Commentary

Article

A Review of Axatilimab in Steroid Refractory Chronic Graft versus Host Disease

Axatilimab-csfr is a colony-stimulating factor-1 receptor (CSFR1) blocking monoclonal antibody indicated for cGVHD after 2 or more lines of prior therapy in adults and pediatric patients that weigh at least 40 kg.

Chronic graft-versus-host disease (cGVHD) remains a major cause of morbidity and mortality for allogeneic stem cell transplant survivors, affecting up to 30% to 70% of patients.1 The pathophysiology of cGVHD involves activation of the donor T cells leading to cytokine release (IL-2, interferons, and TNF-a) which initiates inflammation in target tissues. Regulatory cells (Tregs, NKreg, and Tr1) recruitment in addition to T and B cell activation results in an imbalance of host regulatory cells and donor T and B cells. A dysregulated immune response and alterations in tissue repair mechanisms lead to the deposition of extracellur matrix and fibrosis in affected organs. Macrophages and other pro-fibrotic mediators (TNFa, IL-6, and IL-1β) are involved in this mechanism.2

Axatilimab-csfr for cGVHD is administered as an intravenous infusion | Image credit: © Shisu_ka | stock.adobe.com

Axatilimab-csfr for cGVHD is administered as an intravenous infusion | Image credit: © Shisu_ka | stock.adobe.com

Corticosteroids remain the first-line therapy choice for cGVHD, but an estimated 50% of patients may have an inadequate response or become resistant to steroids over time.3 Steroid refractory cGVHD (SR-cGVHD) is defined as progression of GVHD while on prednisone ≥ 1 mg/kg/day for 1 to 2 weeks or stable GVHD on ≥ 0.5 mg/kg/day (or 1 mg/kg every other day) of prednisone for 1 to 2 months.4 Available therapy options in the steroid refractory setting are variable and the appropriate treatment option is dependent on a variety of factors including tolerability, cost, and organ(s) involved. Current FDA approvals for cGVHD include ruxolitinib (Jakafi; Incyte), ibrutinib (Imbruvica; Pharmacyclics, Johnson & Johnson), and belumosudil (Rezurock; Sanofi).5-7 Despite the available therapies, there remains an unmet need for patients with relapsed or refractory cGVHD.

Axatilimab-csfr (Niktimvo; Incyte) is an immunoglobulin G4 monoclonal antibody that binds to colony-stimulating factor 1 receptors (CSFR1), which are expressed on macrophages and monocytes. Blocking of CSFR1 results in decreased proinflammatory cytokine secretion inhibiting the inflammatory process.CSFR1 blockade also inhibits fibrotic processes by reducing monocyte levels, thereby suppressing their ability to differentiate into profibrotic macrophages.8

Axatilimab-csfr is indicated for the treatment of cGVHD after failure of at least 2 prior lines of systemic therapy in adults and pediatric patients weighing at least 40 kg. It is an intravenous infusion over 30 minutes dosed at 0.3 mg/kg (maximum 35 mg) every 2 weeks and was approved based on the findings of the AGAVE-201 trial (NCT04710576). Patients included in this study were those with active cGVHD based on the 2014 National Institutes of Health (NIH) Consensus criteria who had received 2 or more lines of systemic therapy. Patients were randomized 1:1:1 to receive axatilimab-csfr 0.3 mg/kg IV every 2 weeks, 1 mg/kg IV every 2 weeks, or 3 mg/kg every 4 weeks. The primary end point of the study was overall response according to the NIH Consensus criteria within the first 6 cycles after randomization.There were 241 patients randomized and almost 80% of patients had severe cGVHD according to the global severity rating. The median number of previous systemic cGVHD therapies was 4 with a range of 2 to 15 therapies. Most patients had received ibrutinib, ruxolitinib, belumosudil, or a combination of these agents.9

The primary end point of overall response was met in all 3 groups, with 74% (95% confidence interval [CI], 63 to 83) of patients in the 0.3 mg/kg group, 67% (95% CI, 55 to 77) of patients in the 1 mg/kg group, and 50% (95%, CI 39 to 61) of patients in the 3 mg/kg group. Median time to response was 1.7, 1.4, and 1.9 months, respectively. At 12 months, 53%, 60%, and 60% of patients in the 0.3 mg/kg, 1 mg/kg, and 3 mg/kg groups, respectively, had a durable response. Responses were observed in all organs across the 3 dosing groups, including patients with sclerotic changes. Improvement in percent of skin sclerotic body surface area was seen in 44.2%, 34.1%, and 59.6% of patients in the 0.3 mg/kg, 1 mg/kg, and 3 mg/kg groups, respectively. In addition, skin tightening severity was improved in 66%, 56.4%, and 59.6% of participants in the 0.3 mg/kg, 1 mg/kg, and 3 mg/kg dosing groups, respectively. Improvements in fibrotic manifestations in other organs were observed including lung, esophagus, joints, and fascia.9

The most common adverse effects with axatilimab-csfr were elevations in laboratory abnormalities, including aspartate aminotransferase (AST) and alanine aminotransferase (ALT). These elevations are attributed to decreases in Kupffer cells prompted by CSFR1 blockade, which subsequently leads to decreased serum enzyme clearance. Of note, laboratory abnormalities caused by axatilimab-csfr were not accompanied by end-organ damage. Periorbital edema, which is another on-target adverse effect, is caused by CSFR1 blockade and severity and incidence are dose-dependent, with grade ≥ 3 events occurring in 0, 1%, and 6% of patients in the 0.3 mg/kg, 1 mg/kg, and 3 mg/kg dosing groups. Any grade infection occurring in 70% or more patients in each dosing group and other adverse effects that occurred in ≥ 20% of any dosing group included but were not limited to lipase level increase, amylase level increase, fatigue, diarrhea, headache, and blood creatine kinase level increase. Infusion-related reactions were reported in 18% of patients with grade ≥ 3 reactions occurring in 1.3% of patients. Those with previous reactions to axatilimab-csfr should be premedicated with an antihistamine and an antipyrectic.9

About the Author

Breanna Taylor, PharmD, BCOP, is a transplantation and cellular therapy clinical pharmacist at Novant Health Cancer Institute.

Although the results of the AGAVE-201 study were promising, there was no control group. Future study of axatilimab-csfr may compare it to other agents to further evaluate the efficacy. Moreover, in contrast to other FDA approved therapies in cGVHD, axatilimab-csfr is administered intravenously, which may not be as convenient for some patients. The current approval of axatilimab-csfr requires the use of 2 prior lines of therapy. An upcoming trial (NCT06585774) will aim to evaluate the efficacy of axatilimab-csfr in combination with corticosteroids versus placebo in combination with steroids as initial treatment. Future studies are aiming to evaluate the efficacy of axatilimab-csfr in combination with other therapies such as one (NCT06663722) which will evaluate the efficacy of axatilimab-csfr in combination with extracorporeal photopheresis (ECP). cGVHD remains a profound and debilitating condition among post-allogeneic stem cell transplant patients, and cGHVD with sclerotic and fibrotic changes often responds poorly or is resistant to standard therapies.10 For patients with steroid refractory cGVHD, the use of axatilimab-csfr will expand treatment options.

REFERENCES
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3. Flowers MED, Martin PJ. How we treat chronic graft-versus-host disease. Blood. 2015;125(4):606-615. doi:10.1182/blood-2014-08-551994
4. Schoemans HM, Lee SJ, Ferrara JL, et al. EBMT-NIH-CIBMTR Task Force position statement on standardized terminology & guidance for graft-versus-host disease assessment. Bone Marrow Transplant. 2018;53(11):1401-1415. doi:10.1038/s41409-018-0204-7
5. Jakafi [Prescribing information]. Incyte; 2023. Accessed January 22, 2025. https://www.jakafi.com/jakafi-prescribing-information
6. Imbruvica [prescribing information]. Pharmacyclics; 2024. Accessed January 22, 2025. https://www.rxabbvie.com/pdf/imbruvica_pi.pdf
7. Rezurock [prescribing information]. Kadmon Pharmaceuticals, LLC; 2024. Accessed January 22, 2025. https://products.sanofi.us/rezurock/rezurock.pdf
8. Niktimvo [prescribing information]. Incyte; 2025. Accessed January 22, 2025. https://www.niktimvo.com/niktimvo-prescribing-information
9. Wolff D, Cutler C, Lee SJ, et al. Axatilimab in recurrent or refractory chronic graft-versus-host disease. N Engl J Med. 2024;391(11):1002-1014. doi:10.1056/NEJMoa2401537
10. Kitko CL, White ES, Baird K. Fibrotic and sclerotic manifestations of chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2012;18(1 Suppl):S46-52. doi:10.1016/j.bbmt.2011.10.021
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