Merlen Clémence, Bonnefoy Arnaud, Wagner Eric, Dedeken Laurence, Leclerc Jean-Marie, Laverdière Caroline, Rivard Georges-Etienne
Division of Hematology / Oncology, CHU Sainte-Justine, Montréal, QC, Canada.
Immunology / Histocompatibility laboratory, CHU de Quebec and Department of Microbiology, Infectious Diseases and Immunology, Laval University, Quebec, QC, Canada.
Pediatr Blood Cancer. 2015 Aug;62(8):1381-7. doi: 10.1002/pbc.25515. Epub 2015 Mar 27.
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.
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.
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).
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.
L-天冬酰胺酶是治疗急性淋巴细胞白血病（ALL）患者的关键治疗药物，会显著损害肝脏蛋白质合成。我们研究了长期接触L-天冬酰胺酶对小儿患者抗凝血酶（AT）、纤维蛋白原和甘露糖结合凝集素（MBL）水平的影响，以及对血栓形成事件（TE）和发热性中性粒细胞减少症发作（FN）发生率的影响。
在97名儿童接受L-天冬酰胺酶化疗的30周期间及缓解后长达1年的时间里测量蛋白质水平。在此期间记录TE和FN发作情况。
治疗期间，AT中位数水平从治疗前的0.96 IU/mL（范围：0.69 - 1.38）降至0.55 IU/mL（0.37 - 0.76）。纤维蛋白原和MBL分别从3.18 g/L（1.29 - 7.28）和1,177 ng/mL（57 - 5,343）降至1.56 g/L（0.84 - 2.13）和193 ng/mL（57 - 544）。在停用L-天冬酰胺酶1 - 4周后，这三种蛋白质均恢复。22名（23%）患者报告发生了TE。其中，11例在中位数为10次给予L-天冬酰胺酶后发生。51例FN与感染相关，其中36例发生在L-天冬酰胺酶治疗期间。诊断时MBL水平低的患者发生与感染相关的FN的风险更高（RR = 1.59，95%CI：1.026 - 2.474）。AT和MBL的降低均与纤维蛋白原呈中度相关（r分别为0.51和0.58）。
ALL患儿在接受L-天冬酰胺酶治疗期间，AT、纤维蛋白原和MBL水平显著下降，同时血栓形成和与感染相关的FN风险增加。检测这些肝脏来源蛋白质的血浆水平有助于预测不良事件的发生。
