From the Journals

Plerixafor produced dramatic responses in severe WHIM syndrome



Low-dose treatment with plerixafor, a CXC chemokine receptor 4 antagonist, was well tolerated and markedly improved severe presentations of warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome in three patients who could not receive granulocyte colony-stimulating factor therapy, investigators reported.

“Myelofibrosis, panleukopenia, anemia, and thrombocytopenia were ameliorated, the wart burden and frequency of infection declined, human papillomavirus–associated oropharyngeal squamous-cell carcinoma stabilized, and quality of life improved markedly,” David H. McDermott, MD, of the National Institute of Allergy and Infectious Diseases and his colleagues wrote in the New England Journal of Medicine.

WHIM syndrome is a primary immunodeficiency disorder characterized by panleukopenia and caused by autosomal dominant gain-of-function mutations in CXC chemokine receptor 4 (CXCR4). Granulocyte colony-stimulating factor (G-CSF) therapy improves neutropenia in these patients, but not other cytopenias.

Previously, the investigators treated three WHIM syndrome patients with plerixafor (Mozobil), which was well tolerated and led to sustained increases in circulating neutrophils, lymphocytes, and monocytes. The current report is of three patients with advanced WHIM syndrome who received open-label plerixafor because they were ineligible for a randomized trial of this drug.

After treatment initiation, infection frequency dropped by 85% in one patient and declined markedly in all three patients. Lymphocyte counts improved the most in two patients while neutrophils were most responsive in the third patient. Warts partially resolved in two patients, of which one patient also experienced partial resolution of head and neck squamous cell carcinoma. This patient later died of a multidrug-resistant Pseudomonas aeruginosa infection after undergoing a 9-hour surgery.

In the third patient, plerixafor therapy led to clearance of TSPyV and 17 human papillomavirus (HPV) infections, with consequent resolution of chronic, progressive, multifocal eczematoid and follicular lesions, the researchers reported. The study dose was relatively low – about 10% of the stem-cell mobilization dose – and did not cause bone pain or other treatment-emergent adverse events, despite the relatively long treatment course (19-52 months).

A separate, phase 3 trial (NCT02231879) has enrolled 19 patients. Primary results are expected in 2020.

The National Institutes of Health funded the work. Dr. McDermott reported a pending patent to reduce CXCR4 expression and/or function to enhance engraftment of hematopoietic stem cells.

SOURCE: McDermott DH et al. N Engl J Med. 2019;380:163-70.

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