Linea Natalie Toksvang1, Liv Andrés-Jensen1, Cecilie Utke Rank2,3, Riitta Niinimäki4, Jacob Nersting1, Stine Nygaard Nielsen1, Signe Sloth Mogensen1, Arja Harila-Saari5, Jonas Abrahamsson6, Joel Joelsson7, Ulrik Malthe Overgaard3, Petter Quist-Paulsen8, Laimonas Griškevičius9,10, Ólafur Gisli Jónsson11, Goda Vaitkevičienė10,12, Thomas Leth Frandsen1, Nina Toft3, Kathrine Grell1,13, Kjeld Schmiegelow14,15. 1. Department of Pediatrics and Adolescent Medicine, The Juliane Marie Center, Copenhagen University Hospital - Rigshospitalet, Blegdamsvej 9, DK-2100, Copenhagen, Denmark. 2. Pediatric Oncology Research Laboratory, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark. 3. Department of Hematology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark. 4. Department of Children and Adolescents, Oulu University Hospital and PEDEGO Research Unit, University of Oulu, Oulu, Finland. 5. Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden. 6. Queen Silvia Children's Hospital, Gothenburg, Sweden. 7. Department of Hematology, Karolinska University Hospital, Stockholm, Sweden. 8. Trondheim University Hospital, Trondheim, Norway. 9. Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania. 10. Vilnius University, Vilnius, Lithuania. 11. Department of Pediatrics, Children's Hospital, Reykjavík, Iceland. 12. Center for Pediatric Oncology and Hematology, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania. 13. Section of Biostatistics, Department of Public Health, University of Copenhagen, Copenhagen, Denmark. 14. Department of Pediatrics and Adolescent Medicine, The Juliane Marie Center, Copenhagen University Hospital - Rigshospitalet, Blegdamsvej 9, DK-2100, Copenhagen, Denmark. kschmiegelow@rh.dk. 15. Institute of Clinical Medicine, Faculty of Medicine, University of Copenhagen, Copenhagen, Denmark. kschmiegelow@rh.dk.
Abstract
PURPOSE: Osteonecrosis is a burdensome treatment-related toxicity that is mostly diagnosed during or soon after 6-mercaptopurine (6MP)/methotrexate (MTX) maintenance therapy for acute lymphoblastic leukemia (ALL), possibly indicating a pathogenic role of these drugs. METHODS: We prospectively registered symptomatic osteonecrosis during treatment of 1234 patients aged 1.0-45.9 years treated according to the Nordic Society of Hematology and Oncology (NOPHO) ALL2008 protocol. MTX/6MP metabolites were measured as part of the NOPHO ALL2008 maintenance therapy study. RESULTS: After a median follow-up of 5.6 years [interquartile range (IQR) 3.6-7.5], 68 patients had been diagnosed with symptomatic osteonecrosis. The cumulative incidence was 2.7% [95% confidence interval (CI) 1.6-3.8%] for patients aged < 10 years, 14.9% (95% CI 9.7-20.2%) for patients aged 10.0-17.9 years, and 14.4% (95% CI 8.0-20.8%) for patients aged ≥ 18 years. The median time from diagnosis of ALL to diagnosis of osteonecrosis in these age groups was 1.0 year (IQR 0.7-2.0), 2.0 years (IQR 1.1-2.4), and 2.2 years (IQR 1.8-2.8), respectively (p = 0.001). With 17,854 blood samples available for MTX and 6MP metabolite analysis, neither erythrocyte levels of 6-thioguanine (TG) nucleotides (p > 0.99), methylated 6MP metabolites (p = 0.37), MTX polyglutamates (p = 0.98) nor DNA-TG (p = 0.53) were significantly associated with the hazard of osteonecrosis in Cox models stratified by the three age groups and adjusted for sex. CONCLUSION: Maintenance therapy intensity determined by 6MP and MTX metabolites was not associated with the risk of developing osteonecrosis in the NOPHO ALL2008 cohort.
PURPOSE: Osteonecrosis is a burdensome treatment-related toxicity that is mostly diagnosed during or soon after 6-mercaptopurine (6MP)/methotrexate (MTX) maintenance therapy for acute lymphoblastic leukemia (ALL), possibly indicating a pathogenic role of these drugs. METHODS: We prospectively registered symptomatic osteonecrosis during treatment of 1234 patients aged 1.0-45.9 years treated according to the Nordic Society of Hematology and Oncology (NOPHO) ALL2008 protocol. MTX/6MP metabolites were measured as part of the NOPHO ALL2008 maintenance therapy study. RESULTS: After a median follow-up of 5.6 years [interquartile range (IQR) 3.6-7.5], 68 patients had been diagnosed with symptomatic osteonecrosis. The cumulative incidence was 2.7% [95% confidence interval (CI) 1.6-3.8%] for patients aged < 10 years, 14.9% (95% CI 9.7-20.2%) for patients aged 10.0-17.9 years, and 14.4% (95% CI 8.0-20.8%) for patients aged ≥ 18 years. The median time from diagnosis of ALL to diagnosis of osteonecrosis in these age groups was 1.0 year (IQR 0.7-2.0), 2.0 years (IQR 1.1-2.4), and 2.2 years (IQR 1.8-2.8), respectively (p = 0.001). With 17,854 blood samples available for MTX and 6MP metabolite analysis, neither erythrocyte levels of 6-thioguanine (TG) nucleotides (p > 0.99), methylated 6MP metabolites (p = 0.37), MTX polyglutamates (p = 0.98) nor DNA-TG (p = 0.53) were significantly associated with the hazard of osteonecrosis in Cox models stratified by the three age groups and adjusted for sex. CONCLUSION: Maintenance therapy intensity determined by 6MP and MTX metabolites was not associated with the risk of developing osteonecrosis in the NOPHO ALL2008 cohort.
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Authors: Linea Natalie Toksvang; Bodil Als-Nielsen; Christopher Bacon; Ruta Bertasiute; Ximo Duarte; Gabriele Escherich; Elín Anna Helgadottir; Inga Rinvoll Johannsdottir; Ólafur G Jónsson; Piotr Kozlowski; Cecilia Langenskjöld; Kristi Lepik; Riitta Niinimäki; Ulrik Malthe Overgaard; Mari Punab; Riikka Räty; Heidi Segers; Inge van der Sluis; Owen Patrick Smith; Marion Strullu; Goda Vaitkevičienė; Hilde Skuterud Wik; Mats Heyman; Kjeld Schmiegelow Journal: BMC Cancer Date: 2022-05-02 Impact factor: 4.638