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01-08-2021 | Acute Lymphoblastic Leukemia | Original Article

No association between relapse hazard and thiopurine methyltransferase geno- or phenotypes in non-high risk acute lymphoblastic leukemia: a NOPHO ALL2008 sub-study

Authors: Stine Nygaard Nielsen, Linea Natalie Toksvang, Kathrine Grell, Jacob Nersting, Jonas Abrahamsson, Bendik Lund, Jukka Kanerva, Ólafur Gísli Jónsson, Goda Vaitkeviciene, Kaie Pruunsild, Malin Lindqvist Appell, Lisa Lyngsie Hjalgrim, Kjeld Schmiegelow

Published in: Cancer Chemotherapy and Pharmacology | Issue 2/2021

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/m² for TPMT heterozygous and wildtype patients and was adjusted to a target WBC of 1.5 − 3.0 × 10⁹/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/µg, 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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Title: No association between relapse hazard and thiopurine methyltransferase geno- or phenotypes in non-high risk acute lymphoblastic leukemia: a NOPHO ALL2008 sub-study
Authors: Stine Nygaard Nielsen
Linea Natalie Toksvang
Kathrine Grell
Jacob Nersting
Jonas Abrahamsson
Bendik Lund
Jukka Kanerva
Ólafur Gísli Jónsson
Goda Vaitkeviciene
Kaie Pruunsild
Malin Lindqvist Appell
Lisa Lyngsie Hjalgrim
Kjeld Schmiegelow
Publication date: 01-08-2021
Publisher: Springer Berlin Heidelberg
Keywords: Acute Lymphoblastic Leukemia
Methotrexate
Maintenance Therapy
Methotrexate
Published in: Cancer Chemotherapy and Pharmacology / Issue 2/2021
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-021-04281-7

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