Dr Sykes on the Rationale for Exploring Mavorixafor in Chronic Neutropenia

[Mavorixafor is] designed to release neutrophil progenitors, [known as] band cells or early neutrophils. It’s interesting that oftentimes, the immune target on the neutrophil is only present on the very mature neutrophil, so there’s this appealing idea that by releasing the immature neutrophil into circulation, we might avoid some of that immune response.

David B. Sykes, MD, PhD, an associate physician of medicine-hematology and medical oncology at Massachusetts General Hospital, a clinician investigator and assistant professor at Mass General Brigham Cancer Institute Classical Hematology Massachusetts General Physicians Organization of Mass General Research Institute; and an assistant professor of medicine at Harvard Medical School, discussed the rationale for evaluating the oral CXCR4 antagonist mavorixafor (Xolremdi) in patients with chronic neutropenia.

In the adult population, chronic neutropenia is likely an immune-mediated disease in most patients, presenting as an autoimmune neutropenia, although it remains uncertain whether the process is B-cell, T-cell, or natural killer (NK)-cell mediated, Sykes said. Granulocyte colony-stimulating factor (G-CSF) remains the mainstay of treatment for chronic neutropenia, he noted, but it works simply by telling the bone marrow to make more neutrophils, which is imperfect when neutrophils are actively destroyed.

Mavorixafor, which is currently approved for the treatment of patients 12 years of age and older with WHIM (warts, hypogammaglobulinemia, infections and myelokathexis) syndrome to increase the number of circulating mature neutrophils and lymphocytes, represents an unusual approach for chronic neutropenia management, according to Sykes. As a CXCR4 antagonist, the agent releases immature neutrophils earlier into the bloodstream, and Sykes outlined 2 potential benefits: it is an oral pill rather than an injection, and it mobilizes neutrophil progenitors and band cells rather than mature cells. Because the immune target is often present only on fully mature neutrophils, moving these earlier forms into circulation could, in theory, help them evade the immune response, Sykes explained. He tempered the hypothesis, noting it is difficult to know whether the location of neutrophils in the bone marrow vs the peripheral blood makes a meaningful difference, given that the marrow is highly vascularized.

In an open-label phase 1b/2 trial (NCT04154488), mavorixafor was given as monotherapy (n = 10) or alongside G-CSF (n = 13) in patients with idiopathic, congenital, or cyclic chronic neutropenia. The monotherapy produced durable mean increases in absolute neutrophil count (ANC), with patients who had severe disease achieving nearly 3-fold increases out to 6 months. All patients with congenital neutropenia on G-CSF reduced their dose and maintained a normal mean ANC. The agent is now being evaluated in the pivotal phase 3 4WARD trial (NCT06056297).