A phase 3 randomized trial of mavorixafor, a CXCR4 antagonist, for WHIM syndrome

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare, autosomal-dominant immunodeficiency predominantly caused by gain-of-function variants in the CXCR4 gene that typically results in truncation of the carboxyl terminus of C-X-C chemokine receptor type 4 (CXCR4), leading to impaired leukocyte trafficking between bone marrow and blood.^1-4 Key clinical features include chronic and severe neutropenia, lymphopenia, monocytopenia, hypogammaglobulinemia, and myelokathexis.^3-9 Infections are the most common clinical manifestation, with long-term recurrent complications such as bronchiectasis.^3,8,9 Wart susceptibility, impaired humoral immunity, and malignancy are also often observed.^3,7-9 There are no targeted approved treatments; current therapeutic options are primarily supportive, consisting of granulocyte colony-stimulating factor (G-CSF), immunoglobulin replacement therapy (IgRT), and antimicrobial prophylaxis, none of which target the full range of disease manifestations.^3,7,10 Hematopoietic stem cell transplantation, although corrective, is associated with transplant-related complications and mortality risk.¹¹ 

Improvement of clinical symptoms of WHIM syndrome as well as absolute neutrophil count (ANC) and absolute lymphocyte count (ALC) have been observed with plerixafor, an injectable CXCR4 inhibitor.^12,13 In a proof-of-concept, open-label trial (n = 3), clinical symptoms and hematologic biomarkers of WHIM syndrome improved with plerixafor. In a phase 3 crossover trial, plerixafor was nonsuperior to G-CSF for total infection severity score (P = .54), noninferior to G-CSF in maintaining ANC above 0.5 × 10³/μL (P = .023), and superior to G-CSF in maintaining ALC above 1.0 × 10³/μL (P < .0001).¹² Mavorixafor, an oral, small-molecule, selective CXCR4-antagonist, increased ANCs and ALCs and reduced annualized infection rates and the number of cutaneous warts in a phase 2 study (ClinicalTrials.gov NCT03005327).¹⁴ Here, we report the results of the first randomized, placebo-controlled phase 3 trial of a selective CXCR4 antagonist, mavorixafor, in participants with WHIM syndrome.

The trial included an initial 12-month (52-week) randomized, double-blind, placebo-controlled period followed by an open-label extension (OLE; ongoing) and was conducted at 20 sites in 12 countries in Australia, North America, Europe, and Asia. A list of investigators is provided in the supplemental Appendix, available on the Blood website. The trial complied with Good Clinical Practice, the Declaration of Helsinki, and other applicable regulatory requirements. An institutional review board or independent ethics committee at each site approved the protocol, protocol amendments, and informed consent documents. Participants and/or their parent(s)/guardian(s) gave written consent before trial initiation.

The trial sponsor, X4 Pharmaceuticals, Inc, along with collaborating physicians, designed the trial and were involved in the writing of this manuscript and the decision to submit it for publication. The trial (clinicaltrials.gov NCT03995108, Efficacy and safety study of mavorixafor in participants with warts, hypogammaglobulinemia, infections, and myelokathexis [WHIM] syndrome) was conducted and reported in accordance with the protocol and statistical analysis plan. Data were interpreted jointly with the authors. An independent data monitoring committee reviewed unblinded safety data throughout the trial. LLX Solutions performed all statistical analyses.

Key inclusion criteria included age ≥12 years, clinical diagnosis of WHIM syndrome with a genotype-confirmed CXCR4 variant, and ANC ≤0.4 × 10³/μL (or total white blood cell [WBC] count ≤0.4 × 10³/μL if ANC below the lower limit of detection) at screening. Exclusion criteria included clinically diagnosed active infection (excluding warts) and any of the following treatments within the specified time frame preceding trial start: plerixafor (≤6 months), chronic or prophylactic antibiotics (determined at the discretion of the investigator; ≤4 weeks), chronic or prophylactic G-CSF, granulocyte-macrophage colony-stimulating factor, or systemic glucocorticoid (≤2 weeks), or any investigational therapy (≤5 half-lives or 2 weeks, whichever was longer).

A centralized randomization procedure assigned participants in a 1:1 ratio to receive oral mavorixafor 400 mg once daily for adults and adolescents >50 kg at screening, 200 mg once daily for adolescents ≤50 kg at screening, or matched placebo. Dosing was increased to 400 mg once daily in participants who reached age 18 years or >50 kg during the trial. Randomization was stratified according to whether participants received IgRT (starting ≤5 months before screening). The sponsor, study teams, investigators, and participants were blinded. Participants who completed the randomized period or were granted early release because of infections (supplemental Methods) were eligible to enroll in the OLE and receive mavorixafor per the dosing criteria until commercial availability or trial termination by the sponsor.

Participants in the prior-IgRT stratum continued their same IgRT regimen, avoiding IgRT administration ≤4 days before each visit. Participants in the no-prior-IgRT stratum could not receive IgRT during the trial. Permissible use of other symptom-treating therapies is outlined in the supplemental Methods. Participants were administered vaccines according to a predetermined schedule starting at week 13 (supplemental Methods).

The primary end point in the randomized period was time above threshold ANC (TAT_ANC), defined as time (hours) above ANC threshold ≥500 cells per μL over a 24-hour period, assessed every 3 months for 52 weeks. Key secondary efficacy end points in hierarchical order were time above threshold ALC (TAT_ALC), defined similarly to TAT_ANC but with ALC threshold ≥1.0 × 10³/μL, a composite efficacy score calculated by summing the ranks of total infection score and total wart change score at 52 weeks, total wart change score at 52 weeks, and total infection score (further details provided in the protocol and supplemental Methods).¹⁵ Other selected secondary end points included annualized infection rate; tetanus vaccine titers; and mavorixafor pharmacokinetics, safety, and tolerability (supplemental Methods). Adverse events were graded using the Common Terminology Criteria for Adverse Events v5.0. Results from the OLE will be described in a separate publication.

A sample size of 18 participants (9 in each group) was based on estimates of the mean TAT_ANC for mavorixafor (11.4 hours), and placebo (1.4 hours), and a pooled SD of 4.7 hours from the phase 2 trial.¹⁴ It was predicted to provide >90% power using a 2-sample t test on the mean TAT_ANC over a 24-hour period, given the null hypothesis that the difference between the 2 treatment groups is equal to 0 with a 2-sided significance level (alpha) of 0.05. The univesafety population, comprising all participants randomly assigned to treatment who received ≥1 dose of study treatment (analyzed according to the treatment they actually received), was used for safety analyses. The intent-to-treat population, comprising all participants randomly assigned to treatment, was used for efficacy analyses. The pharmacokinetic population, comprising all participants who received ≥1 dose of study treatment and had ≥1 blood sample providing pharmacokinetic data, was used for pharmacokinetic analyses.

The primary end point (TAT_ANC) was analyzed using mixed-model repeated measures, using TAT as a dependent variable, covariates (per protocol), and participant as the repeated random effect, and was reported as least squares (LS) mean. To control for multiplicity, a single primary end point and hierarchical approach to the analysis of key secondary end points were prespecified. Each end point was tested at the 2-sided alpha level of 0.05. Further information regarding statistical analyses is included in the supplemental Methods.

Institutional review board (IRB) approvals were obtained from the following: UnitingCare Health Human Research Ethics Committee, Queensland, Australia; Children's Health Queensland Hospital and Health Service Human Research Ethics Committee, Queensland, Australia; Ethikkommission der Medizinischen Universität Wien, Vienna, Austria; De Videnskabsetiske Komiteer for Region Midtjylland, Viborg, Denmark; Comité de Protection des Personnes Sud-Est II, Bron, France; Ethics Committee of HaEmek Medical Center, Afula, Israel; Comitato Etico di Brescia-ASST Spedali Civili, Brescia, Italy; Amsterdam UMC, Location AMC, Amsterdam, The Netherlands; Local EC at the Federal State Budgetary Educational Institution of Higher Education I. P. Pavlov First Saint Petersburg State Medical University of the Ministry of Health of the Russian Federation, St Petersburg, Russia; Seoul National University Hospital Institutional Review Board, Seoul, South Korea; CEIm del Hospital 12 de Octubre, Madrid, Spain; Central Research Ethics Committee, Manchester, United Kingdom; Johns Hopkins Medicine Office of Human Subjects Research Institutional Review Boards, Baltimore, MD; WCG IRB (Central IRB), Puyallup, WA; Duke University Health System Institutional Review Board, Durham, NC; University of Texas Southwestern Medical Center Institutional Review Board, Dallas, TX.

Between 24 October 2019 and 9 September 2021, 35 participants were assessed for eligibility. In the intent-to-treat population, 31 participants meeting eligibility criteria were randomly assigned to receive either mavorixafor (n = 14) or placebo (n = 17) (supplemental Figure 1). Baseline characteristics between the 2 groups were balanced (Table 1). At the data cutoff on 11 November 2022, median follow-up times were 359 days (32-372 days) and 364 (336-427 days) for the mavorixafor and placebo groups, respectively. Relative dose intensity ([total actual dose/total planned dose]∗100) for adolescent participants ≤50 kg and adults/adolescents >50 kg was 96.5% (range, 96.5%-96.5%) and 99.6% (range, 82.7%-104.3%), respectively, with mavorixafor and 98.5% (range, 75.6%-100.0%) and 99.6% (range, 83.0%-104.8%) with placebo. Dose modifications (interruptions, reductions, delays, and holds) occurred in 3 (21.4%) and 5 (29.4%) participants receiving mavorixafor and placebo, respectively, with 75% of mavorixafor modifications occurring before week 26. Eleven (78.6%) and 17 (100%) participants in the mavorixafor and placebo groups, respectively, completed treatment in the randomized placebo-controlled period, with 1 (7.1%) participant receiving mavorixafor eligible for early release.

Overall LS mean TAT_ANC in the mavorixafor and placebo groups was 15.0 hours (95% confidence interval [CI], 11.2-18.9) and 2.8 hours (95% CI, 0.0-5.9) (P < .001; 5.3-fold increase), respectively (Table 2; Figure 1A). This increase was sustained and significantly higher with mavorixafor than placebo at weeks 13, 26, and 39. Overall LS mean TAT_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 < .001; a 3.5-fold increase), respectively (Table 2; Figure 1B).

Mean ANC and ALC were increased above 0.5 × 10³/μL and 1.0 × 10³/μL thresholds, respectively, by week 13 in the mavorixafor group and remained consistently higher than the placebo group at time points assessed (Figure 2). Mean absolute monocyte count (AMC) and WBC counts were also increased at week 13 in the mavorixafor group and remained higher than the placebo group at time points assessed (Figure 2). Overall absolute and fold change from baseline for total ANC, ALC, AMC, and WBC counts were increased 2.8- to 3.3-fold with mavorixafor (supplemental Table 1).

LS mean composite efficacy score (total wart change and total infection score) in the mavorixafor and placebo groups was 26.7 (95% CI, 19.9-33.5) and 33.4 (95% CI, 27.9-38.8), respectively, an LS mean difference of −6.6 (95% CI, 15.5-2.2; P = .14; Table 2). When the 2 components of the composite efficacy score were evaluated separately, nonsignificant differences in total wart change score at 52 weeks were observed (Table 2; supplemental Table 2). Fewer participants receiving mavorixafor vs placebo developed warts at a new location at week 52 (21.4% vs 35.3%).

Reductions in total infection score in the mavorixafor vs placebo group (−4.9; 95% CI, −12.6 to 2.9; nominal P = .21) of ∼40% were observed but were not significant (Table 2). Reductions were evident after 3 months of mavorixafor and decreased by ≥80% vs placebo after 6 months (Figure 3A). Median infection rates in the 12 months before the trial in the mavorixafor and placebo groups were 0 (range, 0-4) and 1 (range, 0-3), respectively. The annualized infection rate was reduced by ∼60% in the mavorixafor vs placebo group (1.7 vs 4.2, respectively; 95% CI, 0.2-0.8; nominal P = .007; Table 2). After 6 months of treatment, mean annualized infection rates were reduced by 79% with mavorixafor vs placebo (Figure 3B) with penicillin use in 3 participants receiving mavorixafor vs 10 receiving placebo. In the mavorixafor and placebo groups, participants experienced infections including upper respiratory (7 [50.0%] and 13 [76.5%]), skin (2 [14.3%] and 7 [41.2%]), lower respiratory (0 and 3 [17.6%]), or digestive (2 [14.3%] and 2 (11.8%]), respectively (supplemental Table 3). Five participants in the placebo group and 1 in the mavorixafor group had grade ≥3 infections. The mean annualized infection rate for grade ≥3 infections in the mavorixafor group was 0.4 (95% CI, −0.5 to 1.3) for months ≤3 and then remained at 0 for other time points assessed. In the placebo group, the mean annualized infection rate for grade ≥3 infections was 0.7 (95% CI, −0.80 to 2.2) and 0.2 (95% CI, −0.3 to 0.7) for months ≤3 and 3 to ≤6, respectively, and was consistent at 0.5 (95% CI, −0.2 to 1.2) and 0.5 (95% CI, −0.5 to 1.5) for months 6 to ≤9 and 9 to ≤12, respectively (Figure 3C). The median total duration of infection in the mavorixafor and placebo groups was 8.5 days (range, 0-43 days) and 32 days (8-134 days), respectively, exceeding 10 days in 6 (42.9%) and 16 (94.1%) participants receiving mavorixafor and placebo, respectively. Nine participants (64.3%) receiving mavorixafor experienced ≤1 infection, with only 1 participant (7.1%) experiencing ≥5 infections (Figure 3D). In comparison, 2 (11.8%) participants receiving placebo experienced ≤1 infection, and 5 (29.4%) experienced ≥5 infections.

Overall, tetanus titers were numerically higher in participants receiving mavorixafor than placebo. Analyses of vaccine titers are ongoing and will be presented in a separate manuscript.

Overall, quality of life was not different between participants receiving mavorixafor or placebo, as assessed by Patient Global Impression of Change, Patient Global Impression of Severity, the Short-Form 36-Item Survey, the EuroQol 5-Dimension, 5-Level Visual Analogue score, and the Dermatology Life Quality Index (supplemental Table 4). Small numbers of adolescent participants (mavorixafor, n = 7; placebo, n = 8) included in the study and who completed the Pediatric Quality of Life Inventory Teens surveys or parent survey precluded conclusions based on these survey results (supplemental Table 4).

Other secondary end points results are provided in supplemental Results, supplemental Figure 2, and supplemental Tables 1-6.

No treatment-emergent adverse events (TEAEs) led to treatment discontinuations or deaths; there were no treatment-limiting toxicities. Treatment-emergent serious adverse events occurred in 5 (35.7%) and 2 (11.8%) participants receiving mavorixafor and placebo, respectively (Table 3), of which none were deemed related to treatment. Seven (50%) participants receiving mavorixafor experienced treatment-related TEAEs compared with 3 (17.6%) receiving placebo. Treatment-related TEAEs were reported in ≤1 participant each in both treatment groups with gastrointestinal (eg, dyspepsia, nausea, and vomiting) and skin disorders (eg, dry skin, rash, dermatitis psoriasiform, and pruritus) occurring with mavorixafor vs infections (eg, cellulitis, conjunctivitis, localized infection, skin infection, subcutaneous abscess, and lower and upper respiratory infections) occurring with placebo (Table 3).

Neoplasms were reported in 2 participants in the mavorixafor group (1 treatment-emergent serious adverse event of glioma; 1 nonserious TEAE of stage 0 vaginal cancer), both of which were deemed unrelated to mavorixafor. Thrombocytopenia was reported in 3 participants receiving mavorixafor and was deemed unrelated to mavorixafor. There was no evidence that mavorixafor lowered platelets over the course of the study (supplemental Table 6). In fact, in all participants, platelet counts increased from baseline to week 52 by a mean of 34 × 10³/μL (standard deviation, 75.7) in the mavorixafor group and decreased by a mean of 1.1 × 10³/μL (standard deviation, 63.0) in the placebo group. One participant receiving mavorixafor was transfused with platelets for grade 4 thrombocytopenia (platelet count 17 × 10³/μL), unrelated to mavorixafor but concurrent with sepsis from a gastrointestinal infection. Grade 4 thrombocytopenia and sepsis resolved in 4 days, and the participant continued on mavorixafor and subsequently entered the OLE.

Both local and central ophthalmologic examinations showed no shift from baseline values to abnormal/clinically significant values in both groups. Eye disorders were reported in 2 (14.3%) participants receiving mavorixafor and 3 (17.6%) receiving placebo. Dry eye in 1 participant was considered related to mavorixafor; no ocular TEAEs in the placebo group were deemed treatment-related.

To our knowledge, this is the first randomized, placebo-controlled, multinational trial in participants with WHIM syndrome. The trial met its primary end point with a significantly increased (5.5-fold) LS mean TAT_ANC and its first key secondary end point with a significantly increased (3.4-fold) LS mean TAT_ALC in the mavorixafor vs placebo group. Mavorixafor was generally well tolerated with no discontinuations due to safety reasons, and pharmacokinetic parameters were stable over the 52 weeks.

Decreases in total infection score and annualized infection rate in the mavorixafor group were seen as early as 3 months and were greater at 6 to 12 months. No participant experienced infections ≥ grade 3 after receiving mavorixafor for 3 months. These results suggest early benefits regarding infection prevention and control that have continued to improve over time. This is important, as people with WHIM syndrome experience recurrent severe infections, which can affect quality of life and increase morbidity; thus, agents offering long-term protection are needed.^3,7,10 

Despite no difference in wart change score, minor improvements in wart change scores were observed in both the mavorixafor and placebo groups. A previous phase 2 trial of mavorixafor showed an average 75% reduction in the number of warts observed up to 18 months on trial.¹⁴ In our trial, wart change up to 52 weeks was assessed by a central review using photographs of targeted regions, which may not have permitted enough time for significant reduction in wart change score or to monitor the effect of treatment on improvement of newly emerged warts. Therefore, longer observation times and an alternative form of wart assessment may be needed. There was no assessment by this committee of anogenital warts. Data on wart reduction and new wart formation over longer treatment periods are being collected in the OLE.

Treatment-related vomiting, dyspepsia, and nausea (1 participant each) occurred in participants receiving mavorixafor. No treatment-related ocular issues or retinal abnormalities were reported with mavorixafor except dry eye in 1 participant.¹⁴ WHIM syndrome is a cancer-prone disease, with ∼30% of people experiencing malignancy by age 40 years.⁷ The glioma in 1 participant was deemed by study investigator unrelated to mavorixafor. Mavorixafor has not been studied in any glioma models or in people with glioma.

Limitations of this study include a small participant number given the rarity of the genetic disorder. Despite this, the primary and first key secondary end points showed significant improvement. Five participants (placebo, n = 2; mavorixafor, n = 3) received concomitant medications that may have influenced outcomes. However, the inclusion of these participants provides real-world results and highlights the complexity of patients with WHIM syndrome. In addition, >90% of participants in this trial self-identified as White, and results should be extrapolated with caution to different races. Because the first assessment was not made until 3 months, it is unknown whether clinically important changes in WBC, ANC, ALC, and AMC occurred earlier. Furthermore, because no acute assessments were made at the time of infections, it is unclear how levels of these indices (eg, ANC, ALC, AMC, and WBC) may have changed at the onset of or during an infection. In this trial, no differences in quality of life were seen between the 2 groups using the Patient Global Impression of Change, Patient Global Impression of Severity, the Short-Form 36-Item Survey, the EuroQol 5-Dimension, 5-Level Visual Analogue score, and the Dermatology Life Quality Index. However, these instruments have not been validated in patients with WHIM syndrome. In addition, it is unclear how soon after immune reconstitution the effects of WHIM syndrome are expected to improve, which may require prolonged evaluation of patients with continued treatment.

Individuals with WHIM syndrome have an estimated median life expectancy of ∼55 years, and therapies that may be protective should be evaluated not only for their short-term effect but also from a long-term perspective.^3,7 There is an unmet need in the treatment of WHIM syndrome to prevent immunodeficiency-associated morbidity and mortality. Current therapies like G-CSF and IgRT do not address the underlying molecular defect in WHIM syndrome and cannot be administered orally. Data from this trial suggest daily, oral administration of mavorixafor is effective, safe, and well tolerated, with improvements in cytopenias and reductions in serious infections.

The authors thank the trial participants and their families and caregivers, investigators, and investigational site staff. The authors also acknowledge Atil Bisgin, Diego Cadavid, Eloisa Chapa, Sarah Cohen, Elisa Cordero, Candida Fratazzi, Ken Gorelick, Joanna Haas, Hal Hoffman, Lori Neri, Paula Ragan, Anjali Sharathkumar, Felipe Suarez, Weihua Tang, Valerie Tjon-a-Koy; Istvan Varkonyi, the LLX Solutions Team; and Syneos Health. Members of the data monitoring committee included Charles Davis, Eric Gershwin, and John Levine. Members of the independent adjudication committee included Esther de Vries, Kathryn Edwards, and Craig Platt.

The trial was supported by X4 Pharmaceuticals, Inc. Editorial and writing assistance was provided by PRECISIONscientia in Yardley, PA, with financial support from X4 Pharmaceuticals, Inc, and in compliance with international good publication practice guidelines.

Contribution: R.B., D.D., T.K.T., G.J.B., Y.H., H.J., R.M., and J.D. contributed to the concept and design of the study; R.B., L.A., A.A., Y.B., A.A.B., D.D., À.D.-M., K.E.D., N.E., H.H., H.J.K., S.K.-A., T.W.K., A.K., D.L., C.L., O.N., P.O., Y.R., C.E.R., A.S., M.G.V., S.D., Y.H., H.J., S.L., T.Y., and J.D. provided data acquisition; N.E., T.W.K., D.L., T.K.T., K.C., S.D., Y.H., H.J., S.L., R.M., M.S., A.G.T., and T.Y. performed data analysis; R.B., L.A., D.D., À.D.-M., K.E.D., N.E., H.H., H.J.K., S.K.-A., T.W.K., A.K., D.L., C.L., O.N., P.O., J.P., Y.R., A.S., T.K.T., C.A.W., K.C., S.D., Y.H., H.J., S.L., R.M., M.S., A.G.T., T.Y., and J.D. provided data interpretation; and R.B., L.A., A.A., Y.B., A.A.B., D.D., À.D.-M., K.E.D., N.E., H.H., H.J.K., S.K.-A., T.W.K., A.K., D.L., C.L., O.N., P.O., J.P., Y.R., C.E.R., A.S., T.K.T., M.G.V., C.A.W., A.B., G.J.B., K.C., S.D., Y.H., H.J., R.M., M.S., A.G.T., and J.D. were involved in drafting and revising the manuscript.

Conflict-of-interest disclosure: R.B. is a consultant for X4 Pharmaceuticals, Inc, Angelini Pharma, and Janssen. L.A. has received research funding (to Institu de Recerca Sant Joan de Déu) from CSL Behring, Pharming, and Grifols and is a speaker for Novartis, Sanofi, Roche, and UCB Pharmaceuticals. A.A. has received research funding/grants from X4 Pharmaceuticals, Inc, Grifols, and Argenx; and is a consultant for Grifols, Argenx, Takeda Pharmaceuticals, Adma Biologics, Inc, and Octapharma. A.A.B. has received research funding from X4 Pharmaceuticals, Inc, and the National Institutes of Health. D.D. has consulted, received research funding from, and received honoraria from X4 Pharmaceuticals, Inc. K.E.D. is on the advisory board of Agios. H.J.K. receives research funding from Amgen and is a member on the board of directors or advisory committees for Amgen, Novartis, GPCR Therapeutics, and Cartexell. A.K. has received research funding (to Pavlov University) from X4 Pharmaceuticals, Inc, Alexion, and Apellis and is a speaker for Novartis, Generium, Sobi, AstraZeneca, and Johnson & Johnson. D.L. is a board member for RCPA. C.L. receives research grants from Emek Center Pediatric Hematology University Hospital. J.P. is on the advisory board of Allergy & Anaphylaxis Australia, Food and Allergy Standards Australia and New Zealand, and National Blood Authority and is the director of the Australasian Society of Clinical Immunology and Allergy (QPIAS). A.S. is a speaker for Sobi, Novartis, and Octapharma. T.K.T. is a consultant for X4 Pharmaceuticals, Inc and also receives research funding from X4 Pharmaceuticals, Inc, AbbVie, Inc, Viela Bio, Horizon, and Chiesi. M.G.V. has received research funding outside the current work from Austrian National Bank, a grant from Pfizer, and honoraria from Gilead, Astro Pharma, and Menarini. J.D. is a consultant for X4 Pharmaceuticals, Inc. A.B., K.C., S.D., Y.H., H.J., S.L., R.M., T.Y., and A.G.T. are current employees and/or have equity ownership in X4 Pharmaceuticals, Inc. M.S. was employed by X4 Pharmaceuticals, Inc, at the time of this work, has equity ownership in X4 Pharmaceuticals, Inc, and is a member of the board of directors of X4 Pharmaceuticals, Inc. G.J.B. is a member of the board of directors of X4 Pharmaceuticals, Inc, and has stock options in the company. The remaining authors declare no competing financial interests.

Correspondence: Jean Donadieu, Centre de Référence des Neutropénies Chroniques, APHP Sorbonne Université-Hôpital d’Enfants Armand-Trousseau, 26 Ave du Dr Netter, F-75012 Paris, France; email: jean.donadieu@aphp.fr.