title: Hemolytic anemia in two patients with glioblastoma multiforme: A possible interaction between vorinostat and dapsone.
abstract: Patients undergoing treatment for glioblastoma multiforme are routinely placed on prophylactic treatment for Pneumocystis jirovecii pneumonia because of significant therapy-induced lymphopenia. In patients with sulfa allergies, dapsone prophylaxis is often used due to its efficacy, long half-life, cost effectiveness, and general safety at low doses. However, dapsone may uncommonly induce a hemolytic anemia, particularly in patients deficient of glucose-6-phosphate dehydrogenase. This hemolysis is thought to be a result of oxidative stress on red blood cells induced by dapsone metabolites which produce reactive oxygen species that disrupt the red blood cell membrane and promote splenic sequestration. A single case report of dapsone-induced hemolytic anemia in a patient with glioblastoma multiforme has been reported. We present two patients with glioblastoma multiforme who developed severe hemolytic anemia shortly after initiating therapy with vorinostat, a pan-active histone deacetylase inhibitor, while on prophylactic dapsone. There are several potential mechanisms by which histone deacetylase inhibition may alter dapsone metabolism including changes in hepatic acetylation or N-glucuronidation leading to an increase in the bioavailability of dapsone's hematotoxic metabolites. In addition, vorinostat may lead to increased hemolysis through inhibition of heat shock protein-90, a chaperone protein that maintains the integrity of the red blood cell membrane cytoskeleton. The potential interaction between dapsone and vorinostat may have important clinical implications as more than 10 clinical trials evaluating drug combinations with vorinostat in patients with malignant glioma are either ongoing or planned in North America.
authors.affiliation: Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA jelewis@wakehealth.edu.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Lewis
authors.affiliation: Department of Internal Medicine, Section on Hematology and Oncology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Petty
authors.affiliation: Department of Internal Medicine, Section on Hematology and Oncology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Harmon
authors.affiliation: Department of Internal Medicine, Section on Infectious Disease, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Peacock
authors.affiliation: Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
authors.forename: Kari
authors.initials: K
authors.lastname: Valente
authors.affiliation: Department of Internal Medicine, Section on Hematology and Oncology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
authors.forename: John
authors.initials: J
authors.lastname: Owen
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: Munir
authors.initials: M
authors.lastname: Pirmohamed
authors.affiliation: Department of Internal Medicine, Section on Hematology and Oncology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
authors.forename: Glenn J
authors.initials: GJ
authors.lastname: Lesser
mesh_terms: D000743:Anemia, Hemolytic / Q000139:chemically induced*; D003622:Dapsone / Q000009:adverse effects* / Q000627:therapeutic use*; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D006877:Hydroxamic Acids / Q000009:adverse effects* / Q000627:therapeutic use*; D008875:Middle Aged; D000077337:Vorinostat
chemical_list: D006877:Hydroxamic Acids; D000077337:Vorinostat; D003622:Dapsone
keywords: Dapsone; Pneumocystis jirovecii pneumonia prophylaxis; drug–drug interaction; glioblastoma multiforme; hemolytic anemia; histone deacetylase inhibitor; vorinostat