Session: 612. Acute Lymphoblastic Leukemia: Clinical Studies: Insights in Genomics, MRD, and Toxicities
Hematology Disease Topics & Pathways:
ALL, Leukemia, Diseases, Pediatric, Adverse Events, Study Population, Lymphoid Malignancies, Clinically relevant
Methods: Children aged 1-17.9 years with non high-risk ALL treated according to the NOPHO ALL2008 protocol from July 2008 to March 2016 in the Nordic and Baltic countries were included in the study. Based on median AEA-level measured 14 days (+/-2 days) after administration, patients were grouped into four groups; ‘no enzyme activity’ (0 IU/L, n=201), ‘fast clearance’ (1-99 IU/L, n=82), ‘therapeutic levels’ (100-249 IU/L, n=543), and ‘high levels’ (≥250 IU/L, n=330). Furthermore, groups with AEA-levels <100 IU/L and ≥100 IU/L were used. All types of asp-tox were prospectively registered in the NOPHO-database and defined according to the Ponte di Legno Toxicity Working Group consensus definitions (Schmiegelow et al 2016). We used age-adjusted multiple logistic regression models for all analyses.
Results: We included 1,156 patients and 6,929 samples for AEA-measurements in the study. The median number of samples for each patient was 5 [IQR: 3;9]. A total of 328 asp-tox events were registered in 311 patients (27.5%). The median age for patients with asp-tox was 5 years [Interquartile range (IQR): 2;9] compared with 4 years [IQR: 2;6] for patients without asp-tox (p<.001). Generally, a significantly lower incidence of asp-tox was found in patients with AEA-levels <100 IU/L (OR=1.), when compared with patients with levels ≥100 IU/L (OR=4.32, CI: 2.48, 8.20), P<.001. No significant difference between patients with therapeutic levels (OR=41.2, 95% CI: 9.0, 730.6) or high levels (OR=38.3, 95% CI: 8.2, 682.4) was found compared to patients with no AEA (OR=1). Significantly more cases of allergy in the group with no AEA were found (p<.001). Furthermore, a significantly higher incidence of pancreatitis (p<.001) and thromboembolism (p=.007) was seen in patients with AEA-levels ≥100 IU/L compared to levels <100 IU/L, but no difference in the risk of osteonecrosis was found (p=.08). There was no significant difference in the incidence of any asp-tox in the patients with AEA in the ´therapeutic levels´ compared with the ´high levels´ group. No difference according to AEA-level was observed in severity of asp-tox or other clinical characteristics (e.g. localization and number of sites of osteonecrosis and thromboembolism, treatment in intensive care unit or developing cysts/pseudocyst or diabetes for patients with pancreatitis).
Conclusion: We found no difference in the incidence of toxicities between AEA in ´therapeutic levels´ and ´high levels´ group, and there will be no clinical advantage in using TDM to identify patients with high AEA-levels for dose adjustment. The significantly lower incidence of asp-tox in patients without AEA and AEA-levels <100 UI/L reflects the high proportion of hypersensitivity patients with inactivation of asparaginase and supports that the efficacy of asparaginase treatment is insufficient for these patients.
Disclosures: Ranta: Roche: Other: Amember of Steering committee for a Roche study on Hemlibra (the contract is between Karolinska University Hospital and Roche). No financial benefits.. Wolthers: Novo Nordisk: Current Employment. Heyman: Servier: Other: Research funding in ALLTogether (research protocol). Schmiegelow: Jazz Pharmaceuticals: Other: Speaker and/or Advisory Board Honoraria ; Medscape: Other: Speaker fee; Servier: Other: Educational grant. Speaker and/or Advisory Board Honoraria ; Amgen: Other: Speaker fee. Albertsen: Erytech Pharma: Other: Sponsor of the investigator initiated study: NOR-GRASPALL 2016. No financial benefits..
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