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. Gnekow; Gudrun Fleischhack; Paul Gerhard Schlegel; Holger J. Schünemann; Christian P. Kratz; Gunnar Cario; Martin Schrappe; Matthias Schwab

doi:10.1038/s41375-021-01203-7

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

Clinic of Pediatric and Adolescent Medicine

20 Citations (Scopus)

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.

Original language	English
Journal	Leukemia
Volume	35
Issue number	9
Pages (from-to)	2650-2657
Number of pages	8
ISSN	0887-6924
DOIs	https://doi.org/10.1038/s41375-021-01203-7
Publication status	Published - 09.2021

Funding

Acknowledgements This article is dedicated to our late dear friend and colleague Professor Giuseppe (Beppe) Basso from Padova - an outstanding pediatric hemato-oncologist and passionate leukemia researcher. We are indebted to all patients, parents, nurses, and doctors participating in/contributing to AIEOP-BFM ALL 2000 and AIEOP-BFM ALL 2009. This work was funded by the European Commission (FP7, TRANSCALL 2), the Robert-Bosch-Stiftung, Stuttgart, the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy—EXC 2180—390900677, the Madeleine-Schickedanz-Kinderkrebs-stiftung, Verein für krebskranke Kinder Hannover e.V., and the Deutsche Krebshilfe.

Research Areas and Centers

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41375-021-01203-7

Cite this

Stanulla, M., Schaeffeler, E., Möricke, A., Buchmann, S., Zimmermann, M., Igel, S., Schmiegelow, K., Flotho, C., Hartmann, H., Illsinger, S., Sauerbrey, A., Junk, S. V., Schütte, P., Hinze, L., Lauten, M., Modlich, S., Kolb, R., Rossig, C., Schwabe, G., ... Schwab, M. (2021). Hepatic sinusoidal obstruction syndrome and short-term application of 6-thioguanine in pediatric acute lymphoblastic leukemia. Leukemia, 35(9), 2650-2657. https://doi.org/10.1038/s41375-021-01203-7

@article{a9b5a9e27a10436588b063b452bd1530,

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

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.",

author = "Martin Stanulla and Elke Schaeffeler and Anja M{\"o}ricke and Swantje Buchmann and Martin Zimmermann and Svitlana Igel and Kjeld Schmiegelow and Christian Flotho and Hans Hartmann and Sabine Illsinger and Axel Sauerbrey and Junk, \{Stefanie V.\} and Peter Sch{\"u}tte and Laura Hinze and Melchior Lauten and Simon Modlich and Reinhard Kolb and Claudia Rossig and Georg Schwabe and Gnekow, \{Astrid K.\} and Gudrun Fleischhack and Schlegel, \{Paul Gerhard\} and Sch{\"u}nemann, \{Holger J.\} and Kratz, \{Christian P.\} and Gunnar Cario and Martin Schrappe and Matthias Schwab",

note = "Funding Information: Acknowledgements This article is dedicated to our late dear friend and colleague Professor Giuseppe (Beppe) Basso from Padova - an outstanding pediatric hemato-oncologist and passionate leukemia researcher. We are indebted to all patients, parents, nurses, and doctors participating in/contributing to AIEOP-BFM ALL 2000 and AIEOP-BFM ALL 2009. This work was funded by the European Commission (FP7, TRANSCALL 2), the Robert-Bosch-Stiftung, Stuttgart, the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany{\textquoteright}s Excellence Strategy—EXC 2180—390900677, the Madeleine-Schickedanz-Kinderkrebs-stiftung, Verein f{\"u}r krebskranke Kinder Hannover e.V., and the Deutsche Krebshilfe. Publisher Copyright: {\textcopyright} 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = sep,

doi = "10.1038/s41375-021-01203-7",

language = "English",

volume = "35",

pages = "2650--2657",

journal = "Leukemia",

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Stanulla, M, Schaeffeler, E, Möricke, A, Buchmann, S, Zimmermann, M, Igel, S, Schmiegelow, K, Flotho, C, Hartmann, H, Illsinger, S, Sauerbrey, A, Junk, SV, Schütte, P, Hinze, L, Lauten, M, Modlich, S, Kolb, R, Rossig, C, Schwabe, G, Gnekow, AK, Fleischhack, G, Schlegel, PG, Schünemann, HJ, Kratz, CP, Cario, G, Schrappe, M & Schwab, M 2021, 'Hepatic sinusoidal obstruction syndrome and short-term application of 6-thioguanine in pediatric acute lymphoblastic leukemia', Leukemia, vol. 35, no. 9, pp. 2650-2657. https://doi.org/10.1038/s41375-021-01203-7

TY - JOUR

T1 - Hepatic sinusoidal obstruction syndrome and short-term application of 6-thioguanine in pediatric acute lymphoblastic leukemia

AU - Stanulla, Martin

AU - Schaeffeler, Elke

AU - Möricke, Anja

AU - Buchmann, Swantje

AU - Zimmermann, Martin

AU - Igel, Svitlana

AU - Schmiegelow, Kjeld

AU - Flotho, Christian

AU - Hartmann, Hans

AU - Illsinger, Sabine

AU - Sauerbrey, Axel

AU - Junk, Stefanie V.

AU - Schütte, Peter

AU - Hinze, Laura

AU - Lauten, Melchior

AU - Modlich, Simon

AU - Kolb, Reinhard

AU - Rossig, Claudia

AU - Schwabe, Georg

AU - Gnekow, Astrid K.

AU - Fleischhack, Gudrun

AU - Schlegel, Paul Gerhard

AU - Schünemann, Holger J.

AU - Kratz, Christian P.

AU - Cario, Gunnar

AU - Schrappe, Martin

AU - Schwab, Matthias

N1 - Funding Information: Acknowledgements This article is dedicated to our late dear friend and colleague Professor Giuseppe (Beppe) Basso from Padova - an outstanding pediatric hemato-oncologist and passionate leukemia researcher. We are indebted to all patients, parents, nurses, and doctors participating in/contributing to AIEOP-BFM ALL 2000 and AIEOP-BFM ALL 2009. This work was funded by the European Commission (FP7, TRANSCALL 2), the Robert-Bosch-Stiftung, Stuttgart, the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy—EXC 2180—390900677, the Madeleine-Schickedanz-Kinderkrebs-stiftung, Verein für krebskranke Kinder Hannover e.V., and the Deutsche Krebshilfe. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/9

Y1 - 2021/9

N2 - 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.

AB - 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.

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VL - 35

SP - 2650

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JO - Leukemia

JF - Leukemia

IS - 9

ER -

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

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