TY - JOUR
T1 - No association between relapse hazard and thiopurine methyltransferase geno- or phenotypes in non-high risk acute lymphoblastic leukemia
T2 - a NOPHO ALL2008 sub-study
AU - Nielsen, Stine Nygaard
AU - Toksvang, Linea Natalie
AU - Grell, Kathrine
AU - Nersting, Jacob
AU - Abrahamsson, Jonas
AU - Lund, Bendik
AU - Kanerva, Jukka
AU - Jónsson, Ólafur Gísli
AU - Vaitkeviciene, Goda
AU - Pruunsild, Kaie
AU - Appell, Malin Lindqvist
AU - Hjalgrim, Lisa Lyngsie
AU - Schmiegelow, Kjeld
PY - 2021/8
Y1 - 2021/8
N2 - 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.
AB - 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.
KW - Adolescent
KW - Antimetabolites, Antineoplastic/therapeutic use
KW - Antineoplastic Combined Chemotherapy Protocols/therapeutic use
KW - Child
KW - Child, Preschool
KW - DNA/genetics
KW - Female
KW - Genotype
KW - Humans
KW - Infant
KW - Male
KW - Mercaptopurine/therapeutic use
KW - Methotrexate/therapeutic use
KW - Methyltransferases/genetics
KW - Phenotype
KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
KW - Recurrence
UR - http://www.scopus.com/inward/record.url?scp=85105501608&partnerID=8YFLogxK
U2 - 10.1007/s00280-021-04281-7
DO - 10.1007/s00280-021-04281-7
M3 - Journal article
C2 - 33928426
SN - 0344-5704
VL - 88
SP - 271
EP - 279
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 2
ER -