Continuous Infusion of the CXCR4 Antagonist Plerixafor for WHIM Syndrome

WHIM (Warts, Hypogammaglobulinemia, Infections and Myelokathexis) syndrome is an ultrarare inborn error of immunity caused by heterozygous, gain-of-function CXCR4 mutations that impede leukocyte egress from bone marrow, resulting in panleukopenia. The CXCR4 antagonist plerixafor (AMD3100, Mozobil) durably reverses panleukopenia and in most WHIM patients induces wart regression; however, its short half-life requires twice daily injection. To develop a simpler, cheaper and potentially more effective method of drug delivery, we conducted a Phase 1 study of WHIM patients given plerixafor 0.02-0.08 mg/kg/d by continuous subcutaneous infusion using an OmniPod insulin pump, and assessed compliance as well as effects on blood leukocyte counts, infections, chronic skin conditions and adverse events. Six patients were treated for a total of 6.3 patient-years; one patient dropped out early for personal reasons. The drug infusion rate was adjusted to achieve a normal absolute lymphocyte count and an absolute neutrophil count >500 cells/{micro}l in all patients. An average of 2.1 infections/patient-year occurred (range 0-4). Treatment of two infections involved brief hospitalization. On plerixafor, partial wart regression occurred in 3 of 4 patients, a single molluscum contagiosum infection regressed and a chronic post-Mohs surgical wound epithelialized. There were 3 serious adverse events, but none was attributable to the treatment. All patients preferred pump administration over syringe injection. Thus, in WHIM patients a continuous infusion pump may be a convenient, safe and potentially cost-effective means of delivering plerixafor chronically to correct panleukopenia and to improve chronic skin conditions. Clinicaltrials.gov NCT00967785.