title: Pomalidomide augments fetal hemoglobin production without the myelosuppressive effects of hydroxyurea in transgenic sickle cell mice.
abstract: Pharmacologic induction of fetal hemoglobin (HbF) expression is an effective treatment strategy for sickle cell disease (SCD) and β-thalassemia. Pomalidomide is a potent structural analog of thalidomide and member of a new class of immunomodulatory drugs. Recent reports demonstrated that pomalidomide reduced or eliminated transfusion requirements in certain hematologic malignancies and induced HbF ex vivo in CD34(+) progenitor cells from healthy and SCD donors. We investigated the effects of pomalidomide on erythropoiesis and hemoglobin synthesis in a transgenic mouse model of SCD. We found that 8 weeks of treatment with pomalidomide induced modest increases of HbF with similar efficacy as hydroxyurea. However, in stark contrast to hydroxyurea's myelosuppressive effects, pomalidomide augmented erythropoiesis and preserved bone marrow function. Surprisingly, combinatory therapy with both drugs failed to mitigate hydroxyurea's myelotoxic effects and caused loss of HbF induction. These findings support further evaluation of pomalidomide as a novel therapy for SCD.
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, Georgia Health Sciences University, Augusta, GA, USA. smeiler@georgiahealth.edu
authors.forename: Steffen E
authors.initials: SE
authors.lastname: Meiler
authors.forename: Marlene
authors.initials: M
authors.lastname: Wade
authors.forename: Ferdane
authors.initials: F
authors.lastname: Kutlar
authors.forename: Shobha D
authors.initials: SD
authors.lastname: Yerigenahally
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Xue
authors.forename: Laure A
authors.initials: LA
authors.lastname: Moutouh-de Parseval
authors.forename: Laura G
authors.initials: LG
authors.lastname: Corral
authors.forename: Paul S
authors.initials: PS
authors.lastname: Swerdlow
authors.forename: Abdullah
authors.initials: A
authors.lastname: Kutlar
mesh_terms: D000755:Anemia, Sickle Cell / Q000097:blood*; D000818:Animals; D000986:Antisickling Agents / Q000494:pharmacology*; D001853:Bone Marrow / Q000187:drug effects*; D004195:Disease Models, Animal; D004920:Erythropoiesis / Q000187:drug effects*; D005319:Fetal Hemoglobin / Q000187:drug effects*; D006918:Hydroxyurea / Q000009:adverse effects; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000986:Antisickling Agents; D013792:Thalidomide; D005319:Fetal Hemoglobin; C467566:pomalidomide; D006918:Hydroxyurea