The Journal of Clinical Investigation (Oct 2023)

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

  • 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 volume & issue
Vol. 133, no. 19

Abstract

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BACKGROUND Warts, 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.METHODS In 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.RESULTS Plerixafor 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.CONCLUSION Plerixafor 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 REGISTRATION Clinicaltrials.gov NCT02231879.FUNDING This study was funded by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases.

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