New developments in steroid-refractory acute GvHD

A large unmet need exists in managing patients with refractory acute graft-versus-host disease (GvHD). Prof. Ronjon Chakraverty (University of Oxford, UK) talked about his perspective on this topic and discussed ongoing trials that may provide better outcomes for these patients.

“We still don’t know how to treat steroid-refractory acute GvHD, and we need to address this huge unmet need,” stressed Prof. Chakraverty [1]. The Janus kinase (JAK)1/JAK2 inhibitor ruxolitinib has presented itself as the new standard-of-care for treatment-resistant acute GvHD in the REACH-2 trial, displaying a 28-day response rate of 62.3% compared with 39.4% for participants who were randomised to the control arm (P<0.001) [2]. “However, at the time of the trial closure, approximately 50% of the patients had died,” said Prof. Chakraverty. “Currently, trials will probably be looking not only at corticosteroid-refractory disease but also at ruxolitinib-refractory acute GvHD” [1,3]. In addition, Prof. Chakraverty mentioned that biomarkers may be helpful in quickly identifying patients who are refractory to both ruxolitinib and corticosteroids [1,4].

What is the best treatment approach in 2023?

“Currently, the best approach for treating patients with steroid-refractory acute GvHD is enrolling them in clinical trials,” said Prof. Chakraverty. He highlighted specific trials that are currently ongoing in this area.

Good biological evidence has emerged that ruxolitinib protects intestinal stem cells in the gut and skin [5]. “Therefore, it is a good idea to keep exploring JAK inhibitors for the treatment of this disease,” argued Prof. Chakraverty. Currently, tofacitinib (NCT05112263) and itacitinib (NCT04070781) are being evaluated. When regeneration of epithelial cells is considered, there are ongoing trials assessing progenitors and niche factors, such as lithium carbonate (NCT00408681), growth factors and hormones, like pregnyl and apraglutide (NCT02525029; NCT05415410), immune cells and cytokines, such as IL-22 IgG2-Fc (or F-652) (NCT02406651), and microbial stimuli, like MaaT013 and healthy faeces (NCT04769895; ISRCTN14530574). Prof. Chakraverty specifically mentioned the preclincial STARGAZE trial, evaluating a glucagon-like peptide 2 for the repair of intestinal stem cells and Paneth cells in acute GvHD, and a phase 1 trial assessing faecal microbiota transplant (FMT) in patients with steroid-refractory acute GvHD [6,7]. This last study showed a switch to donor-like microbiota in responders.

“Finally, I would like to emphasise that the priority in clinical trial design is combining regenerative therapies with targeted immune suppression,” concluded Prof. Chakraverty.

1. Chakraverty R. Treatment of corticosteroid-refractory acute GVHD. E06-03, European Society for Blood and Marrow Transplantation (EBMT) 49^th Annual Meeting, 23–26 April 2023, Paris, France.
2. Zeiser R, et al. N Engl J Med 2020;382:1800–1810.
3. Mohty M, et al. Blood. 2020;136(17):1903–1906.
4. Socie G, et al. Blood. DOI:10.1182/blood.2022018579.
5. Takashima S, et al. Science immunology. 2019;4(42):eaay8556.
6. Norona J, et al. Blood. 2020;136(12):1442–1455.
7. Van Lier YF, et al. Sci Transl Med. 2020;12(556):eaaz8926.

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Posted on 15 June 202322 February 2024