4WARD Trial Aims to Build the Case for Mavorixafor in Primary Chronic Neutropenia

The oral CXCR4 antagonist mavorixafor (Xolremdi) has the potential to become an oral treatment option for patients with primary chronic neutropenia who continue to experience recurrent infections, a population with no newly approved therapy in roughly 3 decades, according to Julia T. Warren, MD, PhD, and David B. Sykes, MD, PhD.¹

The randomized, double-blind, placebo-controlled phase 3 4WARD trial (NCT06056297) represents the next crucial step of research, where investigators are evaluating mavorixafor in addition to background therapy vs placebo plus background therapy in patients with congenital or acquired primary chronic neutropenia and recurrent infections, building on findings from an open-label phase 2 study (NCT04154488).^1,2

"The mechanism of action of mavorixafor is to antagonize CXCR4, which is a critical signal that helps retain cells in the bone marrow. By antagonizing that signal, the cells can egress out of the bone marrow, circulate around the bloodstream, and find their way into tissues," Warren said in an interview with OncLive®.

Warren and Sykes discussed the rationale for targeting CXCR4 in chronic neutropenia, broke down the prior phase 2 data, and outlined what the 4WARD trial may mean for a population that currently relies on granulocyte colony-stimulating factor (G-CSF).

Warren is an assistant professor of pediatrics (hematology) at the Perelman School of Medicine at the University of Pennsylvania and a hematologist in the Comprehensive Bone Marrow Failure Center at Children's Hospital of Philadelphia. Sykes is an associate physician of medicine-hematology and medical oncology at Massachusetts General Hospital and an assistant professor of medicine at Harvard Medical School in Boston.

What is the rationale for targeting CXCR4 in chronic neutropenia?

Primary chronic neutropenia includes congenital forms caused by inherited genetic variants and acquired forms such as chronic idiopathic neutropenia, in which neutrophil lifespan is shortened by antineutrophil antibodies or an unknown cause.¹

Injectable G-CSF is the only FDA-approved therapy for severe chronic neutropenia and has been available for approximately 30 years, but this approach is also associated with adverse effects (AEs) such as bone pain, splenomegaly, and osteoporosis. Additionally, long-term, high-dose exposure has been correlated with an increased risk of myelodysplastic syndrome and leukemia in congenital neutropenia. Some patients are also managed with immunoglobulin infusions or prophylactic antibiotics, Warren noted.

Sykes emphasized that most patients with mildly low counts need only monitoring, estimating that fewer than 10% of patients he sees with chronic neutropenia require ongoing treatment and noting that clinical history matters more than the absolute neutrophil count (ANC). For those who do need treatment, options are limited.

"G-CSF simply tells the bone marrow to make more neutrophils. Mavorixafor comes in as a bit of an unusual agent. [It is] designed as a CXCR4 antagonist, which really just releases immature neutrophils a little earlier into the bloodstream," Sykes said. "One, it's a pill and not an injection, and two, it's designed to release these neutrophil progenitors."

Mavorixafor was approved by the FDA in 2024 for the treatment of patients 12 years of age and older with WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome, which is driven by CXCR4 gain-of-function variants, and it has received fast track designation for chronic neutropenia.^1,3 Sykes noted that experience in WHIM syndrome, including in pediatric patients, suggests the agent is "safe and reasonably well tolerated."

What did the phase 2 data show for mavorixafor in chronic neutropenia?

The open-label phase 2 study, which was presented at the 2025 EHA Congress, enrolled patients at least 12 years of age with an ANC of 1000 cells/µL or below (below 10,000 cells/µL if receiving G-CSF) and chronic idiopathic (n = 15), congenital (n = 6), or cyclic (n = 2) neutropenia.¹

Patients received oral mavorixafor once per day alone (n = 10) or with G-CSF (n = 13) for 6 months, with the option to reduce G-CSF after 2 months if ANC remained above 500 cells/µL.

Findings showed that among patients treated with mavorixafor monotherapy, the mean ANC fold change from baseline was 1.9 at month 1 (n = 10), 2.8 at month 3 (n = 8), and 2.6 at month 6 (n = 7), corresponding to a mean ANC of approximately 1200 cells/µL at month 6.¹ Patients with severe baseline neutropenia, defined as an ANC less that 500 cells/µL, had fold changes of 2.4 (n = 5), 3.0 (n = 3) and 3.4 (n = 4) at those respective time points.

In the G-CSF combination cohort (n = 12), the mean ANC fold changes from baseline to months 1, 3, and 6 were 1.9, 2.3, and 3.4, respectively. Notably, 9 of 12 eligible patients reduced G-CSF dosing, including 8 patients who had their G-CSF adjusted at the first opportunity at month 2, plus 3 patients who stopped G-CSF entirely by month 6.

"Those [early-phase] studies were not designed to answer an efficacy question related to infection, and that's really the point of the 4WARD study," Warren said.

Safety data pooled between the monotherapy and combination cohorts (n = 23) demonstrated that treatment-related AEs occurred in 73.9% and were mostly grade 1 or 2, with no deaths or drug-related serious AEs. Gastrointestinal AEs, most commonly nausea (39.1%) and diarrhea (30.4%), typically emerged within the first 2 weeks and led to 3 early discontinuations.

"Mavorixafor should increase the circulating ANC in pretty much everybody who gets it. That's the mechanism of action, [but it] probably will not increase the total body number of neutrophils," Sykes added. "The question is going to be, [do] patients feel better, which is probably number one, and then do patients have fewer complications, [such as] infections or fevers?"

How is the phase 3 4WARD trial designed?

The global 4WARD trial is enrolling patients 12 years of age and older diagnosed with congenital (noncyclic) or acquired primary autoimmune or idiopathic chronic neutropenia at least 6 months before screening.² Patients are required to have an ANC below 1000 cells/µL at screening, confirmed by a trough mean ANC at baseline, and at least 2 infections in the prior 12 months that required antibiotics or a health care visit and were likely related to their neutropenia. Those receiving G-CSF or other background therapy must be on a stable regimen for at least 4 weeks before screening and maintain it throughout the study.

Investigators are excluding patients with cyclic neutropenia, WHIM syndrome, aplastic anemia, and secondary neutropenia.

Patients are being randomly assigned to oral mavorixafor or placebo in addition to background therapy for 52 weeks. Visits occur approximately monthly, and ANC results are blinded to investigators and patients, with an independent safety committee reviewing the data, Warren explained.

The co-primary end points are annualized infection rate, based on infections adjudicated by a blinded committee, and the proportion of patients with an ANC increase of more than 500 cells/µL from baseline, each assessed over up to 52 weeks.² Secondary end points include infection severity and duration, antibiotic use, oral ulcers, and change in PROMIS Short Form Fatigue score at week 52.²

Warren added that select US sites can enroll patients remotely and encouraged clinicians with potentially eligible patients to contact the sponsor or site investigators.

What could mavorixafor mean for the chronic neutropenia treatment paradigm?

Positive results could support submission for regulatory approval and extend mavorixafor beyond its WHIM syndrome indication to patients with other genetic forms of chronic neutropenia or chronic idiopathic neutropenia, Warren said, cautioning that the data will need to be seen first.

"There currently are no other studies available for patients with chronic neutropenia, and no other drugs in development in this late stage in the pipeline. This is a community that has not had a new drug approved for them for over 30 [years]," Warren said. "This really is a pivotal study for us to be able to ask that question: Can this drug be an additional therapy that could be available for patients with chronic neutropenia?"

Sykes pointed to the injectable route of G-CSF and its adverse effects, including bone pain, fevers, and malaise, as gaps an oral agent could address.

"Having an oral agent and a second agent on hand for people that they could use either on demand or even on a chronic basis would really, since there is nothing else, be a huge benefit," he said.

References

1. Warren JT, Dickerson KE, Sharathkumar A, et al. Evaluating the safety and efficacy of mavorixafor, an oral CXCR4 antagonist, in participants with primary chronic neutropenic disorders: results from the phase 2 study. Presented at: 2025 European Hematology Association Congress; June 12-15, 2025; Milan, Italy. Abstract PS1654.
2. A phase 3, randomized, double-blind, placebo-controlled, multicenter study of mavorixafor in participants with congenital and acquired primary autoimmune and idiopathic chronic neutropenic disorders who are experiencing recurrent and/or serious infections. ClinicalTrials.gov. Updated 2026. Accessed November 12, 2026. https://clinicaltrials.gov/study/NCT06056297
3. FDA approves first drug for WHIM syndrome, a rare disorder that can lead to recurrent, life-threatening infections. FDA. April 30, 2024. Accessed November 12, 2026. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-drug-whim-syndrome-rare-disorder-can-lead-recurrent-life-threatening-infections