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

Martin Stanulla,Peter Schütte,Holger J Schünemann,Anja Möricke,Martin Zimmermann,Simon Modlich,Kjeld Schmiegelow,Laura Hinze,Martin Schrappe,Melchior Lauten,Christian Flotho,R Kolb ,Axel Sauerbrey,Sabine Illsinger,Paul G Schlegel ,Astrid Gnekow ,Gunnar Cario,Elke Schaeffeler,Svitlana Igel,Georg C Schwabe ,Christian P Kratz,Stefanie V Junk,Claudia Rössig ,Gudrun Fleischhack,Hans Hartmann,Swantje Buchmann,Matthias Schwab

doi:10.1038/s41375-021-01203-7

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.

Highlights

Pediatric acute lymphoblastic leukemia (ALL) patients treated according to modern treatment protocols can expect to achieve long-term cure in ~90% of cases, but still a significant proportion of patients suffers from relapse and therapy-related toxicities [1, 2]
We identified 17 patients (0.43%) with hepatic sinusoidal obstruction syndrome (SOS) reported as an serious adverse event (SAE) out of 3983 patients in the derivation cohort (AIEOP-BFM ALL 2000)
Short-term exposure to 6-TG during treatment for pediatric ALL was associated with hepatic SOS and patients with thiopurine methyltransferase (TPMT) genotypes conferring low enzyme activity were at increased risk

Summary

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Pediatric acute lymphoblastic leukemia (ALL) patients treated according to modern treatment protocols can expect to achieve long-term cure in ~90% of cases, but still a significant proportion of patients suffers from relapse and therapy-related toxicities [1, 2]. Randomized controlled trials (RCTs) comparing the efficacy and toxicity of 6-MP with 6-TG in interim maintenance and maintenance therapy of childhood ALL have demonstrated dose-dependent high rates (>10%) of severe hepatotoxic side effects [4,5,6] These side effects have features of sinusoidal obstruction syndrome (SOS) and are associated with long-term exposure to 6-TG. From August 1, 2000, to May 31, 2010, a total of 3983 ALL patients between 1 and 18 years of age were diagnosed in one of the participating study centers in Germany and registered in trial AIEOP-BFM ALL 2000 [16,17,18] (Supplementary Fig. 1) Treatment in this trial, which we used as derivation cohort, contained standard multidrug chemotherapeutic regimens (for details see Fig. 1 and Supplementary Table 1) and, in parts of the patient population, cranial irradiation and/or HSCT.

Results

Discussion

Compliance with ethical standards