Treatment with mavorixafor reduced infection frequency, severity and duration of infections, and antibiotic use among individuals with warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome in a phase III placebo-controlled clinical trial. The oral C-X-C chemokine receptor type 4 (CXCR4) antagonist also increased levels of absolute neutrophil and lymphocyte counts among trial participants compared to placebo. The results from the randomized trial were published in Blood.1
Based on the results of the phase III trial, the U.S. Food and Drug Administration (FDA) approved mavorixafor in April in patients 12 years and older with WHIM syndrome to increase the number of circulating mature neutrophils and lymphocytes.2
WHIM syndrome is an extremely rare autosomal- dominant immunodeficiency disorder that is mainly caused by gain-of-function variants in the CXCR4 gene that result in a truncated CXCR4 protein. CXCR4 is a key chemokine receptor in the body. Individuals with WHIM syndrome have reduced numbers of mature neutrophils and lymphocytes, which result in an increased risk of infections. Those with WHIM syndrome are also susceptible to warts, including those from human papillomavirus (HPV) infection, have impaired humoral immunity, and have a higher risk of developing cancer.
“[WHIM syndrome] is not lethal in the first two decades of life, but hampers the quality of life starting in puberty, and may result in early death in individuals in their 30s and 40s. Such patients have an extremely high frequency of cancers, starting in their 30s, mostly related to HPV or Epstein-Barr virus,” said study author Jean Donadieu, MD, PhD, of the Centre de Référence des Nutropénies Chroniques at the APHP Sorbonne Université-Hôpital d’Enfants Armand-Trousseau in Paris. “So far, no more than 150 cases of WHIM CXCR4 are known worldwide.”
The phase III trial enrolled 31 patients with WHIM syndrome aged 12 years and older with a confirmed CXCR4 genetic variant who had an absolute neutrophil count (ANC) of 400/µL or less. Patients were randomized 1:1 to either placebo or 400 mg of mavorixafor (200 mg for individuals weighing 50 kg or less) once daily. The primary endpoint was time above threshold ANC, defined as hours above ANC threshold of 500/µL or greater over a 24-hour period, assessed every three months for 52 weeks. The mean ages were 17.5 (range = 12-58) for the 14 patients treated with mavorixafor and 23 (range = 13-72) for the 17 patients in the placebo control group.
“The surprising result is the drug’s effect on infection rate. Rather than a ‘switch-off effect,’ we observed a progressive change. While the changes in the blood count and immune parameters were very fast in patients on mavorixafor therapy, the treatment also appears to provide protection that is more effective after three months of therapy,” Dr. Donadieu said.
The median follow-up times were 359 days and 364 days for the mavorixafor and placebo groups, respectively. The mean threshold ANC in the mavorixafor and placebo groups was 15.0 hours (95% CI 11.2-18.9) and 2.8 hours (95% CI 0.0-5.9; p<0.001; 5.3-fold increase), respectively. This increase was sustained and significantly higher with mavorixafor than placebo at weeks 13, 26, and 39.
The mean threshold absolute lymphocyte count (ALC) in the mavorixafor and placebo groups was 15.8 hours (95% CI 13.0-18.7) and 4.6 hours (95% CI 2.2-6.9; p<0.001; a 3.5-fold increase), respectively.
The mean ANC and ALC increased above the 500/µL and 1,000/µL thresholds, respectively, by week 13 of the study in the mavorixafor group and remained consistently higher than the placebo group at time points assessed during the 52-week trial. Overall, the absolute and fold-change from baseline total ANC, ALC, absolute monocyte count, and white blood cell counts increased 2.8- to 3.3-fold in the mavorixafor treatment arm.
Reductions in infection rates were seen after three months of mavorixafor therapy and decreased by at least 80% versus placebo after six months. The annualized infection rate decreased by approximately 60% in the mavorixafor versus placebo group (1.7 vs. 4.2, respectively; 95% CI 0.2-0.8; nominal p=0.007). After six months of treatment, mean annualized infection rates decreased 79% with mavorixafor versus placebo with penicillin use in three participants receiving mavorixafor versus 10 receiving placebo. Patients in both groups experienced upper and lower respiratory infections, skin infections, and digestive infections.
None of the participants treated with mavorixafor for three months or more had a grade 3 or higher infection.
Mavorixafor had an acceptable side effect profile. There were no treatment-emergent adverse events (AEs) that led to treatment discontinuations and no treatment-related toxicities. Treatment-emergent serious AEs occurred in five (35.7%) and two (11.8%) participants receiving mavorixafor and placebo, respectively. Treatment-related AEs among those treated with mavorixafor included vomiting, dyspepsia, and nausea.
One limitation of this study was its small size, due to the limited number of patients around the world with WHIM syndrome.
“Another limitation is the duration of the study, as the challenge with WHIM syndrome is to maintain long-term protection from infections,” Dr. Donadieu said. “While a one-year study is already long, longer follow-up would be useful to measure the long-term effect on warts, chronic infections such as chronic obstructive pulmonary disease, and the development of cancer.”
Any conflicts of interest declared by the authors can be found in the original article.
References
- Badolato R, Alsina L, Azar A, et al. Phase 3 randomized trial of mavorixafor, CXCR4 antagonist, in WHIM syndrome [published online ahead of print, 2024 April 21]. Blood. doi: 10.1182/blood.2023022658.
- U.S. Food & Drug Administration. FDA approves first drug for WHIM syndrome, a rare disorder that can lead to recurrent, life-threatening infections. April 30, 2024. Accessed May 5, 2024. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-drug-whim-syndrome-rare-disorder-can-lead-recurrent-life-threatening-infections.
