DNA-incorporated thioguanine to detect potential non-adherence to maintenance therapy in acute lymphoblastic leukemia
Year: 2025
Type: article
Abstract: PURPOSE: Adherence to 6-mercaptopurine (6-MP)/methotrexate maintenance treatment for acute lymphoblastic leukemia (ALL) is pivotal to preventing relapse, and the 6-MP metabolite DNA-incorporated thioguanine (DNA-TG) is associated with relapse risk. In the ALLTogether-1 (A2G1) Maintenance sub-study (EU CT nr 2022-501050-11-01), DNA-TG, thioguanine nucleotides (TGN), and methylated mercaptopurine metabolites (MeMP) are analyzed regularly. Upon levels below preset limits (TGN < 50, or MeMP < 200 or < 100 nmol/mmol hemoglobin for thiopurine S-methyltransferase (TPMT) wild type and heterozygous patients, respectively), the treating physician is informed of potential non-adherence. We investigated the feasibility of using DNA-TG as the primary flagging of potential non-adherence. METHODS: We analyzed 6-MP metabolites in 3,074 blood samples from 368 children enrolled in the A2G1 Maintenance sub-study. RESULTS: In 6% of samples, TGN (median 212, 95% range 40-642), MeMP (median 4,959, 95% range 135-23,880) or both were below the flagging potential non-adherence limits. DNA-TG was associated with TGN (estimate = 1.72, p < 0.0001), MeMP (estimate = 1.10, p < 0.0001), and prescribed 6-MP dose (estimate = 1.083 and 1.132, p < 0.0001, for TPMT wild type and heterozygous patients) in linear effects models, and the predicted probability of treatment interruption in logistic regression models. DNA-TG was below 200 fmol TG/µg DNA (13th percentile of all measurements, median 569, 95% range 73-1,823) in all samples with both TGN and MeMP below the flagging potential non-adherence limits. CONCLUSION: DNA-TG can provide a cost-effective guidance on when to measure TGN and MeMP to determine whether non-adherence should be suspected, which is an additional benefit to monitoring DNA-TG during maintenance therapy.
Authors: Mathilde Rønne Koch, Anna Sofie Buhl Rasmussen, Bodil Als-Nielsen, Ximo Duarte, Gabriele Escherich, Mats Heyman, Kristi Lepik, Johan Malmros, Jacob Nersting, Inga Johannsdottir, Riitta Niinimäki, Malene Johanne Petersen, Heidi Segers, Inge Margriet van der Sluis, Maria Thastrup, Goda Vaitkeviciene, Kjeld Schmiegelow, Linea Natalie Toksvang
Institutions: Rigshospitalet, Instituto Português de Oncologia Francisco Gentil, University Medical Center Hamburg-Eppendorf, Karolinska University Hospital, Karolinska Institutet, Oslo University Hospital, Oulu University Hospital, University of Oulu, Universitair Ziekenhuis Leuven, KU Leuven, Princess Máxima Center, Vilnius University, University of Copenhagen, Copenhagen University Hospital
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,390
Awards: G2112779657, G3019694000, G3782061097
OpenAlex ID: W4412467513