Pharmacogenetic Outcomes of Pediatric Acute Lymphoblastic Leukemia in Korea

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5047-5047
Author(s):  
Hyoung Jin Kang ◽  
Hyery Kim ◽  
Young Jin Seo ◽  
Mi Kyung Jang ◽  
Yongtaek Oh ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Genetic Polymorphism ◽  
Lymphoblastic Leukemia ◽  
Individualized Therapy ◽  
Treatment Result ◽  
Mutant Type ◽  
Term Survival ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Korean Patients ◽  
Significant Difference

Abstract Treatment result of pediatric acute lymphoblastic leukemia (ALL) has been markedly improved, but treatment related toxicities and relapse are still remaining problems. Genetic polymorphism is an important factor in the effectiveness and toxicity of anti-leukemic drugs and pharmacogenetics are beginning to emerge as useful research filed to solve those problems. In our experience in the treatment of ALL, many Korean patients could not tolerate full dosages of Western protocols. To make basis for individualized therapy with pharmacogenetics, we analyzed major genes implicated in the treatment of ALL. Fourteen genes of total 103 patients with ALL were analyzed with TotalPlex gene amplification methods (Mol Cell Probes.2008. 22: 193). Among the drug related genes (percentage of mutant type) including CYP3A4*1B (0%), CYP3A5*3 (0%), GSTP1 (22.3%), GSTM1 (20.4%), GSTT1 (16.5%), MDR1 exon 21 (76.3%), MDR1 exon 26 (61.2%), MTHFR (64.1%), MTHFR 1298 (29.1%), NR3C1 1088 (0%), RFC 80 (79.6%), TPMT combined genotype (7%), VDR intron 8 (10.7%), VDR FokI (67%), incidence of mutant was higher in GSTM1 deletion, lower in MTHFR 1298, TYMS enhancer repeat, and VDR intron 8 comparing with the data of Western whites (Rocha J.C. et al. Blood 2005). As we had modified the dose of anti-leukemic agents depending on the toxicity during the treatment, we analyzed the relationship between the dose percent of actually administered dose and the distribution of each mutant to find out polymorphisms affecting toxicities of chemotherapeutic drugs. The mean dose percent of mercaptopurine was lower in patients with variant TPMT then those with wild type (33.2% vs. 53.5%, P=0.04), but there was no polymorphism that influenced the dose percent of methotrexate, daunorubicin, doxorubicin, and L-asparaginase. There was no significant difference in the incidence of genotypes between risk groups and individual mutant did not affect long term survival and relapse in Korean patients with ALL. In conclusion, we found some difference in the incidence of mutant genotypes related to the pharmacogenetics of ALL between Korean and Western whites, but there was no individual genetic polymorphism that affect on the treatment outcome. We expect more extensive researches about pharmacogenetics of Korean to establish the basis for individualized therapy with the consideration of ethnical difference.

The Experience on Multiparametric Molecular Diagnostic Approach of Pediatric Acute Lymphoblastic Leukemia (ALL) in Greece.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4448-4448
Author(s):  
Agapi Parcharidou ◽  
Constantina Sambani ◽  
Christina Stavropoulou ◽  
George Paterakis ◽  
Chrysoula Belesi ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Genetic Polymorphism ◽  
Lymphoblastic Leukemia ◽  
Molecular Diagnostic ◽  
Detoxifying Enzymes ◽  
Dna Index ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
In Vitro Chemosensitivity ◽  
Pediatric All

Abstract The rate of success in the treatment of pediatric acute lymphoblastic leukemia (ALL) has been increased steadily during the last decades. The five years’ event free survival rate is nearly 80% for children with ALL. Attempts to boost cure rates further with the use of hematopoietic stem cell transplantation have improved for some but not all, subtypes of ALL. The best hope for continued progress lies in a better understanding of the pathogenesis, the basis of resistance to chemotherapy, and finally better organized clinical trials. The present study has been based on organizing and exploring new clinical correlations among clinical data obtained from molecular genetic profile, in vitro chemosensitivity and genetic polymorphisms of detoxifying enzymes. During the last 3 years 43 newly diagnosed ALL patients, 27 boys and 16 girls, aged 23 months to 14 years old were included in this study. Bone marrow and/or peripheral blood samples were studied for karyotyping aberrations. The presence of the specific translocations t(12;21), t(9;22), t(4;11) and t(1;19) was investigated using RT-PCR and FISH. Furthermore, FISH was also used for the detection 9p deletions and MLL rearrangements. Immunophenotype of blasts and DNA index were studied by flow cytometry. In vitro chemosensitivity studies were performed by the MTT assay (ELISA).The GSTT1 genetic polymorphism (null genotype) was detected by multiplex PCR and NQ1 genetic polymorphism was detected by PCR -RFLPs. A cytogenetic/molecular result was achieved in 39/43 patients. Structural or numerical aberrations were detected in 7/39 patients. 9/39 patients were positive for the TEL/AML1 (23%) and 3/39 for the BCR/ABL fusion genes. One patient showed only one MLL allele, no patient had MLL rearrangement and 5/19 patients presented 9p deletion. A null GSTT1 genotype was observed in 5/43children (11,62%) and 14/43 patients were heterozygotes for NQ1(32,5%). 8/36 patients presented in vitro chemoresistance and 8/43 patients had DNA index >1 (18,6%).In our series of patients the frequency of t(12;21) does not seem to differ significantly from the literature data. The patients who showed chemoresistance had also unfavorable prognostic markers according to cytogenetic/molecular diagnostic data or clinical characteristics. The number of the patients is low to correlate detoxifying enzymes to toxicity or response during treatment. The multiparametric diagnostic approaches in pediatric ALL seem to be of great importance in diagnosis and tailored therapy leading to high rates of cure. Our center’s effort is the optimal characterization of the pediatric ALL profile in Greece by the use of multiparametric diagnostic methods targeting a better outcome.

scholarly journals Evaluating Methotrexate Toxicity and Its Association with ABCB1 Genetic Polymorphism in Children with Acute Lymphoblastic Leukemia

2021 ◽  
Vol In Press (In Press) ◽  
Author(s):  
Farima Zakaryaei ◽  
Ebrahim Mohammadi ◽  
Ebrahim Ghaderi ◽  
Fatemeh Zamani ◽  
Borhan Moradveisi
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Genetic Polymorphism ◽  
Gene Mutation ◽  
Mutation Frequency ◽  
Hematologic Malignancy ◽  
Lymphoblastic Leukemia ◽  
Reaction Products ◽  
Methotrexate Toxicity ◽  
Significant Difference ◽  
Pediatric All

Background: Acute lymphoblastic leukemia (ALL) is among the most prevalent type of hematologic malignancy in children. The Children’s Oncology Group protocol recognizes methotrexate (MTX) as a therapy for this problem in children, despite its several complications. The relationship between MTX toxicity and ATP-binding cassette subfamily B member 1 (ABCB1) SNPs in ALL children patients has been investigated in many studies. Objectives: Regarding the controversial findings reported by these studies, the present work aims to evaluate Methotrexate toxicity and its association with ABCB1 Genetic Polymorphism in ALL pediatric patients. Methods: Blood samples were collected from pediatric ALL patients. Next, DNA was extracted and polymerase chain reaction (PCR) was conducted using 300 μMol/μL of direct primers in 50 µL as the ultimate volume. ABCB1 gene was amplified using the PCR technique, and 0.5% agarose gel electrophoresis was used to identify reaction products. Afterward, the PCR fragments’ length was proved by observing through UV-transilluminator. Finally, liver and blood toxicity was studied in all cases under treatment with MTX. Results: In the present study, 81 children with ALL (36 females and 45 males) with a mean age of 6.32 ± 3.08 years old were examined. The ABCB1 1199 G->A gene mutation frequency and the ABCB1 3435 C->T gene mutation frequency was 4.9 and 70.4%, respectively. The results showed no statistically significant difference between leukopenia, gastrointestinal toxicity, renal toxicity, hepatotoxicity, anemia, thrombocytopenia, and neutropenia in cases having homozygous heterozygous ABCB1 3435 C->T and ABCB1 1199 G->A mutant polymorphisms than those having ordinary polymorphism. Conclusions: Overall, it seems that C3435 T, G1199A, and ABCB1 are not significant MTX toxicity markers in pediatric ALL cases.

scholarly journals Implications of intrachromosomal amplification of chromosome 21 on outcome in pediatric acute lymphoblastic leukemia: Does it affect our patients too?

2019 ◽  
Vol 11 (2) ◽  
Author(s):  
Suleimman Al-Sweedan ◽  
Rahaf Altahan
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Chromosome 21 ◽  
Rare Entity ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Prognostic Effect ◽  
King Faisal Specialist Hospital ◽  
Significant Difference ◽  
Cell Acute Lymphoblastic Leukemia

Intrachromosomal amplification (iAMP) of chromosome 21 entity is associated with a dismal outcome in B cell Acute Lymphoblastic Leukemia (B-ALL). This cytogenetic abnormality is caused by a novel mechanism; breakage-fusion-bridge cycles followed by chromothripsis along with major gross rearrangements in chromosome 21.Charts of B-ALL diagnosed at King Faisal Specialist Hospital and Research Center between 2005 and 2015 were reviewed.iAMP is a rare entity occurring at around 2.4% of all pediatrics B-ALL. No statistically significant difference was found among patients with iAMP21, patients with extra copies of 21 and other patients with B-ALL. The reported adverse prognostic effect of iAMP21 could be due to other coexistent adverse factors, including older age at the time of diagnosis. The most common associated abnormality in our population in addition to the hyperdiploidy was ETV6/RUNX1.

Higher Incidence of Treatment-Related Toxicities in Non-Hispanic Patients Undergoing Therapy for Newly Diagnosed Pediatric Acute Lymphoblastic Leukemia on Dana-Farber Cancer Institute ALL Consortium Protocol 05-001

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 248-248 ◽  
Author(s):  
Justine Kahn ◽  
Sergio Barrera ◽  
Randy Davila ◽  
Emily Roberts ◽  
ZheZhen Jin ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Children And Adolescents ◽  
Lymphoblastic Leukemia ◽  
P Value ◽  
Newly Diagnosed ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Dana Farber Cancer Institute ◽  
Significant Difference ◽  
Hispanic Patients ◽  
Pediatric All

Abstract Background: Risk-adapted treatment strategies have contributed to excellent outcomes in pediatric acute lymphoblastic leukemia (ALL); however, treatment-associated acute and long-term toxicities persist. Therapy-associated toxicities of note in pediatric ALL are related to a treatment backbone that relies heavily on corticosteroids (prednisone and dexamethasone) and asparaginase (ASP). The most frequently observed toxicities include, but are not limited to, serious infection, pancreatitis, thrombosis and bony morbidities including osteonecrosis (ON) and fracture. Previous studies suggest that children of racial and ethnic minorities are at higher risk for treatment-associated toxicities. We assessed the incidence of treatment-related toxicities in Hispanic and non-Hispanic patients undergoing treatment for pediatric ALL. Patients and Methods: Retrospective cohort study investigating the incidence of treatment-related toxicities including infection, allergy to ASP, pancreatitis, thrombosis and bony morbidities in Hispanic and non-Hispanic children and adolescents with newly diagnosed ALL undergoing therapy on Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocol 05-001. The ethnicity of each patient was designated at the time of study enrollment by research coordinators. Descriptive statistics were calculated, mean +/- SD for continuous variables and frequency and percentages for categorical variables. Toxicity rates were based on number of patients. Comparison between groups was done by Chi-square test or FisherÕs exact test and p -value < 0.05 was considered significant. Results: Between 2005 and 2011, 794 children and adolescents (ages 1 - 18 years) were enrolled on Protocol 05-001, 730 of whom were evaluable for this investigation: 150 Hispanic (18%), 580 non-Hispanic (73%). Sixty-four patients did not have ethnicity documented. There was no significant difference in disease-risk group, age or gender between the two groups. Weight was significantly higher in Hispanic patients (31.9 ± 24.4 kg in Hispanic and 26.9 ± 18.7 kg in non-Hispanic, p = 0.021). There was no significant difference in the incidence of ASP-related toxicities (allergy, pancreatitis, thrombosis) between Hispanic and non-Hispanic patients. There was no significant difference in the overall incidence of infection between the two groups (42% in Hispanic and 50% in non-Hispanic, p = 0.081). Non-Hispanic patients had significantly higher rates of opportunistic infection (Pneumocystis pneumonia) than Hispanic patients (0.7% in Hispanic and 4% in non-Hispanic, p = 0.041). A similar difference in the incidence of bacteremia between the two groups approached, but did not reach statistical significance (p = 0.052). The overall incidence of fracture in all patients was 14.5% and was significantly higher in non-Hispanic patients (6% in Hispanic and 16.7% in non-Hispanic, p < 0.001). The overall incidence of ON was 8.9% and was significantly higher in non-Hispanic patients (3.3% in Hispanic and 10.3% in non-Hispanic, p = 0.007). (Table 1) Conclusion: The incidence of opportunistic infections and bony morbidities was significantly higher in non-Hispanic patients undergoing treatment for pediatric ALL on the DFCI ALL Consortium Protocol 05-001. The risk for, and impact of therapy-related toxicities varies by a patientÕs treatment tolerance, perhaps as a function of age and gender or as a result of disease biology or genetic polymorphisms affecting drug metabolism. Additionally, non-biologic factors such as medication adherence and nutritional status may also contribute to toxicity incidence in patients undergoing treatment for pediatric ALL. Prospective studies to further investigate our findings are warranted. Table. All Patients, (N = 730) Non-Hispanic, (N = 580) Hispanic, (N = 150) p -value Overall Infection 353/730 (48.4%) 290/580 (50%) 63/150 (42%) 0.081 Bacteremia 289/730 (39.6%) 240/580 (41.4%) 49/150 (9.3%) 0.052 Opportunistic Infection 24/730 (3.3%) 23/580 (4%) 1/150 (0.7%) 0.041 Fracture 106/730 (14.5%) 97/580 (16.7%) 9/150 (6%) <0.001 Osteonecrosis 65/730 (8.9%) 60/580 (10.3%) 5/150 (3.3%) 0.007 Thrombosis* 36/730 (4.9%) 26/580 (4.5%) 10/150 (6.7%) 0.271 Pancreatitis* 78/730 (10.7%) 60/580 (10.3%) 18/150 (12%) 0.559 ASP Allergy* 76/730 (10.4%) 57/580 (9.8%) 19/150 (12.7%) 0.310 *ASP-related toxicity Disclosures No relevant conflicts of interest to declare.

scholarly journals The influence of MTHFR genetic polymorphisms on methotrexate therapy in pediatric acute lymphoblastic leukemia

2021 ◽  
Vol 16 (1) ◽  
pp. 1203-1212
Author(s):  
Yaqing Shen ◽  
Zhujun Wang ◽  
Fen Zhou ◽  
Runming Jin
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Mthfr C677t ◽  
Methotrexate Therapy ◽  
Mthfr Polymorphisms ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Cancer Group ◽  
Increased Risk ◽  
Significant Difference ◽  
The Relationship

Abstract MTHFR is a crucial enzyme in folate metabolism. This study aimed to determine the relationship between MTHFR genetic polymorphism and elimination and toxicities of methotrexate (MTX). To do that, the study enrolled 145 patients diagnosed with acute lymphoblastic leukemia, who received chemotherapy following the Chinese Children’s Cancer Group Acute Lymphoblastic Leukemia (CCCG-ALL)-2015 protocol (clinical trial number: ChiCTR-IPR-14005706). We analyzed the effects of MTHFR C677T and A1298C polymorphisms on MTX elimination and toxicities. Patients with the MTHFR C677T TT genotype could tolerate a significantly higher MTX dose than those with the CC/CT genotype. However, patients with C677T TT genotypes had an increased risk of hypokalemia (1.369 to CC and 1.409 to CT types). The MTX infusion rate in patients with the MTHFR A1298C AC genotype was slightly lower than that in those with CC or AA genotypes. Patients with the A1298C AA genotype had a 1.405-fold higher risk of hepatotoxicity than those with the AC genotype (P > 0.05). There was no significant difference between the prevalence of other toxicities among MTHFR C677T or A1298C genotypes (P > 0.05). Neither MTHFR C677T nor A1298C polymorphisms were significantly associated with delayed MTX clearance. To conclude, MTHFR polymorphisms were not good predictors of MTX-related toxicities.

Nutritional Status of Children with Pediatric Acute Lymphoblastic Leukemia

2021 ◽  
Vol 15 (12) ◽  
pp. 3222-3224
Author(s):  
Wasila Shamim ◽  
Saadia Anwar ◽  
Mahwish Faizan
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Nutritional Status ◽  
Lymphoblastic Leukemia ◽  
Older Age ◽  
Age Group ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Significant Difference ◽  
Nutritional Status Of Children ◽  
Height For Age ◽  
Weight For Age

Aim: To analyze the nutritional status of children with pediatric Acute Lymphoblastic Leukemia (ALL) at presentation. Study design: Descriptive prospective study Place and duration of study: Department of Paediatric Haematology Oncology, Children Hospital, Lahore from March 2018 to April 2019. Methodology: A total of 195 children diagnosed as acute lymphoblastic leukemia on bone marrow biopsy were included. Anthropometric measurements were taken for each patient. Results: Out of 195 diagnosed patients with ALL, majority were having B-cell ALL 165(84.6%) and 30(15.4%) T-cell ALL. There was almost equal number of both standard and high risk patients (49% vs 51%) respectively. Mean age of children was 6.79±3.78 years and there was male predominance 120(61.5%). The percentage of children having weight for age <5th centile was 91(47), only 8(4%) were overweight or obese. Children under the age of five years had a slightly higher propensity of weight <5th centile i.e. 47(51.6%) as compared to older age group 5-10 years 26(28.7%) and >10 years 18(19.7%) (p=0.295).Similarly height for age was <5th centile in 50(26%) children in total, and in under 5 year age group 26(13.3%) but there was no statistically significant difference related to age above 5 years (p=0.547). Conclusion: Pediatric ALL has overall high prevalence of under nutrition and both weight for age and height for age is lower in under-five children as compared to older age group. Keywords: Children, cancer, nutrition, malnutrition, Acute Lymphoblastic leukemia

scholarly journals Mutational patterns and clonal evolution from diagnosis to relapse in pediatric acute lymphoblastic leukemia

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shumaila Sayyab ◽  
Anders Lundmark ◽  
Malin Larsson ◽  
Markus Ringnér ◽  
Sara Nystedt ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Large Scale ◽  
Somatic Mutations ◽  
Lymphoblastic Leukemia ◽  
Clonal Evolution ◽  
Point Mutations ◽  
Driver Genes ◽  
Protein Coding ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Evolutionary Trajectories

AbstractThe mechanisms driving clonal heterogeneity and evolution in relapsed pediatric acute lymphoblastic leukemia (ALL) are not fully understood. We performed whole genome sequencing of samples collected at diagnosis, relapse(s) and remission from 29 Nordic patients. Somatic point mutations and large-scale structural variants were called using individually matched remission samples as controls, and allelic expression of the mutations was assessed in ALL cells using RNA-sequencing. We observed an increased burden of somatic mutations at relapse, compared to diagnosis, and at second relapse compared to first relapse. In addition to 29 known ALL driver genes, of which nine genes carried recurrent protein-coding mutations in our sample set, we identified putative non-protein coding mutations in regulatory regions of seven additional genes that have not previously been described in ALL. Cluster analysis of hundreds of somatic mutations per sample revealed three distinct evolutionary trajectories during ALL progression from diagnosis to relapse. The evolutionary trajectories provide insight into the mutational mechanisms leading relapse in ALL and could offer biomarkers for improved risk prediction in individual patients.

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