A phase III randomized crossover trial of plerixafor versus G-CSF for treatment of WHIM syndrome

• Published in: The Journal of clinical investigation Vol. 133; no. 19; pp. 1 - 16
• Main Authors: McDermott, David H, Velez, Daniel, Cho, Elena, Cowen, Edward W, DiGiovanna, John J, Pastrana, Diana V, Buck, Christopher B, Calvo, Katherine R, Gardner, Pamela J, Rosenzweig, Sergio D, Stratton, Pamela, Merideth, Melissa A, Kim, H Jeffrey, Brewer, Carmen, Katz, James D, Kuhns, Douglas B, Malech, Harry L, Follmann, Dean, Fay, Michael P, Murphy, Philip M
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.10.2023
• Subjects: Antibiotics; B cells; Biomedical research; Blood; Bone marrow; Clinical Medicine; Clinical trials; Comparative analysis; Cross-Over Studies; CXCR4 protein; Drug dosages; Drug therapy; Genetic disorders; Granulocyte colony-stimulating factor; Granulocyte Colony-Stimulating Factor - therapeutic use; Granulocytes; Hematopoietic Stem Cell Mobilization - adverse effects; Heterocyclic Compounds - adverse effects; Humans; Hypogammaglobulinemia; Immunodeficiency; Immunoglobulins; Immunologic Deficiency Syndromes - drug therapy; Immunologic Deficiency Syndromes - genetics; Immunological deficiency syndromes; Immunology; Infection; Infections; Infectious diseases; Leukocytes; Leukocytes (granulocytic); Leukocytes (neutrophilic); Lymphocytes; Lymphopenia; Medical research; Medicine, Experimental; Mutation; Neutropenia; Neutrophils; Patients; Primary immunodeficiencies; Primary Immunodeficiency Diseases - drug therapy; Primary Immunodeficiency Diseases - genetics; Quality of Life; Receptors, CXCR4 - genetics; Testing; Warts; Warts - drug therapy; Warts - genetics; United States; Innate immunity; Immunology; Genetic diseases; Clinical Trials; Neutrophils
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI164918

BACKGROUNDWarts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a primary immunodeficiency disorder caused by heterozygous gain-of-function CXCR4 mutations. Myelokathexis is a kind of neutropenia caused by neutrophil retention in bone marrow and in WHIM syndrome is associated with lymphopenia and monocytopenia. The CXCR4 antagonist plerixafor mobilizes leukocytes to the blood; however, its safety and efficacy in WHIM syndrome are undefined.METHODSIn this investigator-initiated, single-center, quadruple-masked phase III crossover trial, we compared the total infection severity score (TISS) as the primary endpoint in an intent-to-treat manner in 19 patients with WHIM who each received 12 months treatment with plerixafor and 12 months treatment with granulocyte CSF (G-CSF, the standard of care for severe congenital neutropenia). The treatment order was randomized for each patient.RESULTSPlerixafor was nonsuperior to G-CSF for TISS (P = 0.54). In exploratory endpoints, plerixafor was noninferior to G-CSF for maintaining neutrophil counts of more than 500 cells/μL (P = 0.023) and was superior to G-CSF for maintaining lymphocyte counts above 1,000 cells/μL (P < 0.0001). Complete regression of a subset of large wart areas occurred on plerixafor in 5 of 7 patients with major wart burdens at baseline. Transient rash occurred on plerixafor, and bone pain was more common on G-CSF. There were no significant differences in drug preference or quality of life or the incidence of drug failure or serious adverse events.CONCLUSIONPlerixafor was not superior to G-CSF in patients with WHIM for TISS, the primary endpoint. Together with wart regression and hematologic improvement, the infection severity results support continued study of plerixafor as a potential treatment for WHIM syndrome.TRIAL REGISTRATIONClinicaltrials.gov NCT02231879.FUNDINGThis study was funded by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases.