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

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

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.

OriginalsprogEngelsk
TidsskriftCancer Chemotherapy and Pharmacology
Vol/bind88
Udgave nummer2
Sider (fra-til)271-279
Antal sider9
ISSN0344-5704
DOI
StatusUdgivet - aug. 2021

Fingeraftryk

Dyk ned i forskningsemnerne om 'No association between relapse hazard and thiopurine methyltransferase geno- or phenotypes in non-high risk acute lymphoblastic leukemia: a NOPHO ALL2008 sub-study'. Sammen danner de et unikt fingeraftryk.

Citationsformater