Department of Pharmacy, First Affiliated Hospital of Guangxi Medical University, Nanning, China.
Department of Pharmacy, Guangxi Zhuang Autonomous Region Workers' Hospital, Nanning, China.
Can J Gastroenterol Hepatol. 2022 Mar 24;2022:5914593. doi: 10.1155/2022/5914593. eCollection 2022.
The presence of serious toxicities is a major problem in the treatment of childhood acute lymphoblastic leukemia (ALL). The objective of this research is to evaluate drug-induced liver injury (DILI) during consolidation therapy in childhood ALL.
Clinical data of pediatric patients who received consolidation therapy between August 2012 and July 2018 were collected. Characteristics (incidences and patterns) of DILI at different stratifications were determined. Risks of DILI were evaluated using binary logistic regression analysis. Drug causality assessment was carried out by the updated Roussel Uclaf Causality Assessment Method (RUCAM).
Patients with high risk (HR) and standard risk (SR)/intermediate risk (IR) received 270 and 1539 courses of consolidation therapy, respectively; among these courses, 15 (5.6%) and 38 (2.5%) developed DILI. The occurrences of DILI in SR/IR patients were primarily associated with age (≤5.2 years), treatment course (≥5), and baseline serum parameters before treatment (cystatin C > 0.79 mg/L, albumin ≤45 g/L, and gamma-glutamyl transpeptidase (GGT) > 17 U/L). The ROC curve generated using the parameters assigned to specific values achieved an area under the curve (AUC) of 0.846 (95% CI 0.827-0.863) with a cutoff value of 3, and the sensitivity and specificity were 94.7% and 62.3%, respectively. For HR patients, a decrease in baseline albumin and elevation of baseline liver enzymes (GGT and aspartate aminotransferase) were observed in DILI cases compared with the non-DILI subjects. In the SR/IR group with DILI, the causality gradings for high-dose methotrexate (HD-MTX) were highly probable in 5 (13.2%) cases, probable in 31 (81.6%) cases, and possible in 2 (5.3%) cases. Among the DILI cases in HR-1, HR-2, and HR-3 groups, high causality gradings (probable + highly probable) were detected in "100% of HD-MTX + 57% of high-dose cytarabine (HD-Ara-C)," "100% of HD-MTX + 20% of pegylated asparaginase (PEG-ASP)," and "100% of HD-Ara-C + 33.3% of PEG-ASP," respectively.
Incidence of DILI in HR patients was significantly higher than that in SR/IR patients. A number of potential risk factors were identified, among which the preexisting liver conditions were suggested as shared risk factors in all stratification groups. HD-MTX, HD-Ara-C, and PEG-ASP were the main causative agents of DILI. The knowledge generated from this study will be helpful for understanding characteristics of DILI during consolidation treatment in childhood ALL.
严重毒性是儿童急性淋巴细胞白血病（ALL）治疗中的一个主要问题。本研究旨在评估儿童 ALL 巩固治疗期间药物性肝损伤（DILI）。
收集了 2012 年 8 月至 2018 年 7 月接受巩固治疗的儿科患者的临床数据。在不同分层中确定了 DILI 的特征（发生率和模式）。使用二项逻辑回归分析评估 DILI 的风险。使用更新的 Roussel Uclaf 因果关系评估方法（RUCAM）进行药物因果关系评估。
高风险（HR）和标准风险（SR）/中风险（IR）患者分别接受了 270 和 1539 个疗程的巩固治疗；在这些疗程中，分别有 15 例（5.6%）和 38 例（2.5%）发生了 DILI。SR/IR 患者中 DILI 的发生主要与年龄（≤5.2 岁）、治疗疗程（≥5）和治疗前的基线血清参数（胱抑素 C>0.79mg/L、白蛋白≤45g/L 和γ-谷氨酰转肽酶（GGT）>17U/L）有关。根据特定值分配的参数生成的 ROC 曲线的 AUC 为 0.846（95%CI 0.827-0.863），截断值为 3，灵敏度和特异性分别为 94.7%和 62.3%。对于 HR 患者，与非 DILI 患者相比，DILI 患者的基线白蛋白降低，基线肝酶（GGT 和天冬氨酸氨基转移酶）升高。在 DILI 的 SR/IR 组中，高剂量甲氨蝶呤（HD-MTX）的因果关系分级在 5 例（13.2%）中为高度可能，在 31 例（81.6%）中为可能，在 2 例（5.3%）中为很可能。在 HR-1、HR-2 和 HR-3 组的 DILI 病例中，“100%的 HD-MTX+57%的高剂量阿糖胞苷（HD-Ara-C）”、“100%的 HD-MTX+20%的聚乙二醇天冬酰胺酶（PEG-ASP）”和“100%的 HD-Ara-C+33.3%的 PEG-ASP”中检测到高因果关系分级（可能+高度可能）。
HR 患者的 DILI 发生率明显高于 SR/IR 患者。确定了一些潜在的危险因素，其中提示基线肝状况是所有分层组的共同危险因素。HD-MTX、HD-Ara-C 和 PEG-ASP 是 DILI 的主要致病药物。本研究获得的知识将有助于了解儿童 ALL 巩固治疗期间 DILI 的特征。
