The CXCR4 antagonist plerixafor corrects panleukopenia in patients with WHIM syndrome.
Blood
; 118(18): 4957-62, 2011 Nov 03.
Article
en En
| MEDLINE
| ID: mdl-21890643
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 signaling-dependent 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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Verrugas
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Compuestos Heterocíclicos
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Síndromes de Inmunodeficiencia
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Linfopenia
Límite:
Aged80
Idioma:
En
Año:
2011
Tipo del documento:
Article