The NCCN guidelines define steroid refractoriness or resistance in cGvHD as disease progression while on prednisone ≥1 mg/kg/day for 1–2 weeks or stable disease while on prednisone ≥0.5 mg/kg/day (or 1 mg/kg every other day) for 1–2 months.

Abbreviations

cGvHD, chronic graft versus host disease; NCCN, National Comprehensive Cancer Network.

Reference

NCCN. Hematopoietic cell transplantation (HCT). V2.2024. Available at: www.nccn.org/professionals/physician_gls/pdf/hct.pdf (accessed 24 January 2025).

The most common grade ≥3 adverse events observed during clinical trials with ruxolitinib (a JAK1/2 inhibitor) in patients with cGvHD were anaemia, thrombocytopenia, neutropenia and infections.

Abbreviations

cGvHD, chronic graft versus host disease; JAK, janus kinase.

Reference

Food and Drug Administration. Ruxolitinib PI. Available at: www.accessdata.fda.gov/drugsatfda_docs/label/2023/202192s028lbl.pdf (accessed 24 January 2025).

The standard starting dose for cGvHD is typically 10 mg twice daily.¹ However, when patients experience cytopenias (neutropenia, anaemia, or thrombocytopenia), the approach is to initially implement dose reductions rather than dose delays.¹ The dose reduction strategy for ruxolitinib in cGvHD typically follows this pattern:¹

• Start with 10 mg twice daily
• If necessary, reduce to 5 mg twice daily
• If further reduction is needed, decrease to 5 mg once daily
• If patients are unable to tolerate 5 mg once daily, interrupt dosing until clinical parameters recover

It’s important to note that even at lower doses, such as 5 mg once daily, ruxolitinib can still be effective in treating cGvHD in some patients.²

Abbreviations
cGvHD, chronic graft versus host disease.

References

1. Food and Drug Administration. Ruxolitinib PI. Available at: www.accessdata.fda.gov/drugsatfda_docs/label/2023/202192s028lbl.pdf (accessed 24 January 2025).
2. Pattipaka T et al. Bone Marrow Transplant. 2024;59:637–46.

Cutaneous sclerosis is a manifestation of cGvHD that results from inflammation and progressive fibrosis of the dermis and subcutaneous layers.¹  Belumosudil is approved as a third-line therapy in cGvHD² and inhibits ROCK2, a kinase with a key role in multiple fibrotic pathways.³  Thus, belumodusil is believed to have anti-fibrotic activity in cGvHD.³  Axatilimab is approved for third-line therapy in cGvHD⁴ and inhibits the CSF-1R expressed on monocytes and macrophages, a cell type with a key role in establishing the fibrotic niche and driving fibrosis.⁵  Inhibition of CSF-1R with axatilimab has been shown to reduce pro-fibrotic mediators released by macrophages, thereby supporting a role for axatilimab in ameliorating fibrosis in cGvHD.⁵  Ibrutinib is indicated for second-line therapy in cGvHD, but has been associated with serious cardiac arrhythmias and cardiac failure.⁶  As patients with cardiac comorbidities may be at greater risk of these events, ibrutinib should be used with caution in these patients.⁶  As the patient is steroid-refractory, defined as disease progression while on prednisone ≥1 mg/kg/day for 1–2 weeks or stable disease while on ≥0.5 mg/kg/day (or 1 mg/kg every other day) for 1–2 months,⁷ continued steroid monotherapy would not be appropriate.⁵

Abbreviations

cGvHD, chronic graft versus host disease; CSF-1R, colony-stimulating factor 1 receptor; FDA, Food and Drug Administration; ROCK2, rho-associated coiled-coil–containing protein kinase 2.

References

1. Matires KJ, et al. Blood. 2011;118:4250–7.
2. FDA. Belumosudil PI. Available at: www.accessdata.fda.gov/drugsatfda_docs/label/2024/214783s007lbl.pdf (accessed 24 January 2025).
3. Cutler C, et al. Blood. 2021;138:2278–89.
4. FDA. Axatilimab PI. Available at: www.accessdata.fda.gov/drugsatfda_docs/label/2024/761411s000lbl.pdf (accessed 24 January 2025).
5. Bajpai A, et al. Blood. 2023;142:2540–1.
6. FDA. Ibrutinib PI. Available at: www.accessdata.fda.gov/drugsatfda_docs/label/2024/205552s043,210563s019,217003s004lbl.pdf (accessed 24 January 2025).
7. National Comprehensive Cancer Network. Hematopoietic cell transplantation (HCT). V2.2024. Available at: www.nccn.org/professionals/physician_gls/pdf/hct.pdf (accessed 24 January 2025).

Baricitinib is a JAK1/2 inhibitor recently tested in cGvHD,^1,2 while pacritinib, a JAK2/IRAK1/CSF-1R/FLT3 inhibitor, is being assessed in an ongoing clinical trial.³  Vimseltinib, which inhibits the CSF-1R, ixazomib, a proteasome inhibitor and acalabrutinib, a BTK inhibitor, have been or are being tested in clinical trials for cGvHD.^4–7

Abbreviations

BTK, Bruton’s tyrosine kinase; cGvHD, chronic graft versus host disease; CSF-1R, colony-stimulating factor 1 receptor; FLT3, fms-like tyrosine kinase 3; IRAK1, interleukin-1 receptor-associated kinase 1; JAK, janus kinase.

References

1. Clinicaltrials.gov. NCT02759731.
2. Holtzmann NG, et al. Blood 2020;36(Suppl 1):1.
3. Clinicaltrials.gov. NCT05531786.
4. Clinicaltrials.gov. NCT06619561.
5. Clinicaltrials.gov. NCT02513498.
6. Pidala J, et al. Biol Blood Marrow Transplant. 2020;26:1612–9.
7. Clinicaltrials.gov. NCT04198922.
   All clinical trials searchable by NCT number. Available at: https://clinicaltrials.gov/ (accessed 24 January 2025).