title: Portal hypertension develops in a subset of children with standard risk acute lymphoblastic leukemia treated with oral 6-thioguanine during maintenance therapy.
abstract: BACKGROUND
  6-Thioguanine (TG) was recently studied to determine whether TG in maintenance therapy achieves better event free survival than 6-mercaptopurine (MP) for standard risk acute lymphoblastic leukemia (ALL) on the clinical trial, CCG-1952 (5/1996-1/2000). Veno-occlusive disease was previously recognized as a complication of TG on CCG-1952. We report a newly recognized pediatric complication of TG: splenomegaly and portal hypertension (PH) developing during maintenance or after completion of therapy.
  
  
  METHODS
  Twelve patients (3-10 years) had been randomized to receive a targeted dose of 50 mg/m(2)/day of TG during maintenance phases. Actual TG dose ranged from 25 to 77 mg/m(2)/day (median 34 mg/m(2)/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 TG and a boy after 4.6 courses of TG 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 TG causes injury to the liver leading to PH and that thrombocytopenia and splenomegaly are clinical hallmarks of this toxicity.
authors.affiliation: Hematology/Oncology, Children's Medical Center, Wright State University, Dayton, Ohio, USA.
authors.forename: Emmett H
authors.initials: EH
authors.lastname: Broxson
authors.forename: Mukund
authors.initials: M
authors.lastname: Dole
authors.forename: Raymond
authors.initials: R
authors.lastname: Wong
authors.forename: Bernard F
authors.initials: BF
authors.lastname: Laya
authors.forename: Linda
authors.initials: L
authors.lastname: Stork
mesh_terms: D000284:Administration, Oral; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D002648:Child; D002675:Child, Preschool; D004932:Esophageal and Gastric Varices / Q000139:chemically induced; D005260:Female; D006801:Humans; D006975:Hypertension, Portal / Q000139:chemically induced* / Q000473:pathology; D018810:Magnetic Resonance Angiography; D008279:Magnetic Resonance Imaging; D008297:Male; D015122:Mercaptopurine / Q000633:toxicity; D010198:Pancytopenia / Q000139:chemically induced; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D013163:Splenomegaly / Q000139:chemically induced; D013866:Thioguanine / Q000633:toxicity*; D013921:Thrombocytopenia / Q000139:chemically induced
chemical_list: D000964:Antimetabolites, Antineoplastic; D015122:Mercaptopurine; D013866:Thioguanine