The CXCR4 antagonist plerixafor corrects panleukopenia in patients with WHIM syndrome

DH McDermott, Q Liu, J Ulrick… - Blood, The Journal …, 2011 - ashpublications.org
DH McDermott, Q Liu, J Ulrick, N Kwatemaa, S Anaya-O'Brien, SR Penzak, JO Filho…
Blood, The Journal of the American Society of Hematology, 2011ashpublications.org
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 …
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, CXCR4R334X, 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.
ashpublications.org