The Development Of Venous Thromboembolism May Increase The Risk Of Osteonecrosis In Children With Acute Lymphoblastic Leukemia
Bibliographic record
Abstract
Abstract Background Osteonecrosis (ON) is a severely disabling complication of anti-leukemic therapy, specifically long-term corticosteroid use. A hypercoagulable state is thought to underlie corticosteroid-related ON. Children with acute lymphoblastic leukemia (ALL) are also at increased risk of venous thromboembolism (VTE), indicating underlying hypercoagulability in this disease entity. Hence, we explored the relationship between ON and VTE, along with the association of ON with other variables, including age and asparaginase (ASP) therapy, in children with ALL. Methods Health records of children (< 18 yrs.) with de novo ALL treated at McMaster Children’s Hospital from 1992 to 2010 were reviewed. Patients were treated according to Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocols. Data regarding demographics, leukemia diagnosis and therapy, development and characteristics of ON and VTE, and thrombophilia work-up, if any, were collected from computer records and chart review. Osteonecrosis was diagnosed by plain X-ray, computed tomography (CT), magnetic resonance (MR) imaging, and/or technetium-99m (99mTc) bone scan. We included ON diagnosed during therapy and/or at any point during post-treatment follow-up. Standard radiological measures, including venous Doppler ultrasound and/or venography (conventional, CT, MR), confirmed VTE. We included only clinically significant thromboembolic events, defined as symptomatic VTE, or asymptomatic VTE requiring anticoagulation, developing during ALL therapy. Logistic regression analyses were performed to identify possible predictors of ON. Odds ratios (ORs) with 95% confidence intervals (CIs) and corresponding p-values were determined. Results Mean age of the study cohort (n = 208) was 5.4 years and male/female ratio 1.2:1. Seventy-eight (37.5%) patients had high-risk (HR) ALL and 127 (61.1%) received dexamethasone (DEX) as post-induction steroid. One hundred and sixty-two (77.9%) patients received E. coli ASP, 19 (9.1%) Erwinia ASP, and 27 (13.0%) PEG ASP. Twenty-one (10.1%) children developed ON. Joints affected by ON included the ankle in 11 subjects, knee in 10, hip in 8, and heel in one. Fourteen of the 21 patients (66.7%) had involvement of more than one joint. All patients were diagnosed with ON during ALL treatment, with the average being 69.2 weeks following ALL diagnosis. Forty-two (20.2%) subjects had a VTE while receiving therapy at an average of 29.4 weeks after ALL diagnosis. Nine patients had cerebral sinovenous thrombosis, 7 deep vein thrombosis (DVT), and one pulmonary embolism (PE). Twenty-six patients developed a central venous line (CVL)-related VTE. Results of univariate logistic regression analyses for osteonecrosis are presented in Table 1. VTE strongly predicted development of ON – OR 8.85 (95% CI 3.37–23.25, p< 0.001). Thirteen (31.0%) patients with VTE developed ON compared to 8 (4.8%) of 166 subjects without VTE. In 10 of 13 (76.9%) patients who developed both VTE and ON, the diagnosis of VTE preceded that of ON. Given that older age is a known risk factor for both VTE and ON, we conducted a multivariate analysis, which confirmed that age, ASP type, and VTE were independent, significant risk factors for ON (Table 2). Conclusion In addition to the known impact of older age, we identified VTE and type of ASP as independent risk factors for ON in children with ALL. These observations suggest overlap in the etiopathogenesis of ON and VTE. We recommend larger, prospective studies to confirm the association of VTE and PEG ASP with ON and to assess the impact of hypercoagulability on the development of ON. This in turn may help develop preventive strategies (e.g., thromboprophylaxis) for ALL-associated ON. Disclosures: No relevant conflicts of interest to declare.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".