scholarly journals Coagulation abnormalities in childhood acute lymphoblastic leukemia: assessing the impact of L-asparaginase therapy in Ghana

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
William Osei-OWusu ◽  
David Ofosu Ntiamoah ◽  
Gordon Asare Akuffo ◽  
Selina Mintaah ◽  
Michael Owusu ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Protein S ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Induction Phase ◽  
Healthy Controls ◽  
Increased Risk ◽  
Consolidation Phase ◽  
The Impact ◽  
Control Study

Abstract Background Although the rate of childhood acute lymphoblastic leukemia (ALL) is increasing in Africa, there is a dearth of information on the disease and the dynamics of hemostatic parameters with therapy. Methods In this case-control study, we evaluated variations in the level/activity of selected coagulation parameters among cALL in Ghana and healthy controls stratified by stage of therapeutic management. Results In all, the research recruited 104 participants comprising 26 cALL cases and 78 healthy controls. The cALL group had significantly higher prothrombin time (PT) (p = 0.001), activated partial thromboplastin time (APTT) (p < 0.0001) and D-dimers (p = 0.001) but lower platelet (PLT) count, protein C (PC) (p < 0.0001), protein S (PS) (p < 0.0001) and antithrombin III (ATIII) (p < 0.0001) compared to controls. Compared to the healthy controls, activity of PC was lower during induction (p < 0.0001), consolidation (p = 0.005) and maintenance phases of chemotherapy (p = 0.012) while activities of PS and ATIII were lower at both induction (p < 0.0001, p = 0.006) and consolidation (p < 0.0001, p = 0.018) phases of chemotherapy. Conclusion Our findings provide evidence in the context of Africa and corroborates previous reports that cALL could result in a state of hypercoagulability, possibly leading to a high risk of thrombosis and thromboembolic complications. This possibly increased risk is not limited to the induction phase but also the consolidation phase.

scholarly journals Rs4846049 Polymorphism at the 3′-UTR of MTHFR Gene: Association with Susceptibility to Childhood Acute Lymphoblastic Leukemia

2019 ◽  
Vol 2019 ◽  
pp. 1-12
Author(s):  
Xiaolei Li ◽  
Shunguo Zhang ◽  
Feng Yu
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Mrna Expression ◽  
Protective Factor ◽  
Lymphoblastic Leukemia ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Allele Carrier ◽  
Genotype Distribution ◽  
Healthy Controls ◽  
Mthfr Polymorphisms ◽  
Increased Risk

Background. Accumulating evidence has suggested the polymorphisms of methylenetetrahydrofolate reductase (MTHFR) were associated with susceptibility to childhood acute lymphoblastic leukemia (ALL). However, the known conclusions of currently known polymorphic loci (677 C > T and 1298 A > C) remain controversial. This study was to investigate new genetic biomarkers for ALL by analyzing the MTHFR polymorphisms at the 3′-untranslated region, which is a location bound by miRNAs. Methods. Polymorphisms of rs4846049 (miR-555 binding) were assessed by PCR amplification and direct sequencing in 110 ALL patients and 105 healthy controls. The relative expression of MTHFR was detected by qRT-PCR. Results. Overall, genotype distribution or allele carrier frequencies were not significantly different between patients with ALL and healthy controls (P>0.05). Subgroup analysis results showed that T allele (OR = 0.134, 95% CI = 0.028–0.639; P=0.005) or genotypes with T allele (TT + GT) (OR = 0.133, 95% CI: 0.024–0.727; P=0.017) may be a protective factor for ALL susceptibility in patients with age >8 years. This conclusion was also true for the group only focusing on the precursor B-cell ALL patients. Furthermore, karyotype abnormality was more commonly observed in patients with the GG genotype (56.0%) compared to carriers of TT (0%) or GT (40.6%) genotypes, while c-myc break frequency was significantly higher in TT carriers (33%) than that of patients with GT (3.1%) or GG (0%) genotypes. PCR analysis showed patients carrying the GG genotype of rs4846049 exhibited the reduced mRNA expression of MTHFR. Conclusion. MTHFR rs4846049 polymorphism may be associated with increased risk of childhood with ALL and MTHFR mRNA expression.

scholarly journals ABERRANT PROMOTER HYPERMETHYLATION OF SELECTED APOPTOTIC GENES IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA AMONG NORTH INDIAN POPULATION

2017 ◽  
Vol 39 (1) ◽  
pp. 57-64 ◽  
Author(s):  
M Nikbakht ◽  
A K Jha ◽  
K Malekzadeh ◽  
M Askari ◽  
S Mohammadi ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Mrna Expression ◽  
Indian Population ◽  
Lymphoblastic Leukemia ◽  
Promoter Hypermethylation ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Healthy Controls ◽  
North Indian Population ◽  
Childhood All ◽  
The Impact

Promoter hypermethylation mediates gene silencing in many neoplasms. Acute leukemia has been reported to harbor multiple genes aberrantly silenced by hypermethylation. Aim: In present study, we investigated the prevalence of hypermethylation of caspase-8 (CASP8), TMS1 and DAPK genes in correlation with clinicopathological factors in childhood acute lymphoblastic leukemia (ALL). Materials and Methods: A case-control study has been conducted based on bone marrow and peripheral blood samples from 125 ALL patients and 100 sex-age matched healthy controls. Methylation specific polymerase chain reaction (PCR) and bisulfite sequencing PCR was performed to analyze the methylation status of these genes. Reverse transcription PCR and real time PCR was carried out to determine changes in the mRNA expression level of the genes due to hypermethylation. Results: Hypermethylation of the 5´CpG islands of the CASP8, TMS1 and DAPK gene promoters was found in 3.2, 6.4, and 13.6% of 125 childhood ALL samples from north Indian population, respectively. There were significant differences in pattern of hypermethylation of TMS1 (p = 0.045) and DAPK (p < 0.001) between patients and healthy controls. Down-regulation of mRNA expression was found in cases in which CASP8, TMS1 and DAPK were hypermethylated. Conclusions: The present study indicated the impact of hypermethylation-mediated inactivation of CASP8, TMS1 and DAPK genes, which is associated with risk of childhood ALL. This abnormality occurs in leukemogenesis and it may be used as a biomarker and for predicting the prognosis of ALL.

scholarly journals Increase in polymorphonuclear myeloid-derived suppressor cells and regulatory T-cells in children with B-cell acute lymphoblastic leukemia

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Asmaa M. Zahran ◽  
Azza Shibl ◽  
Amal Rayan ◽  
Mohamed Alaa Eldeen Hassan Mohamed ◽  
Amira M. M. Osman ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Critical Role ◽  
Suppressor Cells ◽  
Healthy Controls ◽  
Blast Cells ◽  
Cell Acute Lymphoblastic Leukemia ◽  
The Impact

AbstractOur study aimed to evaluate the levels of MDSCs and Tregs in pediatric B-cell acute lymphoblastic leukemia (B-ALL), their relation to patients’ clinical and laboratory features, and the impact of these cells on the induction response. This study included 31 pediatric B-ALL patients and 27 healthy controls. All patients were treated according to the protocols of the modified St. Jude Children’s Research Hospital total therapy study XIIIB for ALL. Levels of MDSCs and Tregs were analyzed using flow cytometry. We observed a reduction in the levels of CD4 + T-cells and an increase in both the polymorphonuclear MDSCs (PMN-MDSCs) and Tregs. The frequencies of PMN-MDSCs and Tregs were directly related to the levels of peripheral and bone marrow blast cells and CD34 + cells. Complete postinduction remission was associated with reduced percentages of PMN-MDSCs and Tregs, with the level of PMN-MDCs in this subpopulation approaching that of healthy controls. PMN-MDSCs and Tregs jointly play a critical role in maintaining an immune-suppressive state suitable for B-ALL tumor progression. Thereby, they could be independent predictors of B-ALL progress, and finely targeting both PMN-MDSCs and Tregs may be a promising approach for the treatment of B-ALL.

scholarly journals Methotrexate-Induced Neurotoxicity and Leukoencephalopathy in Childhood Acute Lymphoblastic Leukemia

2014 ◽  
Vol 32 (9) ◽  
pp. 949-959 ◽  
Author(s):  
Deepa Bhojwani ◽  
Noah D. Sabin ◽  
Deqing Pei ◽  
Jun J. Yang ◽  
Raja B. Khan ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Multivariable Analysis ◽  
Brain Magnetic Resonance Imaging ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Intrathecal Therapy ◽  
High Dose ◽  
Asymptomatic Patients ◽  
A Genome ◽  
Increased Risk

Purpose Methotrexate (MTX) can cause significant clinical neurotoxicity and asymptomatic leukoencephalopathy. We sought to identify clinical, pharmacokinetic, and genetic risk factors for these MTX-related toxicities during childhood acute lymphoblastic leukemia (ALL) therapy and provide data on safety of intrathecal and high-dose MTX rechallenge in patients with neurotoxicity. Patients and Methods Prospective brain magnetic resonance imaging was performed at four time points for 369 children with ALL treated in a contemporary study that included five courses of high-dose MTX and 13 to 25 doses of triple intrathecal therapy. Logistic regression modeling was used to evaluate clinical and pharmacokinetic factors, and a genome-wide association study (GWAS) was performed to identify germline polymorphisms for their association with neurotoxicities. Results Fourteen patients (3.8%) developed MTX-related clinical neurotoxicity. Of 13 patients rechallenged with intrathecal and/or high-dose MTX, 12 did not experience recurrence of neurotoxicity. Leukoencephalopathy was found in 73 (20.6%) of 355 asymptomatic patients and in all symptomatic patients and persisted in 74% of asymptomatic and 58% of symptomatic patients at the end of therapy. A high 42-hour plasma MTX to leucovorin ratio (measure of MTX exposure) was associated with increased risk of leukoencephalopathy in multivariable analysis (P = .038). GWAS revealed polymorphisms in genes enriched for neurodevelopmental pathways with plausible mechanistic roles in neurotoxicity. Conclusion MTX-related clinical neurotoxicity is transient, and most patients can receive subsequent MTX without recurrence of acute or subacute symptoms. All symptomatic patients and one in five asymptomatic patients develop leukoencephalopathy that can persist until the end of therapy. Polymorphisms in genes related to neurogenesis may contribute to susceptibility to MTX-related neurotoxicity.

Risk of adverse events in children completing treatment for acute lymphoblastic leukemia: St. Jude Total Therapy studies VIII, IX, and X.

1991 ◽  
Vol 9 (8) ◽  
pp. 1341-1347 ◽  
Author(s):  
C H Pui ◽  
R K Dodge ◽  
A T Look ◽  
S L George ◽  
G K Rivera ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Adverse Events ◽  
Lymphoblastic Leukemia ◽  
Rank Test ◽  
Late Failure ◽  
Increased Risk ◽  
Viii And Ix ◽  
Total Therapy ◽  
Therapy Studies ◽  
The Impact

We studied the frequency, causes, and predictors of adverse events in 624 patients who had completed treatment for acute lymphoblastic leukemia (ALL) in three consecutive total therapy studies (VII, IX, and X, 1972 to 1983). Event-free survival in study X was significantly better overall than that in studies VIII and IX (P less than .0001 by the log-rank test). In study X, 75% of the patients were electively taken off therapy, compared with 54% in studies VIII and IX. However, the risks of having an adverse event during the first 5 years after completion of therapy were remarkably similar: 22% (95% confidence interval, 17% to 29%) in study X versus 24% (20% to 29%) in studies VIII and IX. Bone marrow, testicular, and CNS relapses accounted for the majority of failures in both groups (85% in study X and 92% in studies VIII and IX). Late adverse events consisted largely of hematologic relapses and the development of solid tumors. Black race (P = .001) and leukemia without an anterior mediastinal mass (P = .05) were associated with an increased risk of failure after completion of treatment in the two earlier clinical trials, whereas a lower leukemic cell DNA content (DNA index less than 1.16) was the only predictor of late treatment failure in the more recent trial (P = .019). None of the other presenting features that were examined (eg, age, leukocyte count, and sex) had value as predictors of late failure. Thus, improved treatment altered the impact of specific prognostic factors and the distribution of sites of relapse, but it did not significantly affect the risk of delayed failure.

scholarly journals IKZF1 genetic variants rs4132601 and rs11978267 and acute lymphoblastic leukemia risk in Tunisian children: a case-control study

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Sana Mahjoub ◽  
Vera Chayeb ◽  
Hedia Zitouni ◽  
Rabeb M. Ghali ◽  
Haifa Regaieg ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Case Control Study ◽  
Lymphoblastic Leukemia ◽  
Case Control ◽  
Snp Genotyping ◽  
Control Subjects ◽  
False Discovery ◽  
Increased Risk ◽  
The Common ◽  
Control Study

Abstract Background Associations between IKZF1 gene variants and Acute Lymphoblastic Leukemia (ALL) was recently reported. We examined whether the common IKZF1 polymorphisms rs4132601 T/G and rs111978267 A/G are associated with ALL among a Tunisian pediatric cohort. Methods This case-control study involved 170 patients with ALL and 150 control subjects. SNP genotyping was performed by TaqMan® SNP Genotyping Assay. Results The minor allele G of IKZF1 gene polymorphism rs4132601 T/G was significantly higher in ALL cases than in control subjects (P = 0.029), with 1.54-fold increased risk of ALL. The association of rs4132601 with ALL was seen under co-dominant (P = 0.009), recessive (P = 0.006), and additive (P = 0.027) genetic models, of which the co-dominant (P = 0.027) and recessive (P = 0.027) association remained significant after adjusting for covariates, and False Discovery Rate correction. In contrast, no association was noted for rs111978267 variant. Two-locus (rs4132601-rs11978267) IKZF1 haplotype analysis demonstrated association of GA (P = 0.053), with increased ALL risk [OR (95% CI) = 1.58 (1.00–2.51)], which remained significant after controlling for key covariates [aP = 0.046; aOR (95% CI) = 1.61 (1.01–2.57)]. Conclusion We demonstrated the association of IKZF1 polymorphism rs4132601 T/G with increased risk of ALL among Tunisian pediatric cohort, with altered phenotypic changes among ALL patients.

Impact of anti‐oxidant status and apoptosis on the induction phase of chemotherapy in childhood acute lymphoblastic leukemia

Hematology ◽  
2011 ◽  
Vol 16 (1) ◽  
pp. 14-19 ◽  
Author(s):  
Youssef Al‐Tonbary ◽  
Samir Abou Al‐Hasan ◽  
Maysaa Zaki ◽  
Ayman Hammad ◽  
Shaimaa Kandil ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Induction Phase ◽  
Anti Oxidant ◽  
Oxidant Status

Implication of Genetic Variations of Ikzf1, ARIDB5, and CEBPE Genes In the Risk of Childhood Acute Lymphoblastic Leukemia In Korea

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3235-3235
Author(s):  
Dong Kyun Han ◽  
Hee Nam Kim ◽  
Min Ho Shin ◽  
Minenori Eguchi-Ishimae ◽  
Mariko Eguchi ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Genetic Variations ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Asian Countries ◽  
Childhood All ◽  
Genomic Variations ◽  
Genotype Frequencies ◽  
The Impact

Abstract Abstract 3235 Background: Recent western studies have showed the implication of the germline genomic variations in IKZF1 gene at 7p12.2, ARIDB5 gene at 10q21.2, and CEBPE gene at 14q11.2 on the risk of childhood acute lymphoblastic leukemia (ALL); the most significant association was observed in the single nucleotide polymorphism (SNP) rs4132601 which located at 3' region of the IKZF1. IKZF1 plays important role in lymphocyte differentiation, proliferation and function, ARIDB5 in embryogenesis and growth regulation, and CEBPE in regulation of myelopoiesis. Genomic variants in these genes are therefore considered to be involved in transcriptional regulation and differentiation of B cell progenitors. However, there have been no reports on the role of germline variations in leukemogenesis of childhood ALL in Asian countries. The aim of this study is to show the impact of these genetic variants on childhood ALL in Korea. Patients and Methods: To examine the association between genetic variations (IKZF1 rs4132601, ARIDB5 rs7089424, and CEBPE rs2239633) and the risk of childhood ALL, we here analyzed 228 children with ALL and 508 healthy individuals in Korea. Results: In ARIDB5 rs7089424, TG and GG genotypes were significantly associated with a risk for ALL (odds ratio [OR], 1.63; 95% confidential interval [CI], 1.07–2.48; P=0.02 for TG genotype, OR, 2.69; 95% CI, 1.42–5.07; P=0.002 for GG genotype). The allele incidence of ARIDB5 rs7089424 was also significantly associated with a risk for ALL (OR, 1.66; 95% CI, 1.24–2.22; P=0.0006). CEBPE rs2239633 TT genotype showed a significant association with a decreased risk for ALL (OR, 0.54; 95% CI, 0.33–0.90; P=0.02 for TT genotype). The allele incidence of CEBPE rs2239633 was also associated with a decreased risk for ALL (OR, 0.77; 95% CI, 0.61–0.97; P=0.02). There was no significant association between IKZF1 rs4132601 polymorphism and a risk for ALL in this study. Conclusion: These results suggest that genomic variations of ARIDB5 and CEBPE may play an important role in the risk for childhood ALL in Korea, compared with findings from western countries showing a significant relation between IKZF1 and childhood ALL. Several factors should be considered to explain a discrepancy between our results and the previous studies, which include different genotype frequencies in polymorphisms and varied susceptibility to ALL in different ethnic groups. Further studies incorporating larger number of cases and analyzing other SNPs or other Asian countries are warranted in childhood ALL. Disclosures: No relevant conflicts of interest to declare.

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