology Group (COG) Study AALL03B2.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 709-709
Author(s):  
Leo H. Hamilton ◽  
Leonard A. Mattano ◽  
Harland N. Sather ◽  
Mary V. Relling
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Acute Lymphoblastic Leukemia ◽  
Odds Ratio ◽  
Lymphoblastic Leukemia ◽  
Plasminogen Activator Inhibitor ◽  
Serum Levels ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Increased Risk ◽  
Pai 1

Abstract As intensity of glucocorticoid use has increased, osteonecrosis has become an increasingly frequent complication of modern intensive chemotherapy for pediatric patients with acute lymphoblastic leukemia (ALL). Although patient age &gt; 10 years is a well-known risk factor, other host risk factors that may predispose to this complication are not well described. We tested whether 12 polymorphisms in 11 candidate genes were associated with osteonecrosis among up to 344 patients ≥ 10 years old treated on the Children’s Cancer Group protocol CCG 1882 for newly diagnosed high-risk ALL, adjusting for gender, age, and treatment arm (augmented versus standard treatment). Genes tested (TYMS, ER, MTHFR, ABCB1, BGLAP (osteocalcin), ACP5, LRP5, ESR, SERPINE1, VDR, PTH, and PTHR) were chosen because they are candidates based on the putative mechanisms underlying osteonecrosis risk, including involvement in antifolate pharmacodynamics, drug pharmacokinetics, thrombosis risk, and possible hormonal influence on glucocorticoid effects. All children received dexamethasone during the delayed intensification phase of therapy, with doses varying by treatment arm (one dexamethasone pulse in the standard chemotherapy arm vs. two dexamethasone pulses in the augmented chemotherapy arm). Of the 11 candidate polymorphisms, a single nucleotide polymorphism (dbSNP rs6092) in the SERPINE1 gene (plasminogen activator inhibitor type 1 or PAI-1) was the only polymorphism associated with an increased risk of osteonecrosis in both univariate (p=0.0039) and multivariate (p=0.0019) analyses (adjusting for gender, age, and treatment arm), with an odds ratio of 2.51 (95% CI 1.32 to 4.74). Overall, 23.9% of the 88 children heterozygous or homozygous for the SERPINE1 T allele, versus 11.1% of the 234 children homozygous for the C allele, developed osteonecrosis. The combined CT or TT genotypes were present in a greater percentage (27%) of whites than in blacks (12%, p = 0.016), consistent with a higher risk (p = 0.003) of osteonecrosis in whites than blacks that was originally reported for CCG-1882 (J Clin Oncol18:3262–72, 2000). In a multivariate analysis, only the SERPINE1 polymorphism and sex predicted AVN, with the incidence of osteonecrosis lower in boys (odds ratio 0.49, 95% confidence interval 0.25 to 0.96, p = 0.034). No statistically significant gene-gene interactions between SERPINE1 and any other tested genotype were noted. SERPINE1 polymorphisms and PAI-1 serum levels have previously been associated with a clinical pro-thrombotic state. We conclude that polymorphisms in SERPINE1 may contribute to the risk of osteonecrosis in patients treated with glucocorticoids.

scholarly journals Increased Levels of Adipocyte and Epidermal Fatty Acid-Binding Proteins in Acute Lymphoblastic Leukemia Survivors

2021 ◽  
Vol 10 (8) ◽  
pp. 1567
Author(s):  
Katarzyna Konończuk ◽  
Eryk Latoch ◽  
Beata Żelazowska-Rutkowska ◽  
Maryna Krawczuk-Rybak ◽  
Katarzyna Muszyńska-Rosłan
Keyword(s):  
Metabolic Syndrome ◽  
Fatty Acid ◽  
Acute Lymphoblastic Leukemia ◽  
Binding Proteins ◽  
Lymphoblastic Leukemia ◽  
Fatty Acid Binding Proteins ◽  
Fatty Acid Binding ◽  
The Metabolic Syndrome ◽  
Increased Risk ◽  
Significant Difference

Childhood cancer survivors are highly exposed to the development of side effects after many years of cessation of anticancer treatment, including altered lipid metabolism that may result in an increased risk of overweight and metabolic syndrome. Adipocyte (A-FABP) and epidermal (E-FABP) fatty acid-binding proteins are expressed in adipocytes and are assumed to play an important role in the development of lipid disturbances leading to the onset of metabolic syndrome. The aim of this study was to investigate the association between serum A-FABP and E-FABP levels, overweight, and components of the metabolic syndrome in acute lymphoblastic leukemia survivors. Sixty-two acute lymphoblastic leukemia (ALL) survivors (34 females) were included in the study. The mean age at the time of the study was 12.41 ± 4.98 years (range 4.71–23.43). Serum levels of A-FABP and E-FABP were analyzed using a commercially available ELISA kit. The ALL survivors presented statistically higher A-FABP levels in comparison with the healthy controls (25.57 ± 14.46 vs. 15.13 ± 7.61 ng/mL, p < 0.001). The subjects with body mass index (BMI) above the normal range (18 overweight, 10 obese) had a greater level of A-FABP compared to the ALL group with normal BMI (32.02 ± 17.10 vs. 20.33 ± 9.24 ng/mL, p = 0.006). Of all participants, 53.23% had at least one risk factor of metabolic syndrome; in this group, only the A-FABP level showed a statistically significant difference compared to the healthy control group (30.63 ± 15.91 vs. 15.13 ± 7.61 ng/mL, p < 0.001). The subjects with two or more metabolic risk factors (16.13%) presented higher levels of both A-FABP (33.62 ± 17.16 vs. 15.13 ± 7.61 ng/mL, p = 0.001) and E-FABP (13.37 ± 3.62 vs. 10.12 ± 3.21 ng/mL, p = 0.021) compared to the controls. Univariable regression models showed significant associations between BMI and systolic blood pressure with the A-FABP level (coeff. 1.02 and 13.74, respectively; p < 0.05). In contrast, the E-FABP level was only affected by BMI (coeff. 0.48; p < 0.01). The findings reported herein suggest that the increased levels of A-FABP and E-FABP may be involved in the pathogenesis of overweight and the onset of metabolic syndrome in acute lymphoblastic leukemia. However, further longitudinal, prospective studies of fatty acid-binding proteins and their potential role in the pathogenesis of obesity and metabolic syndrome in ALL survivors remain to be performed.

ALL-414: Obesity is Not Associated with an Increased Risk of Venous Thromboembolism in AYA Patients with Acute Lymphoblastic Leukemia

2021 ◽  
Vol 21 ◽  
pp. S276
Author(s):  
Sandra Renee Jones ◽  
Roshni Bharati Patel ◽  
Mahvish Qureshi Rahim ◽  
Sandra K. Althouse ◽  
Sandeep Batra
Keyword(s):  
Venous Thromboembolism ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Increased Risk

An Assessment of Serum Cholesterol level and BMI in Women: Study in Several Private Chambers in Mymensingh

2019 ◽  
Vol 8 (2) ◽  
pp. 4-9
Author(s):  
Nahid Bintay Ansary ◽  
Arup Ratan Paul ◽  
Md Mahamudur Rahman ◽  
Maria Hussain ◽  
Rubiat Naznin
Keyword(s):  
Cardiovascular Disease ◽  
Health Status ◽  
Cholesterol Level ◽  
Serum Cholesterol ◽  
Serum Cholesterol Level ◽  
Normal Weight ◽  
Cholesterol Levels ◽  
Increased Risk ◽  
The Mean ◽  
Study Participants

The increased risk of cardiovascular disease associated with higher serum cholesterol levels in middle-aged persons has been established, but there have been few studies conducted regarding the issues in Mymensingh. For evaluation of serum cholesterol and BMI in women of Mymensingh, across-sectional studywas conducted in several private chambers in the districts of Mymensingh, Bangladesh during the period from January 2017 to December 2017. A total of 48 Female patients participated in the study. In the study, participants were aged between 18 to 29 years of age. The study suggested that the serum cholesterol was below 4.99 were 15(31.25%), 5.00 to 6.49 were 13(26.08%) and above 6.50 were 20 (41.67%), the Mean ± SD was 4.45 (0.76). The health status according to BMI showed that 12.50% (n=6) of the participants were underweight <18.49, majority 50.00% (n=24) of the population were from normal weight range (18.5-24.9), 16.67% (n=8) of the participants were overweight and 20.83 %( n=10) of the participants were obese >30. The Mean ± SD was 18.93± (3.68). Measurement of BMI and Serum Cholesterol levels can help doctors to treat patients properly for reducing the burden of death in our country. CBMJ 2019 July: Vol. 08 No. 02 P: 4-9

scholarly journals Study of Some Biochemical Parameters in Iraqi Children with Acute Lymphoblastic Leukemia

2015 ◽  
Vol 12 (2) ◽  
pp. 371-378
Author(s):  
Baghdad Science Journal
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Biochemical Parameters ◽  
Serum Proteins ◽  
Lymphoblastic Leukemia ◽  
White Blood Cells ◽  
Total Serum ◽  
Childhood All ◽  
Marrow Cavity ◽  
Increased Risk

Leukemia or cancer of the blood is the most common childhood cancer, Acute lymphoblastic leukemia (ALL), is the most common form of leukemia that occurs in children. It is characterized by the presence of too many immature white blood cells in the child’s blood and bone marrow, Acute lymphoblastic leukemia can occur in adults too, treatment is different for children. Children with ALL develop symptoms related to infiltration of blasts in the bone marrow, lymphoid system, and extramedullary sites, such as the central nervous system (CNS). Common constitutional indications consist of fatigue (50%), pallor (25%), fever (60%), and weight loss (26%). Infiltration of blast cells in the marrow cavity and periosteum often lead to bone pain (23%) and disturbance of normal hematopoiesis. Thrombocytopenia with platelet counts less than 100,000 are seen in approximately 75% of patients. About 40% of patients with childhood ALL present with hemoglobin levels less than 7 g/dL. Although leukocyte counts greater than 50,000/mm3 occur in 20% of cases, neutropenia defined as an absolute neutrophil count less than 500 is common at presentation and is associated with an increased risk of infection. The aim of this study was to investigate the differentiations in some biochemical parameters (Hb, PCV, total serum proteins Aspartate amino transferase(AST), Alanin amino transferase (ALT), and Malondialdehyde (MDA) in blood which can be conceder as a marker of ALL. Samples were collected from 50 patients (between 1-16 years old) diagnosed with ALL after one month treatment with induction therapy, compared with 30 control samples taken from healthy persons at the same age . The ALT and MDA showed a significant increase p < 0.001 and p

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