scholarly journals Analysis of polymorphisms in the TPMT gene in children with acute leukemia in the Krasnoyarsk Territory

Author(s):  
A. A. Karnyushka ◽  
T. N. Subbotina ◽  
R. V. Shaikhutdinova ◽  
M. V. Borisova ◽  
S. M. Lobanova ◽  
...  

Introduction.Leukemia accounts for 40 % of all malignant neoplasms under the age of 15 years in children. Determination of the genetic portrait of patients with acute lymphoblastic leukemia (ALL) helps to identify polymorphisms in the genes responsible for the metabolism of drugs included in standard treatment protocols.Materials and methods.51 children with confirmed diagnosis of acute lymphoid leukemia (ALL) were included in the analysis of the frequency of polymorphism of TPMT gene. The detection of polymorphisms TPMT*2, TPMT*3A and TPMT*3 was performed using a set of reagents “AmpliSens® Pyroskrin” & “FARMA-screen-2b”.Results.Polymorphisms in the TPMT gene of 51 patients were found in 6 (11.8 %) children. Of these, 4 patients have variant alleles TPMT*3A and TPMT*3C and 2 patients have only TPMT*3C. Of the 6 patients with TPMT polymorphism, two have a translocation t(12;21).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2827-2827
Author(s):  
Gabriele Stocco ◽  
Meyling Cheok ◽  
Wenjian Yang ◽  
Thierry Dervieux ◽  
Kristine Crews ◽  
...  

Abstract Germline polymorphisms can be significant determinants of toxicity to anti-leukemic therapy. For mercaptopurine (6MP) it is established that variant alleles of the thiopurine-S-methyl-transferase (TPMT) gene, resulting in low enzymatic activity, are associated with an increase in the concentration of thioguanine-nucleotide metabolites (TGN) and in the risk of hematotoxicity. Polymorphisms of genes encoding other enzymes involved in 6MP metabolism could also influence its pharmacokinetics and consequently its efficacy and toxicity. Among possible candidate genes, inosine-triphosphate-pyrophosphatase (ITPA) has been related to adverse events to thiopurine treatment of inflammatory bowel disease, but it has not been fully investigated for leukemia therapy. The aim of this study was to assess the association between severe life-threatening toxicities (Grade 3–4) during the continuation treatment of acute lymphoblastic leukemia (ALL) and the variant alleles of TPMT and ITPA genes, and the influence of these variant alleles on the concentration of 6MP metabolites, TGN and methylated nucleotides (MMPN). Patients with ALL on the St. Jude Total 13B protocol were assessed for toxicity according to NCI criteria. Relevant variant alleles of TPMT (SNPs rs1142345, rs1800462, rs1800660) and ITPA (SNP rs41320251) were determined using PCR assays. The association between the variant alleles and the development of adverse events during the continuation phase of treatment was assessed using weighted logistic regression. Concentrations of the two main metabolites of 6MP were measured in erythrocytes by HPLC; the association between genotypes and the concentrations of 6MP metabolites was evaluated using mixed linear effects models. TPMT and ITPA genotypes were determined for 233 patients; 13 (5.2%) were heterozygous for variant alleles of the TPMT gene and 31 (13.3%) for the ITPA gene; no patient had two variant alleles of either gene and 1 patient (0.4%) had a variant allele for both TPMT and ITPA. Since 6MP dose was individualized based on the TPMT variant allele among patients treated in the protocol, genetic polymorphisms of TPMT, not surprisingly, were not associated with toxicity. On the other hand, the presence of an ITPA variant allele was significantly associated with the incidence of Grade 3–4 fever with neutropenia in the univariate and in the multiple weighted logistic regression (odds ratio 3.0, 95% C.I. 1.2–7.8, p = 0.021). 6MP metabolites were measured in 257 samples from 108 patients, and the results revealed that variant alleles of both candidate genes were associated with changes in the concentration of the MMPN metabolites: TPMT with a reduction (p = 0.048) and ITPA with an increase (p = 0.047). Genetic polymorphism of ITPA rs41230251 is a significant determinant of severe and life-threatening fever with neutropenia and of 6MP metabolism in patients with ALL who are treated with 6MP doses individualized based on TPMT genotype.


Introduction: Acute leukemias have generated great interest in the world to be within the ten most common cancers, and children ranks first in malignancies. Objective: Analyze the demographic, genetic, environmental, pre and perinatal factors associated with acute lymphoblastic leukemia in pediatric acute leukemia group in Medellin during 2008 - 2011. Methods: Cross-sectional study in children under 15 years with leukemia acute in Medellin and the metropolitan area during 2008 -2011.Se implemented a logistic regression model to identify factors associated with acute lymphoblastic leukemia. Results: 80 patients were studied. Factors associated with multivariate analysis were acute lymphoid leukemia: Daily consumption of alcohol by the father (OR: 3.95; 95% CI 1.26 to 7.55) and that the child had been breastfed (OR: 0.036, 95% CI 0.002 to 0.83). Conclusions: The identification of risk and protective factors associated with acute lymphoid leukemia (ALL) in Medellin and its metropolitan area; they are a useful tool for health planning input.


Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 26-27
Author(s):  
Shehab Fareed Mohamed ◽  
Elabbass Abdelmahmuod ◽  
Elrazi Awadelkarim A Ali ◽  
Abdulqadir Jeprel Nashwan ◽  
Dina Sameh Soliman ◽  
...  

Introduction Acute leukemias can be divided into acute myeloid leukemia and acute lymphoblastic leukemia. Common presentations of acute leukemia include fever, symptoms of anemia, bleeding, bone pain palpable Lymph nodes or spleen and symptoms due inflation or leukocystasis. Extramedullary mass is rare and can be of myeloid tissue and known as Chloroma or myeloid (granulocytic) sarcoma which one of the WHO classifications for acute myeloid leukemia. Common sites of occurrence are skin, sinuses, bone and other. It's rarely involve central nervous system. Spinal cord involvement usually manifest as epidural mass causing cord compression. Spinal epidural tumor with acute leukemia and myeloid sarcoma is rare and can be found in 3-9% in patients with leukemia. In this review we decide to review the cases of spinal cord compression caused by acute myeloid leukemia (including Chloroma) and acute lymphoblastic leukemia due to the significance of such presentation in addition to reports that Myeloid sarcoma of the spine has very poor prognosis Methodology: We have reviewed the literature using: PubMed, google scholar, Scopus for patient with spinal cord compression and acute leukemia. We used the search term and synonyms : : acute myeloid leukemia , acute myelocytic leukemia , acute monocytic leukemia , acute lymphoblastic leukemia , acute lymphoid leukemia, chloroma , myeloid sarcoma ,granulocytic sarcoma, spinal cord compression .We included adult patients above 18 years old only cases we exclude pediatrics cases and cases of chronic leukemia's and other myeloproliferative disorders as well as cases of central nervous system involvement other than spinal cord Results We gathered the information from 98 cases with general demographics, presentation, image modality, cytogenetics and molecular in addition to management and outcome. We have found mean age for the patients is 38 years old with male predominance with 70% of the cases. The most presenting symptom was back pain in around 75% of the cases. Neurological findings showed sensory loss and parapreresis in most of the documented cases. MRI was most performed modality of imaging 63% followed by Computed tomography(CT) 15 % and then myelogram 13 %, which is least used due to invasive nature and before the era of MRI. The most common affected site on spinal cord were thoracic followed by lumbar. Cytogenetics and molecular data was not reported in most of the cases. Patients were treated with either steroids or surgery or radiotherapy and or chemotherapy while few underwent bone marrow transplant, but the most common approach was surgery+ radiotherapy + chemotherapy combination. Steroids used in most of the cases especially in the cases of acute lymphoblastic leukemia and dexamethasone was the steroids of the choice mainly. The outcome of the patients were variable, 30 % were alive at the time of the reports 30 % died and 30 % between relapse and complete remission. Conclusions Acute leukemia can be presented as mass causing spinal cord compression which is very serious. There are is no standardized management of patients with acute leukemia who presented with spinal cord compression nether guidelines or steps to follow. Some reports speculated also specific morphology and cytogenetics association with predisposition to have Extramedullary mass, however there lack of reporting of such a valuable information. Large studies including all adjusted variables required to determine if spinal cord compression presentation can be an independent risk facto or not Effective diagnosis and prompt action should take place. Figure Disclosures No relevant conflicts of interest to declare.


2005 ◽  
Vol 57 (1) ◽  
pp. 11-17 ◽  
Author(s):  
Bojana Slavkovic ◽  
Marija Guc-Scekic ◽  
Gordana Bunjevacki ◽  
S. Djuricic ◽  
Aleksandra Krstic ◽  
...  

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.


2020 ◽  
Author(s):  
Gholamreza Bahoush ◽  
Gholamreza Bahoush ◽  
Marzieh Nojomi

In acute lymphoblastic leukemia (ALL) patients treated with L-asparaginase, discontinuation of the drug occasionally occur due to severe drug complications or resistance, however, due to the high efficacy of this drug in the recovery of patients and the prevention of disease recurrence, resuming the drug regimen is preferred in most patients. What we did in this study was to evaluate and compare the effects of clinical outcomes in the two modes of continuing and discontinuing drug use. In this retrospective cohort study, all children with ALL who had been treated with L-asparaginase during the years 2005 to 2015 were included in the study and categorized into two groups receiving complete treatment regimen (n=160) and those who had to discontinue the drug due to appearing complications (n=9). The rate of relapse and mortality rate was determined and compared across the two groups with a median follow-up time of more than 5 years. 5-yrs Overall survival of all enrolled patients in the groups continued and discontinued was 91.4±2.5% and 71.4±17.1%, respectively (P=0.792). Also, 5-yrs event-free survival of the two groups was 75.8±3.5% and 71.4±17.1%, respectively (P=0.557. Relapse was revealed in 17.5% and 33.3% respectively and mortality in 16.9% and 0.0% (P=0.261). However, the overall prevalence of hypersensitivity reaction to the drug was significantly higher in those patients who discontinued their drug regimen (100% versus 24.4%, P<0.001). Hypersensitivity reaction to drugs may be an important factor in discontinuing L-asparaginase in patients with ALL. The discontinuation of L-asparaginase supplementation due to various complications such as hypersensitivity reactions may be effective in the survival of these patients. However, accurate determination of the effect of discontinuation of this drug on the outcome of children with ALL requires a more comprehensive study with more complicated cases.


2007 ◽  
Vol 131 (11) ◽  
pp. 1697-1699
Author(s):  
Maysaa El Sayed Zaki

Abstract Context.—Immunocompromised patients suffer from prolonged viral infections often without detectable immune response. However, even if the immune response occurs, can it clear the virus completely? Objective.—To detect parvovirus B19 DNA and its antibodies in bone marrow cells and in serum by polymerase chain reaction (PCR) in children with acute lymphoblastic leukemia receiving chemotherapy to highlight the relation of humoral immune response to the presence of viremia. Also, to evaluate the optimal diagnostic test(s) for a correct diagnosis of parvovirus B19 disease in immunocompromised patients. Design.—Forty-eight children with acute lymphoblastic leukemia receiving maintenance chemotherapy were included in the study in addition to 20 healthy children with matched age and sex. Study for parvovirus B19 was performed by serologic determination of specific immunoglobulin (Ig) M and IgG, and viral DNA was determined by PCR in both serum and bone marrow aspiration. Results.—Parvovirus B19 DNA was detected in both serum and bone marrow in 20% of patients. Specific IgG was found in 40% and IgM in 26.7%. Two cases (10%) in the control group were positive for IgG. The agreement between IgG and positive results of PCR in the bone marrow was 33.3%, and the agreement for IgM and PCR in the serum was 33.3%. Conclusions.—Parvovirus B19 is considered a common viral infection in children with acute lymphoblastic leukemia receiving chemotherapy. We must use our full potential to exclude such infection, which can mimic the side effects of chemotherapy in these patients. In immunocompromised patients, there are immunologic discrepancies in humoral immune responses for both IgM and IgG between individuals with parvovirus B19 persistence and healthy individuals, findings that may reflect both failed immunity and antigenic exhaustion. The contemporaneous determination of parvovirus B19 DNA by PCR in both bone marrow and peripheral blood and specific serologic markers appears to be the most appropriate diagnostic protocol for the correct laboratory diagnosis of parvovirus B19 infection in these patients.


2016 ◽  
Author(s):  
Richard A. Larson ◽  
Roland B Walter

The acute leukemias are malignant clonal disorders characterized by aberrant differentiation and proliferation of transformed hematopoietic progenitor cells. These cells accumulate within the bone marrow and lead to suppression of the production of normal blood cells, with resulting symptoms from varying degrees of anemia, neutropenia, and thrombocytopenia or from infiltration into tissues. They are currently classified by their presumed cell of origin, although the field is moving rapidly to genetic subclassification. This review covers epidemiology; etiology; classification of leukemia by morphology, immunophenotyping, and cytogenetic/molecular abnormalities; cytogenetics of acute leukemia; general principles of therapy; acute myeloid leukemia; acute lymphoblastic leukemia; and future possibilities. The figure shows the incidence of acute leukemias in the United States. Tables list World Health Organization (WHO) classification of acute myeloid leukemia and related neoplasms, expression of cell surface and cytoplasmic markers for the diagnosis of acute myeloid leukemia and mixed-phenotype acute leukemia, WHO classification of acute lymphoblastic leukemia, WHO classification of acute leukemias of ambiguous lineage, WHO classification of myelodysplastic syndromes, European LeukemiaNet cytogenetic and molecular genetic subsets in acute myeloid leukemia with prognostic importance, cytogenetic and molecular subtypes of acute lymphoblastic leukemia, terminology used in leukemia treatment, and treatment outcome for adults with acute leukemia. This review contains 1 highly rendered figure, 9 tables, and 117 references.


Blood ◽  
1990 ◽  
Vol 76 (11) ◽  
pp. 2348-2353 ◽  
Author(s):  
S Kojima ◽  
T Matsuyama ◽  
T Sato ◽  
K Horibe ◽  
S Konishi ◽  
...  

Abstract The clinical, hematologic, and immunophenotypic features in 20 patients with Down's syndrome (DS) and acute leukemia were analyzed. Of the 20 patients, all 14 patients who were 3 years old and less were diagnosed as having acute megakaryoblastic leukemia (AMKL) by use of platelet- specific monoclonal antibodies and platelet peroxidase (PPO) reaction in electron microscopy. They were characterized by the presence of bone marrow fibrosis, having a history of myelodysplastic syndrome (MDS) and a poor response to chemotherapy. Only one patient has remained in continuous complete remission for more than 1 year. Acute leukemia in six patients who were older than 4 years was classified as common acute lymphoblastic leukemia antigen (CALLA)-positive acute lymphoblastic leukemia (ALL). In one of six patients classified as ALL, the leukemic blasts simultaneously expressed myeloid-associated surface antigens. All six patients achieved a complete remission and have remained in continuous complete remission and have remained in continuous complete remission from 10 to 52 months from the initial diagnosis. Although it has been suggested that the distribution of types of acute leukemia in patients with DS is similar to that in normal children, the present study shows that the distribution of acute leukemia types is quite different from that in patients without Down's syndrome.


Reports ◽  
2019 ◽  
Vol 2 (3) ◽  
pp. 18 ◽  
Author(s):  
Miller ◽  
Park ◽  
Saxe ◽  
Lew ◽  
Raikar

Lineage switch in acute leukemias is a well-reported occurrence; however, most of these cases involve a switch from either lymphoid to myeloid or myeloid to lymphoid lineage. Here, we report a case of a 14-year-old male with B-cell acute lymphoblastic leukemia (B-ALL) who initially responded well to standard chemotherapy but then later developed mixed phenotype acute leukemia (MPAL) at relapse, likely reflecting a clonal evolution of the original leukemia with a partial phenotypic shift. The patient had a del(9)(p13p21) in his leukemia blasts at diagnosis, and the deletion persisted at relapse along with multiple additional cytogenetic aberrations. Interestingly, the patient presented with an isolated testicular lesion at relapse, which on further analysis revealed both a lymphoid and myeloid component. Unfortunately, the patient did not respond well to treatment at relapse and eventually succumbed to his disease. To our knowledge, an isolated extramedullary MPAL at relapse in a patient with previously diagnosed B-ALL has not been reported in the literature before.


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