Hepatic sinusoidal obstruction syndrome (SOS) was associated with short-term exposure to 6-thioguanine (6-TG) during the treatment of pediatric patients with acute lymphoblastic leukemia (ALL), and SOS risk was increased in patients with low-activity thiopurine methyltransferase (TPMT) genotypes, according to a study published in Leukemia.

Investigators analyzed the association between hepatic SOS reported as a serious adverse event (SAE) and short-term application of 6-TG in 3983 pediatric ALL patients who were treated in the AIEOP-BFM ALL 2000 trial (ClinicalTrials.gov Identifiers: NCT00430118 and NCT01117441). The patients, aged 1 to 18 years, were diagnosed in a participating center in Germany from August 1, 2000 to May 31, 2010. Treatment involved standard multidrug chemotherapeutic regimens, and 6-TG (60 mg/m2/d) was applied for 2 weeks during late-intensification therapy. A total of 813 patients had TPMT genotype information available.

A replication cohort included 1566 patients aged 1 to 18 years who were diagnosed with pediatric ALL from June 1, 2010 to December 31, 2016, and treated in the nonexperimental arms.


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The researchers found that 17 patients (0.43%; 70.6% were male; 82.4% were younger than 10 years at ALL diagnosis) with hepatic SOS reported an SAE in the derivation cohort. No significant differences were observed in relevant clinical characteristics between patients with hepatic SOS and those who did not have hepatic SOS (3966 patients; 55.3% male; 74.3% younger than 10 years at ALL diagnosis). Among the 17 patients, 4 developed hepatic SOS during induction treatment with a glucocorticoid, vincristine, l-asparaginase, daunorubicin, and intrathecal methotrexate. Of the 4 cases of hepatic SOS, 2 were related to acute pancreatitis or severe sepsis.

Hepatic SOS was strongly clustered with short-term exposure to 6-TG during the second phase of late-intensification therapy in 13 patients, according to the study authors. The difference in frequency of hepatic SOS in 6-TG–containing treatment compared with other treatment was highly significant (P ≤.0001).

In addition, from the group of 13 patients, 8 were heterozygous for low-activity TPMT variants. The odds ratio for hepatic SOS when exposed to 6-TG was 22.4 (95% CI, 7.1-70.7; P ≤.0001) for TPMT heterozygotes compared with patients who were TPMT wild-type. These findings were supported by an independent replication analysis.

The researchers noted that they may not have identified all and less severe cases of hepatic SOS and recommended careful monitoring for signs of hepatic SOS in association with short-term 6-TG exposure in future studies.

“Particularly for TPMT heterozygotes, replacement of 6-TG by [6-mercaptopurine] may be an effective measure to reduce the incidence of hepatic SOS during treatment for pediatric ALL,” the study authors concluded.

Reference

Stanulla M, Schaeffeler E, Möricke A, et al. Hepatic sinusoidal obstruction syndrome and short-term application of 6-thioguanine in pediatric acute lymphoblastic leukemia. Leukemia. Published online March 13, 2021. doi:10.1038/s41375-021-01203-7