Mavorixafor: a new hope for WHIM syndrome Free

In this issue of Blood, Badolato and colleagues report on a placebo-controlled phase 3 trial of the selective CXCR4 antagonist mavorixafor in patients with warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome, a rare multisystem combined immunodeficiency.¹ 

In medical school, students learn “when you hear hoofbeats, think of horses, not zebras.” WHIM syndrome is indeed a zebra, with fewer than 300 cases described worldwide in the literature.² WHIM syndrome is commonly caused by autosomal-dominant pathogenic variants in the C-terminus of the CXCR4 gene, leading to decreased CXCR4 internalization and hyperactive downstream signaling. This disrupts the migration of myeloid and lymphoid cells in response to CXCL12 gradients, preventing them from leaving the bone marrow and moving to the periphery or to inflammation sites.³ Consequently, neutrophils overmature in the bone marrow, resulting in a unique pathological condition known as myelokathexis.⁴ This dysfunction extends beyond myeloid cells, also impairing B- and T-cell functions and development.⁵ “WHIM” is an acronym for the condition’s diagnostic tetrad: warts, hypogammaglobulinemia, infections, and myelokathexis. Most patients with WHIM syndrome have panleukopenia, which includes neutropenia and lymphopenia, along with hypogammaglobulinemia. Patients may also experience a range of other issues, such as recurrent infections, susceptibility to human papillomavirus, conotruncal heart defects, autoimmunity, and an increased risk of cancer (see figure).⁶ 

For some time, granulocyte colony–stimulating factor and immunoglobulin replacement therapy were the primary treatments for WHIM syndrome, improving blood neutrophil counts and immunoglobulin levels but having little effect on warts and lymphopenia. Additionally, these treatments did not correct the underlying molecular defect of WHIM syndrome.^2,7 Plerixafor, a CXCR4 antagonist approved for mobilizing hematologic stem cells, emerged as a specific remedy to temper overactive CXCR4 signaling. Plerixafor reduced neutropenia and lymphopenia and led to wart regression. However, the requirement for twice-daily subcutaneous injections due to its short half-life raised concerns regarding adherence to plerixafor treatment.⁸ 

Badolato and colleagues have now demonstrated that the oral CXCR4 antagonist mavorixafor, administered to patients with WHIM syndrome, significantly increases neutrophil and lymphocyte counts. In this phase 3 trial, 31 participants aged 12 years and over with WHIM syndrome were randomized in a 1:1 ratio to receive either mavorixafor or a placebo daily for 52 weeks. Results showed that the mavorixafor group had a significantly longer duration of neutrophil counts above the threshold (15.0 hours) compared with the placebo group (2.8 hours). Likewise, the mavorixafor group had a greater duration of lymphocyte counts above the threshold (15.8 hours) compared with the placebo group (4.6 hours). Furthermore, the trial reported a 60% reduction in the annualized rate of infection for the mavorixafor group compared with placebo. The safety profile of mavorixafor was manageable, with no treatment discontinuations due to adverse events. The most common adverse events in the mavorixafor group were gastrointestinal symptoms and skin disorders, but these were typically mild to moderate. No serious adverse events related to treatment were reported.

Conducting a placebo-controlled phase 3 clinical trial with a precision approach for patients with orphan diseases is extremely important, and the authors deserve recognition for this undertaking. Although it is commendable that the trial successfully enrolled patients from around the world with this rare disease, questions remain regarding the primary end points and the trial’s duration in reflecting clinical reality. There are also questions about safety issues associated with long-term or lifelong treatment with mavorixafor, whether antibody responses will normalize, and whether the frequency or severity of malignancies associated with WHIM syndrome will be reduced or prevented. Only time will provide these answers.

Conflict-of-interest disclosure: C.B.G. declares no competing financial interests.