Clémence Merlen1, Arnaud Bonnefoy1, Eric Wagner2, Laurence Dedeken3, Jean-Marie Leclerc1, Caroline Laverdière1, Georges-Etienne Rivard1. 1. Division of Hematology / Oncology, CHU Sainte-Justine, Montréal, QC, Canada. 2. Immunology / Histocompatibility laboratory, CHU de Quebec and Department of Microbiology, Infectious Diseases and Immunology, Laval University, Quebec, QC, Canada. 3. Department of Hematology and Oncology, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, Belgium.
Abstract
BACKGROUND: L-asparaginase, a key therapeutic agent in the management of patients with acute lymphoblastic leukemia (ALL), dramatically impairs hepatic protein synthesis. We investigated the effects of prolonged exposure to L-asparaginase on antithrombin (AT), fibrinogen and mannan-binding-lectin (MBL) levels, and on the occurrence of thrombotic events (TE) and febrile neutropenia episodes (FN) in pediatric patients. PROCEDURE: Protein levels were measured in 97 children during 30 weeks of chemotherapy with L-asparaginase and up to 1 year following remission. TE and FN episodes were recorded during this period. RESULTS: Median AT level decreased from 0.96 IU/mL prior to treatment (range: 0.69-1.38) to 0.55 IU/mL (0.37-0.76) during therapy. Fibrinogen and MBL decreased from 3.18 g/L (1.29-7.28) and 1,177 ng/mL (57-5,343) to 1.56 g/L (0.84-2.13) and 193 ng/mL (57-544), respectively. All three proteins had recovered 1-4 weeks after L-asparaginase cessation. TE were reported in 22 (23%) patients. Of these, 11 occurred after a median of 10 administrations of L-asparaginase. Fifty-one FN were associated with infections, of which 36 occurred during treatment with L-asparaginase. Patients with low levels of MBL at diagnosis were at higher risk of FN associated with infections (RR = 1.59, 95%CI: 1.026-2.474). Both AT and MBL decreases were moderately correlated with fibrinogen (r = 0.51 and 0.58, respectively). CONCLUSIONS: Children with ALL are exposed to significant decrease in AT, fibrinogen and MBL levels, and concomitant increased risk of thrombosis and FN with infection during L-asparaginase treatment. Measuring plasma levels of these liver-derived proteins could help predict the occurrence of adverse events.
BACKGROUND:L-asparaginase, a key therapeutic agent in the management of patients with acute lymphoblastic leukemia (ALL), dramatically impairs hepatic protein synthesis. We investigated the effects of prolonged exposure to L-asparaginase on antithrombin (AT), fibrinogen and mannan-binding-lectin (MBL) levels, and on the occurrence of thrombotic events (TE) and febrile neutropenia episodes (FN) in pediatric patients. PROCEDURE: Protein levels were measured in 97 children during 30 weeks of chemotherapy with L-asparaginase and up to 1 year following remission. TE and FN episodes were recorded during this period. RESULTS: Median AT level decreased from 0.96 IU/mL prior to treatment (range: 0.69-1.38) to 0.55 IU/mL (0.37-0.76) during therapy. Fibrinogen and MBL decreased from 3.18 g/L (1.29-7.28) and 1,177 ng/mL (57-5,343) to 1.56 g/L (0.84-2.13) and 193 ng/mL (57-544), respectively. All three proteins had recovered 1-4 weeks after L-asparaginase cessation. TE were reported in 22 (23%) patients. Of these, 11 occurred after a median of 10 administrations of L-asparaginase. Fifty-one FN were associated with infections, of which 36 occurred during treatment with L-asparaginase. Patients with low levels of MBL at diagnosis were at higher risk of FN associated with infections (RR = 1.59, 95%CI: 1.026-2.474). Both AT and MBL decreases were moderately correlated with fibrinogen (r = 0.51 and 0.58, respectively). CONCLUSIONS:Children with ALL are exposed to significant decrease in AT, fibrinogen and MBL levels, and concomitant increased risk of thrombosis and FN with infection during L-asparaginase treatment. Measuring plasma levels of these liver-derived proteins could help predict the occurrence of adverse events.
Authors: Anna Sokołowska; Anna S Świerzko; Gabriela Gajek; Aleksandra Gołos; Mateusz Michalski; Mateusz Nowicki; Agnieszka Szala-Poździej; Anna Wolska-Washer; Olga Brzezińska; Agnieszka Wierzbowska; Krzysztof Jamroziak; Marek L Kowalski; Steffen Thiel; Misao Matsushita; Jens C Jensenius; Maciej Cedzyński Journal: Sci Rep Date: 2020-06-29 Impact factor: 4.379