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

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 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.

OriginalsprogEngelsk
TidsskriftLeukemia
Vol/bind35
Udgave nummer9
Sider (fra-til)2650-2657
Antal sider8
ISSN0887-6924
DOI
StatusUdgivet - sep. 2021

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