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

Abstract

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.

• Authors: David H McDermott, Daniel Velez, Elena Cho, Edward W Cowen, John J DiGiovanna, Diana V Pastrana, Christopher B Buck, Katherine R Calvo, Pamela J Gardner, Sergio D Rosenzweig, Pamela Stratton, Melissa A Merideth, H Jeffrey Kim, Carmen Brewer, James D Katz, Douglas B Kuhns, Harry L Malech, Dean Follmann, Michael P Fay, Philip M Murphy
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 133 Issue 19 (10 02 2023) ISSN: 1558-8238 [Electronic] United States
• PMID: 37561579 (Publication Type: Randomized Controlled Trial, Clinical Trial, Phase III, Journal Article, Research Support, N.I.H., Intramural, Research Support, N.I.H., Extramural)

Chemical References

• Granulocyte Colony-Stimulating Factor
• Heterocyclic Compounds
• Receptors, CXCR4

Topics

• Humans
• Immunologic Deficiency Syndromes (drug therapy, genetics)
• Granulocyte Colony-Stimulating Factor (therapeutic use)
• Hematopoietic Stem Cell Mobilization (adverse effects)
• Cross-Over Studies
• Quality of Life
• Heterocyclic Compounds (adverse effects)
• Primary Immunodeficiency Diseases (drug therapy, genetics)
• Warts (drug therapy, genetics)
• Receptors, CXCR4 (genetics)