| 1. |
- Nielsen, S. N., et al.
(författare)
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No association between relapse hazard and thiopurine methyltransferase geno- or phenotypes in non-high risk acute lymphoblastic leukemia: a NOPHO ALL2008 sub-study
- 2021
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Ingår i: Cancer Chemotherapy and Pharmacology. - : Springer Science and Business Media LLC. - 0344-5704 .- 1432-0843. ; 88, s. 271-279
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Tidskriftsartikel (refereegranskat)abstract
- Purpose 6-mercaptopurine(6MP)/methotrexate maintenance therapy is essential to reduce relapse of childhood acute lymphoblastic leukemia (ALL). Common germline variants in TPMT cause low activity of thiopurine methyltransferase (TPMT) and higher 6MP metabolite (TGN) levels. Higher levels of TGNs incorporated into DNA (DNA-TG) and low TPMT activity have previously been associated with a lower relapse risk. We explored if TPMT geno- or phenotype was associated with DNA-TG levels and relapse rate in NOPHO ALL2008. Methods TPMT genotype, repeated phenotyping, and DNA-TG measurements were collected in 918 children with non-high risk ALL (NOPHO ALL2008 maintenance therapy study). Maintenance therapy started with 6MP at 50 and 75 mg/m(2) for TPMT heterozygous and wildtype patients and was adjusted to a target WBC of 1.5 - 3.0 x 10(9)/L. Results Of 918 patients, 78 (8.5%) were TPMT heterozygous and 903 had at least one TPMT measurement (total 3063). Mean TPMT activities were higher with wildtype than heterozygous TPMT (N = 752, 16.6 versus 9.6 U/mL ery., p < 0.001). The 5-year cumulative incidence of relapse was 6.4% and 6.0% for TPMT heterozygous and wildtype patients, and there was no association between genotype and relapse rate (N = 918, hazard ratio = 1.01, 95% confidence interval [CI] 0.40 - 2.54, p = 0.98). Although TPMT heterozygous patients had higher DNA-TG (N = 548, median 760.9 [interquartile range (IQR) 568.7 - 890.3] versus 492.7 [IQR 382.1 - 634.6] fmol/mu g, p < 0.001), TPMT activity was not associated with relapse rate (N = 813; hazard ratio = 0.98 per one U/mL ery. increase in TPMT activity, 95% CI 0.91 - 1.06, p = 0.67). Conclusion TPMT geno- and phenotype were not associated with relapse in non-high risk NOPHO ALL2008.
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| 2. |
- Wahlund, Martina, et al.
(författare)
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Genetic Sequence Variants in TLR4, MBL or IL-1 Receptor Antagonist is not Associated to Increased Risk for Febrile Neutropenia in Children with ALL
- 2020
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Ingår i: Children. - : MDPI. - 2227-9067. ; 7:12
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Tidskriftsartikel (refereegranskat)abstract
- Sequence variants in genes involved in the immune system have previously been linked to neutropenia as well as infections in cancer patients. Sequence variants in genes coding for TLR4, MBL, and IL-1Ra were investigated in relation to clinical utility of identifying severe episodes of febrile neutropenia (FN) in a cohort of children undergoing treatment for acute lymphoblastic leukemia. The study included 122 children, where data on FN and microbiological findings were retrospectively collected from medical records. Sequence variants in genes coding for MBL, TLR4, and IL-1Ra were identified by pyrosequencing, TaqMan SNP genotyping assay, and gel electrophoresis. A total of 380 episodes of FN were identified and in 139 episodes, there was a microbiological defined infection. Age and treatment intensity were all associated with the risk of developing FN. No sequence variant was associated to increased numbers of FN episodes. Two sequence variants in the TLR4 gene increased the risk of viral infection, whilst sequence variants in the IL-1Ra gene were associated to a decreased risk of bacterial blood-stream infection (BSI). The investigated sequence variants did not associate with increased risk for FN or to severe infections, as to why the clinical utility as a risk-stratification tool is low. Most episodes of FN were classified as fever with unknown origin, emphasizing the need for improved microbial detection methods.
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| 3. |
- Wahlund, Martina, et al.
(författare)
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The Role of TPMT, ITPA, and NUDT15 Variants during Mercaptopurine Treatment of Swedish Pediatric Patients with Acute Lymphoblastic Leukemia
- 2020
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Ingår i: The Journal of Pediatrics. - : MOSBY-ELSEVIER. - 0022-3476 .- 1097-6833. ; 216, s. 150-
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Tidskriftsartikel (refereegranskat)abstract
- Objective To evaluate the roles of thiopurine methyltransferase (TPMT), inosine triphosphatase (ITPA), and Nudix hydrolase 15 (NUDT15) in 6-mercaptopurine (6-MP) sensitivity during treatment of pediatric patients with acute lymphoblastic leukemia (ALL). Study design The study included 102 pediatric patients with ALL subject to the Nordic society Of Paediatric Haematology and Oncology (NOPHO) ALL-2000 and ALL-2008 protocols. Episodes of neutropenia and febrile neutropenia, TPMT sequence variants, as well as 6-MP end doses, were collected retrospectively from medical records. TPMT, ITPA, and NUDT15 sequence variants were analyzed using pyrosequencing. Results TPMT variants were associated with a reduced risk of neutropenia and febrile neutropenia during the maintenance II period (P = .019 and P amp;lt; .0001, respectively). In addition, a NUDT15 variant was associated with a lower end dose of 6-MP (P = .0097), but not with neutropenia and febrile neutropenia. ITPA variants were not associated with an increased risk of neutropenia, febrile neutropenia, nor lower end dose of 6-MP. However, when analyzing the entire treatment period, ITPA variants were associated with a decreased risk of febrile neutropenia. Conclusions White blood cell count-based dose adjustments are regularly performed for known TPMT- deficient patients and results in a reduced risk of neutropenia and febrile neutropenia. Also in NUDT15-deficient patients dose adjustments are performed as indicated by low end dose of 6-MP. ITPA-deficient patients had a decreased risk of febrile neutropenia when analyzing the entire treatment period. Our data suggest that NUDT15 plays an important role in 6-MP treatment and the results should be confirmed in larger cohorts. Future studies should also follow up whether white blood cell count-based dose adjustments affect the risk of relapse.
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| 4. |
- Zimdahl, Anna, 1987-
(författare)
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Pharmacogenetic studies of thiopurine methyltransferase genotype-phenotype concordance and effect of methotrexate on thiopurine metabolism
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The thiopurines (6-mercaptopurine [6-MP], 6-thioguanine and azathioprine) are cytotoxic drugs used in the treatment of acute lymphoblastic leukemia (ALL), inflammatory bowel diseases, certain autoimmune diseases and after transplantation. The metabolism of thiopurines is complex with several enzymes involved in the conversion into active drug metabolites. One of the enzymes, thiopurine methyltransferase (TPMT), is one of the best examples of implemented pharmacogenetics so far. Due to lowered TPMT enzyme activity caused by genetic polymorphism, carriers of heterozygous or homozygous defective TPMT alleles need dose reduction to avoid cytotoxic adverse reactions like myelosuppression or hepatotoxicity if treated with thiopurines.To determine TPMT status before the start of treatment, genotyping (for the three most occurring TPMT alleles) and/or phenotyping (TPMT enzyme activity measurements) are used in the clinical setting. In the focus of this thesis, concordance of these methods was investigated in a large cohort of unique samples (n=12,663) collected in the routine analysis service of TPMT status determinations in Linköping. By sequencing all exons in samples where the results of the two methods differed, rare or novel TPMT alleles were discovered. Four TPMT alleles (TPMT*41, *42, *43, *44), not previously described, were characterized in terms of clinical in vivo data as well as protein structure and stability data obtained from recombinant human TPMT (rTPMT) produced by E. Coli and biophysical methods.The clinical cohort was also used in the search for other factors (except genetic factors) that influence TPMT enzyme activity, and both age and gender turned out to affect TPMT enzyme activity level. In addition, TPMT enzyme activity in the early treatment of ALL was investigated and shown to be significantly lower at time of ALL diagnosis.In the treatment protocol of ALL, the combined treatment using 6-MP and methotrexate (MTX) has increased the positive outcomes since the start in the 1950s. Despite this, the synergistic effect of these drugs is not yet fully understood. To evaluate the effect of MTX on thiopurine metabolism specifically, TPMT enzyme activity, TPMT gene expression, and thiopurine metabolite levels were determined before and after MTX infusions in vivo and after cotreatment in lymphoblasts in vitro. In the presence of MTX, TPMT enzyme activity and metabolite levels decreased, both in vivo and in vitro, although dose- and time-dependent. In addition, MTX bound to rTPMT and caused inhibition of rTPMT enzyme activity.The results found in the scope of this thesis may be used for further individualization of thiopurine treatment.
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| 5. |
- Zimdahl, Anna, 1987-, et al.
(författare)
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Pharmacogenetic studies of thiopurine methyltransferase genotype-phenotype concordance and effect of methotrexate on thiopurine metabolism
- 2021
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Ingår i: Basic & Clinical Pharmacology & Toxicology. - : Wiley-Blackwell Publishing Inc.. - 1742-7835 .- 1742-7843. ; 128:1, s. 52-65
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Forskningsöversikt (refereegranskat)abstract
- The discovery and implementation of thiopurine methyltransferase (TPMT) pharmacogenetics has been a success story and has reduced the suffering from serious adverse reactions during thiopurine treatment of childhood leukaemia and inflammatory bowel disease. This MiniReview summarizes four studies included in Dr Zimdahl Kahlin's doctoral thesis as well as the current knowledge on this field of research. The genotype-phenotype concordance of TPMT in a cohort of 12 663 individuals with clinically analysed TPMT status is described. Notwithstanding the high concordance, the benefits of combined genotyping and phenotyping for TPMT status determination are discussed. The results from the large cohort also demonstrate that the factors of gender and age affect TPMT enzyme activity. In addition, characterization of four previously undescribed TPMT alleles (TPMT*41, TPMT*42, TPMT*43 and TPMT*44) shows that a defective TPMT enzyme could be caused by several different mechanisms. Moreover, the folate analogue methotrexate (MTX), used in combination with thiopurines during maintenance therapy of childhood leukaemia, affects the metabolism of thiopurines and interacts with TPMT, not only by binding and inhibiting the enzyme activity but also by regulation of its gene expression.
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