Comparing osteonecrosis clinical phenotype, timing, and risk factors in children and young adults treated for acute lymphoblastic leukemia

Mogensen, Signe Sloth; Harila‐Saari, Arja; Mäkitie, Outi; Myrberg, Ida Hed; Niinimäki, Riitta; Vestli, Anne; Hafsteinsdóttir, Solveig; Griškevičius, Laimonas; Saks, Kadri; Hallböök, Heléne; Retpen, Jens B; Helt, Louise Rold; Toft, Nina; Schmiegelow, Kjeld; Frandsen, Thomas Leth

doi:10.1002/pbc.27300

Cited by 38 publications

(58 citation statements)

References 48 publications

(124 reference statements)

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“…Age >10 years is the most widely accepted risk factor for osteonecrosis in children with ALL. 5,[7][8][9]12,25 The presumed etiology is the rapid bone growth and epiphyseal closure during puberty that may increase intramedullary pressure. 14 Female gender has also been previously described as a risk factor for osteonecrosis.…”

Section: Discussionmentioning

confidence: 99%

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

Barzilai‐Birenboim

Yacobovich

Zalcberg

et al. 2021

Pediatric Blood & Cancer

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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 longterm impact, the identification of patients at high risk for osteonecrosis is important for their inclusion in further studies evaluating potential therapeutic adjustments.

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Section: Discussionmentioning

confidence: 99%

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

Barzilai‐Birenboim

Yacobovich

Zalcberg

et al. 2021

Pediatric Blood & Cancer

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“…Overall the 5-year cumulative incidence of osteonecrosis was 6.3%, being 28% in female adolescents. 6 The median interval between ALL and osteonecrosis diagnosis was signifi cantly shorter in children aged < 10 years (0.7 years (range: 0.2-2.1)) compared with adolescents (1.8 years (0.3-3.7); P < 0.001) and adults (2.1 years (0.4-5.3); P = 0.001). Female sex was a risk factor in adolescents, but not in children aged < 10 years or adults.…”

Section: Osteonecrosismentioning

confidence: 92%

Management of Asparaginase Toxicity in AYAs with ALL

Schmiegelow

Rank

2020

Clinical Lymphoma Myeloma and Leukemia

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“…Osteonecrosis is a known complication in 15-45% of patients, especially AYA patients, undergoing treatment for ALL. 103,104 Glucocorticoids, notably dexamethasone, are believed to induce inhibition of angiogenesis, bone marrow adipogenesis, hypercoagulation, and apoptosis of endothelial cells and osteocytes. 105 Asparaginase decreases the clearance of dexamethasone due to its hypoproteinemia effect.…”

Section: Osteonecrosismentioning

confidence: 99%

Clinical Utility of Pegaspargase in Children, Adolescents and Young Adult Patients with Acute Lymphoblastic Leukemia: A Review

Bender¹,

Maese²,

Carter-Febres³

et al. 2021

BLCTT

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Acute lymphoblastic leukemia (ALL) is a heterogenous hematological malignancy representing 25% of all cancers in children less than 15 years of age. Significant improvements in survival and cure rates have been made over the past four decades in pediatric ALL treatment. Asparaginases, derived from Escherichia coli and Erwinia chrysanthemi, have become a critical component of ALL therapy since the 1960s. Asparaginases cause depletion of serum asparagine, leading to deprivation of this critical amino acid for protein synthesis, and hence limit survival of lymphoblasts. Pegaspargase, a conjugate of monomethoxypolyethylene glycol (mPEG) and L-asparaginase, has become an integral component of pediatric upfront and relapsed ALL protocols due to its longer half-life and improved immunogenicity profile compared to native asparaginase preparations. Over the past two decades great strides have been made in outcomes for pediatric ALL due to risk stratification, incorporation of multiagent chemotherapy protocols, and central nervous system prophylaxis with pegaspargase having played an important role in this success. However, adolescents and young adults (AYA) with ALL when treated on contemporaneous trials using adult ALL regimens, continue to have poor outcomes. There is increasing realization of adapting pediatric trial regimens for treating AYAs, especially those incorporating higher intensity of chemotherapeutic agents with pegaspargase being one such agent. Dose or treatment-limiting toxicity is observed in 25-30% of patients, most notable being hypersensitivity reactions. Other toxicities include asparaginase-associated pancreatitis, thrombosis, liver dysfunction, osteonecrosis, and dyslipidemia. Discontinuation or subtherapeutic levels of asparaginase are associated with inferior disease-free survival leading to higher risk of relapse, and in cases of relapse, a higher risk for remission failure. This article provides an overview of available evidence for use of pegaspargase in pediatric acute lymphoblastic leukemia.

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Comparing osteonecrosis clinical phenotype, timing, and risk factors in children and young adults treated for acute lymphoblastic leukemia

Abstract: We provide a detailed phenotype of patients with ALL with symptomatic ON, including description of risk factors and timing of ON across age groups. This awareness is essential in exploring measures to prevent development of ON.

Cited by 38 publications

References 48 publications

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

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

Management of Asparaginase Toxicity in AYAs with ALL

Clinical Utility of Pegaspargase in Children, Adolescents and Young Adult Patients with Acute Lymphoblastic Leukemia: A Review

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