Hepatic sinusoidal obstruction syndrome and short-term application of 6-thioguanine in pediatric acute lymphoblastic leukemia

Martin Stanulla*, Elke Schaeffeler, Anja Möricke, Swantje Buchmann, Martin Zimmermann, Svitlana Igel, Kjeld Schmiegelow, Christian Flotho, Hans Hartmann, Sabine Illsinger, Axel Sauerbrey, Stefanie V. Junk, Peter Schütte, Laura Hinze, Melchior Lauten, Simon Modlich, Reinhard Kolb, Claudia Rossig, Georg Schwabe, Astrid K. GnekowGudrun Fleischhack, Paul Gerhard Schlegel, Holger J. Schünemann, Christian P. Kratz, Gunnar Cario, Martin Schrappe, Matthias Schwab

*Corresponding author for this work


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 TPMT genotype 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 TPMT variants, 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 TPMT wild-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 TPMT genotypes.

Original languageEnglish
Issue number9
Pages (from-to)2650-2657
Number of pages8
Publication statusPublished - 09.2021

Research Areas and Centers

  • Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)


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