학술논문
Hepatic sinusoidal obstruction syndrome and short-term application of 6-thioguanine in pediatric acute lymphoblastic leukemia
Document Type
Article
Author
Stanulla, Martin; Schaeffeler, Elke; Möricke, Anja; Buchmann, Swantje; Zimmermann, Martin; Igel, Svitlana; Schmiegelow, Kjeld; Flotho, Christian; Hartmann, Hans; Illsinger, Sabine; Sauerbrey, Axel; Junk, Stefanie V.; Schütte, Peter; Hinze, Laura; Lauten, Melchior; Modlich, Simon; Kolb, Reinhard; Rossig, Claudia; Schwabe, Georg; Gnekow, Astrid K.; Fleischhack, Gudrun; Schlegel, Paul Gerhard; Schünemann, Holger J.; Kratz, Christian P.; Cario, Gunnar; Schrappe, Martin; Schwab, Matthias
Source
Leukemia; September 2021, Vol. 35 Issue: 9 p2650-2657, 8p
Subject
Language
ISSN
08876924; 14765551
Abstract
Long-term treatment with 6-thioguanine (6-TG) for pediatric acute lymphoblastic leukemia (ALL) is associated with high rates of hepatic sinusoidal obstruction syndrome (SOS). Nevertheless, current treatment continues to use short-term applications of 6-TG with only sparse information on toxicity. 6-TG is metabolized by thiopurine methyltransferase (TPMT) which underlies clinically relevant genetic polymorphism. We analyzed the association between hepatic SOS reported as a serious adverse event (SAE) and short-term 6-TG application in 3983 pediatric ALL patients treated on trial AIEOP-BFM ALL 2000 (derivation cohort) and defined the role of TPMTgenotype in this relationship. We identified 17 patients (0.43%) with hepatic SOS, 13 of which with short-term exposure to 6-TG (P< 0.0001). Eight of the 13 patients were heterozygous for low-activity TPMTvariants, resulting in a 22.4-fold (95% confidence interval 7.1–70.7; P≤ 0.0001)increased risk of hepatic SOS for heterozygotes in comparison to TPMTwild-type patients. Results were supported by independent replication analysis. All patients with hepatic SOS after short-term 6-TG recovered and did not demonstrate residual symptoms. Thus, hepatic SOS is associated with short-term exposure to 6-TG during treatment of pediatric ALL and SOS risk is increased for patients with low-activity TPMTgenotypes.