Ebbesen Maria S, Nygaard Ulrikka, Rosthøj Susanne, Sørensen Ditte, Nersting Jacob, Vettenranta Kim, Wesenberg Finn, Kristinsson Jon, Harila-Saari Arja, Schmiegelow Kjeld
*Department of Pediatrics and Adolescent Medicine, Rigshospitalet †Section of Biostatistics, Department of Public Health #The Institute Clinical Medicine, University of Copenhagen, Copenhagen Denmark ‡Department of Pediatrics, University Hospital, Tampere, Finland §Department of Pediatrics, The University Hospital, Oslo, Norway ∥Department of Pediatrics, University Hospital, Reykjavik, Iceland ¶Department of Women's and Children's Health, Karolinska University Hospital and Karolinska Institutet, Solna, Stockholm, Sweden.
J Pediatr Hematol Oncol. 2017 Apr;39(3):161-166. doi: 10.1097/MPH.0000000000000733.
Hepatotoxicity is a known toxicity to treatment of childhood acute lymphoblastic leukemia. Hepatotoxicity occurs during maintenance therapy and is caused by metabolites of 6-Mercaptopurine (6 MP) and Methotrexate (MTX). Our objective was to investigate the association between alanine aminotransferases (ALAT) levels and relapse rate. We included 385 patients enrolled in the NOPHO ALL-92 protocol. Data on ALAT levels, 6 MP and MTX doses, cytotoxic MTX/6 MP metabolites, and thiopurine methyltransferase (TPMT) activity were prospectively registered. In total, 91% of the patients had a mean ALAT (mALAT) level above upper normal limit (40 IU/L) and ALAT levels were positively correlated to 6 MP doses (rs=0.31; P<0.001). In total, 47 patients suffered a relapse, no difference in mALAT levels were found in these compared with nonrelapse patients (median, 107 vs. 98 IU/L; P=0.39). mALAT levels in patients classified as TPMT high activity (TPMT) were higher than in TPMT low-activity patients (median, 103 vs. 82 IU/L; P=0.03). In a Cox regression model risk of relapse was not associated with ALAT levels (P=0.56). ALAT levels increased 2.7%/month during the last year of maintenance therapy (P<0.001). In conclusion, elevated ALAT levels are associated with TPMT and may indicate treatment adherence in these patients. If liver function is normal, elevated ALAT levels should not indicate treatment adaptation.
肝毒性是儿童急性淋巴细胞白血病治疗中一种已知的毒性反应。肝毒性发生在维持治疗期间，由6-巯基嘌呤（6-MP）和甲氨蝶呤（MTX）的代谢产物引起。我们的目的是研究丙氨酸转氨酶（ALAT）水平与复发率之间的关联。我们纳入了385例参加NOPHO ALL-92方案的患者。前瞻性记录了ALAT水平、6-MP和MTX剂量、细胞毒性MTX/6-MP代谢产物以及硫嘌呤甲基转移酶（TPMT）活性的数据。总体而言，91%的患者平均ALAT（mALAT）水平高于正常上限（40 IU/L），且ALAT水平与6-MP剂量呈正相关（rs=0.31；P<0.001）。共有47例患者复发，与未复发患者相比，这些患者的mALAT水平无差异（中位数分别为107与98 IU/L；P=0.39）。分类为TPMT高活性（TPMT）的患者的mALAT水平高于TPMT低活性患者（中位数分别为103与82 IU/L；P=0.03）。在Cox回归模型中，复发风险与ALAT水平无关（P=0.56）。在维持治疗的最后一年，ALAT水平每月升高2.7%（P<0.001）。总之，ALAT水平升高与TPMT有关，可能表明这些患者的治疗依从性。如果肝功能正常，ALAT水平升高不应提示调整治疗。
