Asparaginase Enzyme Activity Levels and Toxicity in Childhood Acute Lymphoblastic Leukemia: a NOPHO ALL2008 study.

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 1,155 children aged 1.0-17.9 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 (6,944 trough values). AEA was measurable (or above >0 IU/L) in 955 patients while 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% CI, 0.98-1.41; p=0.09). For pancreatitis, thromboembolism, and osteonecrosis, the HRs were 1.40 (95% CI, 1.12-1.75; p=0.002), 0.99 (95% CI, 0.70-1.40; p = 0.96), and 1.36 (95% CI, 1.04-1.77; p=0.02) 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=0.35). 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.