The CXCR4 antagonist plerixafor corrects panleukopenia in patients with WHIM syndrome

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, CXCR4 R334X , 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 signalingdependent 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.

A phase 1 clinical trial of long-term, low-dose treatment of WHIM syndrome with the CXCR4 antagonist plerixafor

“…Three unrelated white adults with WHIM syndrome were recruited: a 44-year-old female (P1), a 30-year-old female (P2), and a 51-year-old male (P3). P1 was first reported in Wetzler et al, 3 whereas P2 and P3 were first reported in McDermott et al 18 All 3 patients had the 4 major clinical features of WHIM syndrome and were heterozygous for CXCR4 R334X , the most common mutation in the disease, which truncates the receptor by 19 amino acids. Each had previously participated in a 7-day, phase 1 dose-escalation study of plerixafor at the National Institutes of Health reported previously and had a hematologic response to the drug with an increase in most subsets of circulating leukocytes without significant side effects.…”

“…Specifically, in two phase 1 clinical trials lasting 1 to 2 weeks in patients with WHIM syndrome, plerixafor was able to safely and rapidly increase absolute lymphocyte, monocyte, and neutrophil counts in the peripheral blood in a dose-dependent manner, including at the lowest dose tested, 0.02 mg/kg per day by subcutaneous administration, which is 8% of the FDA-approved dose for stem cell mobilization (0.24 mg/kg per day). 17,18 These trials were not designed to test the effect of the The online version of this article contains a data supplement.…”

“…P3 began this study 2 days after the dose-escalation study 18 ; he had not received G-CSF for .2 years because of severe bone pain but had been taking monthly IVIg. G-CSF was stopped on day 27, and IVIg was not given during the period of plerixafor treatment.…”

The role of chemokines in the pathogenesis of neurotropic flaviviruses

“…It may also be informative to test the changes in leukocyte mobilization stimulated by AMD3100. In mice and humans, AMD3100 is capable of mobilizing T cells (and other leukocytes), which may have also contributed to the resistance phenotype observed in these mice [29,55,56].…”

Children with rare diseases of neutrophil granulocytes: from therapeutic orphans to pioneers of individualized medicine

“…Early reports have shown that plerixafor reversed leukopenia in WHIM patients. 41,42 More recently, a phase 1 clinical trial of long-term, low-dose therapy of WHIM syndrome patients with plerixafor showed lack of toxicity and durably increased circulating leukocytes. The concept of targeted CXCR4 inhibition in WHIM patients warrants further clinical studies.…”