Bone pain at leukemia diagnosis and other risk factors for symptomatic osteonecrosis in children with acute lymphoblastic leukemia

Shlomit Barzilai-Birenboim*, Joanne Yacobovich, Yair Zalcberg, Nira Arad-Cohen, Galia Avrahami, Gil Gilad, Naomi Litichever, Shai Izraeli, Sarah Elitzur

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Background: Osteonecrosis is a major cause of acute and long-lasting complications of acute lymphoblastic leukemia (ALL) therapy in children. Our study aimed to evaluate the prevalence, characteristics, risk factors, and outcome of osteonecrosis in children with ALL. Procedure: The cohort included 559 children aged 1–20 years diagnosed with ALL between 2003 and 2018 at two tertiary medical centers in Israel and enrolled in two consecutive protocols: ALL-IC BFM 2002 and AIEOP-BFM ALL 2009. Symptomatic osteonecrosis was prospectively captured as an adverse event. Results: Osteonecrosis occurred in 51 patients (9.1%). Ninety-four percent of the events were graded as moderate or severe (grades 3–4, Ponte di Legno Toxicity Working Group classification) and multiple bone involvement was common. Full resolution of osteonecrosis was documented in only 16% of the children (median follow-up 4.2 years). Stepwise logistic regression identified five risk factors for osteonecrosis, with a high predictive value (AUC = 0.88): older ageat ALL diagnosis, high-risk ALL group, T-cell immunophenotype, female gender, and a novel risk factor: bone pain at the time of leukemia diagnosis. In addition, osteonecrosis was less common among children of Arab ethnicity. Thrombophilia and an elevated age-adjusted body mass index were not confirmed as risk factors for osteonecrosis. Conclusion: Due to the low rates of osteonecrosis resolution and its debilitating long-term impact, the identification of patients at high risk for osteonecrosis is important for their inclusion in further studies evaluating potential therapeutic adjustments.

Original languageEnglish
Article numbere29033
JournalPediatric Blood and Cancer
Issue number8
StatePublished - Aug 2021


FundersFunder number
Israel Cancer Association


    • acute lymphoblastic leukemia
    • bone pain
    • osteonecrosis
    • risk factors


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