Portal hypertension develops in a subset of children with standard risk acute lymphoblastic leukemia treated with oral 6-thioguanine during maintenance therapy

Background. 6-Thioguanine (TC) was recently studied to determine whether TC in maintenance therapy achieves better event free survival than 6-mercaptopurine (MP) for standard risk acute lymphoblastic leukemia (ALL) on the clinical trial, CCC-1952 (5/1996-1/2000). Veno-occlusive disease was previously recognized as a complication of TC on CCC-1952. We report a newly recognized pediatric complication of TC: splenomegaly and portal hypertension (PH) developing during maintenance or after completion of therapy. Procedure. Twelve patients (3-10 years) had been randomized to receive a targeted dose of 50 mg/m²/day of TC during maintenance phases. Actual TC dose ranged from 25 to 77 mg/m²/day (median 34 mg/m²/day). Results. The initial patient, a boy who had marked thrombocytopenia and intermittent splenomegaly during maintenance therapy, was evaluated for persistent pancytopenia and progressive splenomegaly 3 months after completion of therapy. Dilated splenic vein and collaterals consistent with PH were documented by MRI/MRA. Esophagogastroduodenoscopy found esophageal varices. Liver biopsy showed periportal fibrosis and marked dilatation of veins and venules. Of the other 12 patients, 9 patients studied had abnormal MRI/MRAs with evidence of varices in 4. Eight patients had splenomegaly on physical examination. Liver biopsies in a girl after 3.3 courses of TC and a boy after 4.6 courses of TC showed periportal fibrosis and dilatation of venules and sinusoids and minimal focal fatty changes. Subsequent MRI/MRAs have been stable or improved. Conclusions. The evaluations of these 12 patients suggest that treatment with TC causes injury to the liver leading to PH and that thrombocytopenia and splenomegaly are clinical hallmarks of this toxicity.