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Asparaginase enzyme activity levels and toxicity in childhood acute lymphoblastic leukemia: a NOPHO ALL2008 study.

ABSTRACT: Asparaginase treatment is a mainstay in contemporary treatment of acute lymphoblastic leukemia (ALL), but substantial asparaginase-related toxicity may lead to jeopardized protocol compliance and compromises survival. We investigated the association between risk of asparaginase-associated toxicities (AspTox) and asparaginase enzyme activity (AEA) levels in 1155 children aged 1.0 to 17.9 years, diagnosed with ALL between July 2008 and March 2016, and treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol. Patients with ≥2 blood samples for AEA measurement drawn 14 ± 2 days after asparaginase administration were included (6944 trough values). AEA was measurable (or >0 IU/L) in 955 patients, whereas 200 patients (17.3%) had asparaginase inactivation and few AspTox recorded. A time-dependent multiple Cox model of time to any first asparaginase-associated toxicity adjusted for sex and age was used. For patients with measurable AEA, we found a hazard ratio (HR) of 1.17 per 100 IU/L increase in median AEA (95% confidence interval [CI], 0.98-1.41; P = .09). For pancreatitis, thromboembolism, and osteonecrosis, the HRs were 1.40 (95% CI, 1.12-1.75; P = .002), 0.99 (95% CI, 0.70-1.40; P = .96), and 1.36 (95% CI, 1.04-1.77; P = .02) per 100 IU/L increase in median AEA, respectively. No significant decrease in the risk of leukemic relapse was found: HR 0.88 per 100 IU/L increase in AEA (95% CI, 0.66-1.16; P = .35). In conclusion, these results emphasize that overall AspTox and relapse are not associated with AEA levels, yet the risk of pancreatitis and osteonecrosis increases with increasing AEA levels.

SUBMITTER: Lynggaard LS

PROVIDER: S-EPMC8753199 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Thromboembolism frequently occurs during acute lymphoblastic leukemia (ALL) therapy. We prospectively registered thromboembolic events during the treatment of 1772 consecutive Nordic/Baltic patients with ALL aged 1 to 45 years who were treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol (July 2008-April 2017). The 2.5-year cumulative incidence of thromboembolism (N = 137) was 7.9% (95% confidence interval [CI], 6.6-9.1); it was higher in patients aged at least 10 years (P < .0001). Adjusted hazard ratios (HRas) were associated with greater age (range, 10.0-17.9 years: HRa, 4.9 [95% CI, 3.1-7.8; P < .0001]; 18.0-45.9 years: HRa, 6.06 [95% CI, 3.65-10.1; P < .0001]) and mediastinal mass at ALL diagnosis (HRa, 2.1; 95% CI, 1.0-4.3; P = .04). In a multiple absolute risk regression model addressing 3 thromboembolism risk factors, age at least 10 years had the largest absolute risk ratio (RRage, 4.7 [95% CI, 3.1-7.1]; RRenlarged lymph nodes, 2.0 [95% CI, 1.2-3.1]; RRmediastinal mass, 1.6 [95% CI, 1.0-2.6]). Patients aged 18.0 to 45.9 years had an increased hazard of pulmonary embolism (HRa, 11.6; 95% CI, 4.02-33.7; P < .0001), and patients aged 10.0 to 17.9 years had an increased hazard of cerebral sinus venous thrombosis (HRa, 3.3; 95% CI, 1.5-7.3; P = .003) compared with children younger than 10.0 years. Asparaginase was truncated in 38/128 patients with thromboembolism, whereas thromboembolism diagnosis was unassociated with increased hazard of relapse (P = .6). Five deaths were attributable to thromboembolism, and patients younger than 18.0 years with thromboembolism had increased hazard of dying compared with same-aged patients without thromboembolism (both P ? .01). In conclusion, patients aged at least 10 years could be candidates for preemptive antithrombotic prophylaxis. However, the predictive value of age 10 years or older, enlarged lymph nodes, and mediastinal mass remain to be validated in another cohort.

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Asparaginase enzyme activity levels and toxicity in childhood acute lymphoblastic leukemia: a NOPHO ALL2008 study.

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