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

Cast your vote
 
Your vote was cast
Thank you for your feedback
Authors
Nielsen, Stine Nygaard
Toksvang, Linea Natalie
Grell, Kathrine
Nersting, Jacob
Abrahamsson, Jonas
Lund, Bendik
Kanerva, Jukka
Jónsson, Ólafur Gísli
Vaitkeviciene, Goda
Pruunsild, Kaie
Issue Date
2021-04-29

Metadata
Show full item record
Citation
Nielsen SN, Toksvang LN, Grell K, Nersting J, Abrahamsson J, Lund B, Kanerva J, Jónsson ÓG, Vaitkeviciene G, Pruunsild K, Appell ML, Hjalgrim LL, Schmiegelow K. No association between relapse hazard and thiopurine methyltransferase geno- or phenotypes in non-high risk acute lymphoblastic leukemia: a NOPHO ALL2008 sub-study. Cancer Chemother Pharmacol. 2021 Aug;88(2):271-279. doi: 10.1007/s00280-021-04281-7.
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. Keywords: 6-mercaptopurine; Childhood acute lymphoblastic leukemia; Maintenance therapy; Relapse; Thiopurine methyltransferase.
Description
To access publisher's full text version of this article click on the hyperlink below
Additional Links
https://link.springer.com/article/10.1007%2Fs00280-021-04281-7
Collections