The promise of novel treatments for severe chronic neutropenia

ABSTRACT

Introduction

Severe chronic neutropenia, i.e. absolute neutrophil count (ANC) less than 0.5 × 10⁹/L, is a serious health problem because it predisposes patients to recurrent bacterial infections. Management radically changed with the discovery that granulocyte colony-stimulating factor (G-CSF) could be used to effectively treat most patients; therapy required regular subcutaneous injections. In the early days of G-CSF therapy, there were concerns that it might somehow overstimulate the bone marrow and cause myelodysplasia (MDS) or acute myeloid leukemia (AML). Detailed research records from the Severe Chronic Neutropenia International Registry (SCNIR) indicate that this is a relatively low-risk event. The research records suggest that certain patient groups are primarily at risk. Presently, allogeneic hematopoietic stem cell therapy serves as an alternate form of therapy.

Areas Covered

Due to these concerns and the desire for an easy-to-take oral alternative, several new treatments are under investigation. These treatments include neutrophil elastase inhibitors, SGLT-2 inhibitors, mavorixafor – an oral CXCR4 inhibitor, gene therapy, and gene editing.

Expert Opinion

All of these alternatives to G-CSF are promising. The risks, relative benefits, and costs are yet to be determined.

KEYWORDS:

• CXCR4
• ELANE
• gene editing
• granulocyte colony-stimulating factor (G-CSF)
• mavorixafor
• neutropenia
• neutrophil elastase (NE)
• Severe chronic neutropenia (SCN)

Article highlights

• This review highlights the benefits and limitations of treating severe chronic neutropenia (SCN) with granulocyte colony-stimulating factor (G-CSF).

• Recent studies show that Warts, Hypogammaglobulinemia, Infections, Myelokathexis (WHIM) syndrome, which causes neutropenia and lymphocytopenia, can be treated with mavorixafor, an oral CXCR4 antagonist.

• Current studies are underway to see if Mavorixafor has broader applications for the treatment of SCN.

• The SLGT-2 inhibitors, drugs approved for the treatment of diabetes, appear to be effective for the treatment of neutropenia due to mutations in glucose metabolism.

• Laboratory investigations suggest that an orally available antagonist of neutrophil elastase (NE) may be a treatment for neutropenia due to mutations in ELANE, the gene for NE.

• Several laboratories are currently investigating gene therapy and gene editing as promising treatments for SCN.

• Laboratory studies and clinical trials are very encouraging for the development of new therapies for SCN.

Declaration of interest

DC Dale has previously received research funding from the NIH, EmendoBio, and the Ella Jewel Foundation. He has also completed research work on mavorixafor funded by XH Pharmaceuticals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.