TY - JOUR
T1 - The CXCR4 antagonist plerixafor corrects panleukopenia in patients with WHIM syndrome
AU - McDermott, David H.
AU - Liu, Qian
AU - Ulrick, Jean
AU - Kwatemaa, Nana
AU - Anaya-O'Brien, Sandra
AU - Penzak, Scott R.
AU - Filho, Joao Oliveira
AU - Long Priel, Debra A.
AU - Kelly, Corin
AU - Garofalo, Mary
AU - Littel, Patricia
AU - Marquesen, Martha M.
AU - Hilligoss, Diane
AU - DeCastro, Rosamma
AU - Fleisher, Thomas A.
AU - Kuhns, Douglas B.
AU - Malech, Harry L.
AU - Murphy, Philip M.
PY - 2011/11/3
Y1 - 2011/11/3
N2 - 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 trackedthe 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.
AB - 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 trackedthe 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.
UR - http://www.scopus.com/inward/record.url?scp=80855144801&partnerID=8YFLogxK
U2 - 10.1182/blood-2011-07-368084
DO - 10.1182/blood-2011-07-368084
M3 - Article
C2 - 21890643
AN - SCOPUS:80855144801
VL - 118
SP - 4957
EP - 4962
JO - Blood
JF - Blood
SN - 0006-4971
IS - 18
ER -