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

• Published in: Blood 2014-04, Vol.123 (15), p.2308-2316
• Main Authors: McDermott, David H., Liu, Qian, Velez, Daniel, Lopez, Lizbeeth, Anaya-O'Brien, Sandra, Ulrick, Jean, Kwatemaa, Nana, Starling, Judy, Fleisher, Thomas A., Priel, Debra A. Long, Merideth, Melissa A., Giuntoli, Robert L., Evbuomwan, Moses O., Littel, Patricia, Marquesen, Martha M., Hilligoss, Dianne, DeCastro, Rosamma, Grimes, George J., Hwang, Samuel T., Pittaluga, Stefania, Calvo, Katherine R., Stratton, Pamela, Cowen, Edward W., Kuhns, Douglas B., Malech, Harry L., Murphy, Philip M.
• Format: Article
• Language: English
• Subjects: Adult; Benzylamines; Clinical Trials and Observations; Cyclams; Female; Flow Cytometry; Heterocyclic Compounds - administration & dosage; Heterocyclic Compounds - pharmacokinetics; Heterocyclic Compounds - therapeutic use; Humans; Immunologic Deficiency Syndromes - drug therapy; Male; Middle Aged; Primary Immunodeficiency Diseases; Receptors, CXCR4 - antagonists & inhibitors; Time Factors; Warts - drug therapy
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2013-09-527226

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare immunodeficiency disorder caused by gain-of-function mutations in the G protein–coupled chemokine receptor CXCR4. The CXCR4 antagonist plerixafor, which is approved by the US Food and Drug Administration (FDA) for stem cell mobilization in cancer and administered for that indication at 0.24 mg/kg, has been shown in short-term (1- to 2-week) phase 1 dose-escalation studies to correct neutropenia and other cytopenias in WHIM syndrome. However, long-term safety and long-term hematologic and clinical efficacy data are lacking. Here we report results from the first long-term clinical trial of plerixafor in any disease, in which 3 adults with WHIM syndrome self-injected 0.01 to 0.02 mg/kg (4% to 8% of the FDA-approved dose) subcutaneously twice daily for 6 months. Circulating leukocytes were durably increased throughout the trial in all patients, and this was associated with fewer infections and improvement in warts in combination with imiquimod; however, immunoglobulin levels and specific vaccine responses were not fully restored. No drug-associated side effects were observed. These results provide preliminary evidence for the safety and clinical efficacy of long-term, low-dose plerixafor in WHIM syndrome and support its continued study as mechanism-based therapy in this disease. The ClinicalTrials.gov identifier for this study is NCT00967785. •Plerixafor can be given safely to WHIM syndrome patients twice daily for a 6-month period and appears promising as a treatment.