Maintenance therapy and risk of osteonecrosis in children and young adults with acute lymphoblastic leukemia: a NOPHO ALL2008 sub-study

Linea Natalie Toksvang, Liv Andrés-Jensen, Cecilie Utke Rank, Riitta Niinimäki, Jacob Nersting, Stine Nygaard Nielsen, Signe Sloth Mogensen, Arja Harila-Saari, Jonas Abrahamsson, Joel Joelsson, Ulrik Malthe Overgaard, Petter Quist-Paulsen, Laimonas Griškevičius, Ólafur Gisli Jónsson, Goda Vaitkevičienė, Thomas Leth Frandsen, Nina Toft, Kathrine Grell, Kjeld Schmiegelow

5 Citationer (Scopus)

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.

OriginalsprogEngelsk
TidsskriftCancer Chemotherapy and Pharmacology
Vol/bind88
Udgave nummer5
Sider (fra-til)911-917
Antal sider7
ISSN0344-5704
DOI
StatusUdgivet - nov. 2021

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