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

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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

Nielsen, S. N. (author): Univ Copenhagen, Denmark

Toksvang, L. N. (author): Univ Copenhagen, Denmark

Grell, K. (author): Univ Copenhagen, Denmark; Univ Copenhagen, Denmark

Nersting, J. (author): Univ Copenhagen, Denmark

Abrahamsson, Jonas, 1954 (author): Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för pediatrik,Institute of Clinical Sciences, Department of Pediatrics,Univ Gothenburg, Sweden

Lund, B. (author): Norwegian Univ Sci & Technol, Norway

Kanerva, J. (author): Univ Helsinki, Finland; Univ Helsinki, Finland

Jonsson, O. G. (author): Landspitali Univ Hosp, Iceland

Vaitkeviciene, G. (author): Vilnius Univ, Lithuania

Pruunsild, K. (author): Tallinn Childrens Hosp, Estonia

Lindqvist Appell, Malin (author): Linköpings universitet,Avdelningen för klinisk kemi och farmakologi,Medicinska fakulteten

Hjalgrim, L. L. (author): Univ Copenhagen, Denmark

Schmiegelow, K. (author): Univ Copenhagen, Denmark; Univ Copenhagen, Denmark

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2021-04-29
2021
English.
In: Cancer Chemotherapy and Pharmacology. - : Springer Science and Business Media LLC. - 0344-5704 .- 1432-0843. ; 88, s. 271-279

Related links:: https://gup.ub.gu.se...; show more...; https://doi.org/10.1...; https://urn.kb.se/re...; show less...

Journal article (peer-reviewed)

Abstract Subject headings

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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Pediatrik (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Pediatrics (hsv//eng)

Keyword

Childhood acute lymphoblastic leukemia
Maintenance therapy
6-mercaptopurine
Thiopurine methyltransferase
Relapse
Oncology
Pharmacology & Pharmacy
Childhood acute lymphoblastic leukemia; Maintenance therapy; 6-mercaptopurine; Thiopurine methyltransferase; Relapse

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By the author/editor: Nielsen, S. N.; Toksvang, L. N.; Grell, K.; Nersting, J.; Abrahamsson, Jon ...; Lund, B.; show more...; Kanerva, J.; Jonsson, O. G.; Vaitkeviciene, G ...; Pruunsild, K.; Lindqvist Appell ...; Hjalgrim, L. L.; Schmiegelow, K.; show less...

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Cancer and Oncol ...

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Pediatrics

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By the university: University of Gothenburg; Linköping University

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