CXCR4 blockade reverses panleukopenia in patients with WHIM syndrome (153.11)

Abstract WHIM syndrome is a rare congenital immunodeficiency disorder characterized by warts, hypogammaglobulinemia, infections and myelokathexis (neutropenia due to impaired egress from bone marrow); most patients also have severe panleukopenia. The disease is caused by autosomal dominant gain-of-function truncation mutations in the C-terminus of chemokine receptor CXCR4. CXCR4 normally controls neutrophil and hematopoietic stem cell distribution between blood and bone marrow, T cell development and B cell lymphopoiesis. Here we present preliminary data from a Phase 1 study of the safety and efficacy of the FDA-approved CXCR4 antagonist Mozobil as mechanism-based therapy in WHIM syndrome, using a 7-day dose-escalation protocol. To date, we have recruited two unrelated adult patients, both having the most common WHIM mutation, CXCR4 R334X. In both patients, Mozobil increased lymphocytes and monocytes in blood to the normal range, and neutrophils in blood to the safe level (>500 cells/microliter). One patient has now been treated with Mozobil daily for 6 months with no loss of efficacy. No side effects were noted in either patient. Thus, our data provide the first pharmacologic evidence that panleukopenia in WHIM syndrome is due to CXCR4-dependent leukocyte retention in storage sites, and justify continued study of Mozobil as mechanism-based therapy for patients with this disease.