Plerixafor for the Treatment of WHIM Syndrome
Summ a r y WHIM syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis), a primary immunodeficiency disorder involving panleukopenia, is caused by autosomal dominant gain-of-function mutations in CXC chemokine receptor 4 (CXCR4). Myelokathexis is neutropenia caused by neutrophil retention in bone marrow. Patients with WHIM syndrome are often treated with granulocyte colony-stimulating factor (G-CSF), which can increase neutrophil counts but does not affect cytopenias other than neutropenia. In this investigator-initiated, open-label study, three severely affected patients with WHIM syndrome who could not receive G-CSF were treated with low-dose plerixafor, a CXCR4 antagonist, for 19 to 52 months. Myelofibrosis, panleukopenia, anemia, and thrombocytopenia were ameliorated, the wart burden and frequency of infection declined, human papillomavirus-associated oropharyngeal squamous-cell carcinoma stabilized, and quality of life improved markedly. Adverse events were mainly infections attributable to the underlying immunodeficiency. One patient died from complications of elective reconstructive surgery. (Funded by the National Institutes of Health.) C XC chemokine receptor 4 (CXCR4), which binds CXC chemokine ligand 12 (CXCL12), is expressed on most leukocyte subsets and regulates leukocyte development and trafficking, among other activities. 1 In WHIM syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis), autosomal dominant gain-of-function CXCR4 mutations impair CXCL12-induced receptor down-regulation, thereby increasing CXCR4 signaling. 2,3 Hematologic consequences include myelokathexis and defective early B-cell and T-cell development, which result in panleukopenia, abnormal architecture of secondary lymphoid tissue, and immunodeficiency. [4] ] Moreover, G-CSF does not correct monocytopenia, lymphopenia, and hypogammaglobulinemia, and disabling bone pain and hematopathologic conditions may occur as a consequence of its use. Here, we evaluate the CXCR4 antagonist plerixafor as a mechanismbased treatment in patients with WHIM syndrome who cannot receive G-CSF.