The CXCR4 antagonist plerixafor corrects panleukopenia in patients with WHIM syndrome

Blood. 2011 Nov 3;118(18):4957-62. doi: 10.1182/blood-2011-07-368084. Epub 2011 Sep 2.

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.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Anti-HIV Agents / administration & dosage
  • Anti-HIV Agents / pharmacokinetics
  • Anti-HIV Agents / pharmacology
  • Anti-HIV Agents / therapeutic use
  • Blood Cell Count
  • Dose-Response Relationship, Drug
  • Female
  • Heterocyclic Compounds / administration & dosage
  • Heterocyclic Compounds / pharmacokinetics
  • Heterocyclic Compounds / pharmacology
  • Heterocyclic Compounds / therapeutic use*
  • Humans
  • Immunologic Deficiency Syndromes / blood
  • Immunologic Deficiency Syndromes / complications
  • Immunologic Deficiency Syndromes / drug therapy*
  • Immunologic Deficiency Syndromes / genetics
  • Leukocytes / drug effects
  • Leukocytes / pathology
  • Lymphopenia / complications
  • Lymphopenia / drug therapy*
  • Lymphopenia / pathology
  • Male
  • Middle Aged
  • Primary Immunodeficiency Diseases
  • Receptors, CXCR4 / antagonists & inhibitors
  • Receptors, CXCR4 / genetics
  • Treatment Outcome
  • Warts / blood
  • Warts / complications
  • Warts / drug therapy*
  • Warts / genetics
  • Young Adult

Substances

  • Anti-HIV Agents
  • CXCR4 protein, human
  • Heterocyclic Compounds
  • Receptors, CXCR4
  • plerixafor

Supplementary concepts

  • WHIM syndrome

Associated data

  • ClinicalTrials.gov/NCT00967785