Discussion
wart, B cell deficiency, Eczematous rash, WHIM, Dermatitis, bone pain, WHIM syndrome, infections, arthritis, psoriasis, pain, infection, IgA, Neutrophils, arbitrariness, WHIM immunodeficiency
RECURRENCE, RESPIRATORY INFECTION, STERILE, SIDE EFFECTS, REGRESSION, WART, ECZEMATOUS RASH, HYPOGAMMAGLOBULINEMIA, SIDE EFFECT, WHIM SYNDROME, INFECTIONS, PSORIASIS, SELECTIVE IGA DEFICIENCY, INFECTION, DERMATITIS, DISEASE, ARTHRITIS, REACTIVE ARTHRITIS, IMMUNODEFICIENCY
In this crossover treatment study for WHIM syndrome, plerixafor was not superior to G-CSF for the primary endpoint of total infection severity scored over 1 year for each drug. The study had limitations for demonstrating a potential plerixafor advantage over G-CSF for controlling infections, including (a) the primary endpoint, which includes subjective measures of medical decision-making and judgment (diagnostic accuracy, level of care, antibiotic usage), as well as the simple classification of infections (sterile versus nonsterile site), and which does not require a pattern of recurrence typical of WHIM syndrome or exclude common infections unrelated to immunodeficiency that might attenuate a benefit signal; (b) using G-CSF, the standard-of-care in SCN (Since WHIM syndrome is a type of SCN, and G-CSF is the SCN standard-of-care, we chose G-CSF as the comparator instead of placebo. Nevertheless, it is important to point out that G-CSF efficacy has not specifically been assessed by a placebo-controlled clinical trial in WHIM syndrome. Restricting the primary endpoint to a particular type of infection or level of severity or else to recurrent infections would have imposed a level of arbitrariness on how to set boundaries and made adequately powering the study impractical. However, not doing so imposed a potential cost of attenuating an infection efficacy signal. Strikingly, few severe infections occurred on either drug. No patient was hospitalized during a treatment phase for respiratory infection, the most common cause of hospitalization in patients with WHIM (Our exploratory results confirm previous reports of clinically significant wart regression in patients with WHIM treated with plerixafor or the unrelated CXCR4 antagonist mavorixafor (Our results also highlight the diverse mobilization sensitivity of different leukocyte subsets to plerixafor. Neutrophils appeared less responsive than monocytes, B cells, and memory CD4Our study confirmed the disparity between severe circulating B cell deficiency in patients with WHIM and the relatively modest effect on circulating immunoglobulin levels affecting a subset of patients, with IgG more consistently and quantitatively affected than IgA or IgM. Nevertheless, we made a potentially new observation of unexpectedly high incidence of selective IgA deficiency at baseline in 4 of 19 patients on study, which may represent an incompletely penetrant WHIM phenotype. Despite sustained normalization of the circulating absolute total B cell count by plerixafor, hypogammaglobulinemia did not improve.With regard to safety, both drugs caused one unexpected and idiosyncratic but reversible inflammatory side effect in patients with risk factors for the condition but no prior expression of it (psoriasis, reactive arthritis). We speculate that WHIM immunodeficiency may protect from immunologically mediated disease in such predisposed patients. Bone pain was common in patients receiving G-CSF, despite the low doses used. Eczematous rash of the palms and soles was common on plerixafor, but it was transient and did not result in any dropouts. Side effects, especially bone pain, were most commonly cited by patients in deciding their drug preference, which trended in favor of plerixafor. This result from the study will be important during informed decision making between physicians and patients.The lower age limit for participation (10 years of age) precluded our ability to judge the safety and efficacy of plerixafor in younger children. Our findings, together with recent results suggesting that early diagnosis may improve outcomes in WHIM syndrome (In conclusion, plerixafor was not superior to G-CSF for control of infection severity, the primary endpoint. The study was not designed to answer whether plerixafor is noninferior to G-CSF for infection severity; however, no differences between the G-CSF and plerixafor arms were found for any infection outcome measures. The exploratory endpoints suggested that plerixafor may be noninferior to G-CSF for durably increasing the ANC and may have an advantage over G-CSF for elevating the ALC, for wart regression, and for limiting bone pain. Dermatitis or arthritis severe enough to stop treatment occurred in 3 patients while on plerixafor and 1 patient while on G-CSF.