title: The CXCR4 antagonist plerixafor corrects panleukopenia in patients with WHIM syndrome.
abstract: WHIM syndrome is a rare congenital immunodeficiency disorder characterized by warts, hypogammaglobulinemia, infections, and myelokathexis (neutropenia because of impaired egress from the BM); most patients also have severe panleukopenia. Because WHIM syndrome is caused by mutations in the chemokine receptor CXCR4 that result in increased agonist-dependent signaling, we hypothesized that the CXCR4 antagonist plerixafor (Mozobil [Genyzme Corporation], AMD3100), might be an effective treatment. To test this, we enrolled 3 unrelated adult patients with the most common WHIM mutation, CXCR4(R334X), in a phase 1 dose-escalation study. Plerixafor increased absolute lymphocyte, monocyte, and neutrophil counts in blood to normal without significant side effects in all 3 patients. Peak responses occurred at 3-12 hours after injection and waned by 24 hours after injection which tracked the drug's pharmacokinetics. All 3 cell types increased in a dose-dependent manner with the rank order of responsiveness absolute lymphocyte > monocyte > neutrophil. These data provide the first pharmacologic evidence that panleukopenia in WHIM syndrome is caused by CXCL12-CXCR4 signaling-dependent leukocyte sequestration, and support continued study of plerixafor as mechanism-based therapy in this disease. This study is registered at http://www.clinicaltrials.gov as NCT00967785.
authors: Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. dmcdermott@nih.gov
authors: David H
authors: DH
authors: McDermott
authors: Qian
authors: Q
authors: Liu
authors: Jean
authors: J
authors: Ulrick
authors: Nana
authors: N
authors: Kwatemaa
authors: Sandra
authors: S
authors: Anaya-O'Brien
authors: Scott R
authors: SR
authors: Penzak
authors: Joao Oliveira
authors: JO
authors: Filho
authors: Debra A Long
authors: DA
authors: Priel
authors: Corin
authors: C
authors: Kelly
authors: Mary
authors: M
authors: Garofalo
authors: Patricia
authors: P
authors: Littel
authors: Martha M
authors: MM
authors: Marquesen
authors: Diane
authors: D
authors: Hilligoss
authors: Rosamma
authors: R
authors: Decastro
authors: Thomas A
authors: TA
authors: Fleisher
authors: Douglas B
authors: DB
authors: Kuhns
authors: Harry L
authors: HL
authors: Malech
authors: Philip M
authors: PM
authors: Murphy
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D001596:Benzylamines; D001772:Blood Cell Count; D000080027:Cyclams; D004305:Dose-Response Relationship, Drug; D005260:Female; D006571:Heterocyclic Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D007962:Leukocytes / Q000187:drug effects / Q000473:pathology; D008231:Lymphopenia / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D000081207:Primary Immunodeficiency Diseases; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000235:genetics; D016896:Treatment Outcome; D014860:Warts / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D001596:Benzylamines; C527276:CXCR4 protein, human; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; C088327:plerixafor