The CXCR4 antagonist plerixafor corrects panleukopenia in patients with WHIM syndrome

David H. McDermott, Qian Liu, Jean Ulrick, Nana Kwatemaa, Sandra Anaya-O'Brien, Scott R. Penzak, Joao Oliveira Filho, Debra A. Long Priel, Corin Kelly, Mary Garofalo, Patricia Littel, Martha M. Marquesen, Diane Hilligoss, Rosamma DeCastro, Thomas A. Fleisher, Douglas B. Kuhns, Harry L. Malech, Philip M. Murphy

Research output: Contribution to journalArticlepeer-review

110 Scopus citations


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 trackedthe 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:// as NCT00967785.

Original languageEnglish
Pages (from-to)4957-4962
Number of pages6
Issue number18
StatePublished - 3 Nov 2011


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