Clinical Decision Making in the Second-Line Treatment of Chronic Graft-Versus-Host Disease

Second-line therapy in chronic graft-versus-host disease (cGVHD) is indicated for steroid-refractory cGVHD: when prednisone 1 mg/kg/day fails to produce improvement for 2 weeks, when disease is stable or progressing despite ≥0.5 mg/kg/day prednisone for 4 to 6 weeks, or when steroid toxicity precludes shorter therapy.¹ The FDA has approved the use of four therapies, ibrutinib, ruxolitinib, belumosudil, and axatilimab as acceptable systemic options after steroid failure.²  

Why Clinicians Choose Ruxolitinib as a Second-Line Therapy 

JAKAFI^®(ruxolitinib) is an FDA-approved treatment for cGVHD in adult and pediatric patients aged 12 years or older after previous failure of one or two lines of systemic therapy.³ Top transplant programs increasingly add ruxolitinib within 2 to 4 weeks of starting steroids if organ scores are unchanged or worse or if steroid-related adverse effects emerge, reflecting expert guidance to escalate early.¹ Long-term data from REACH3 demonstrates the durable benefit of ruxolitinib versus investigator-selected best available therapy (BAT): median failure-free survival was 38.4 months with ruxolitinib versus 5.7 months with BAT (hazard ratio: 0.36 [95% CI, 0.27 to 0.49]). Therefore, ruxolitinib increased the duration for patients to be free from treatment failure or death by 64%, with non-relapse mortality and relapse events being low over 3 years.⁴ Exposure-adjusted grade ≥3 adverse events and serious adverse events were numerically lower with ruxolitinib than with BAT, supporting sustained use once a response is documented.⁴ These outcomes, together with the ability to taper steroids when responses occur, of early second-line ruxolitinib use, rather than prolonged steroid monotherapy.^1,4 

How to Use Ruxolitinib Safely 

Before and during therapy, monitor complete blood counts every 2 to 4 weeks until doses are stabilized; monitor for infection and conduct prompt evaluation and use appropriate prophylactic measures. Common toxicities include anemia and thrombocytopenia.³ Dose adjustments may be needed for renal or hepatic impairment and for drug interactions involving certain azoles; follow label-specified modifications.³   

Alternatives in the Second-Line setting 

IMBRUVICA® (ibrutinib) is a kinase inhibitor FDA-approved for use after failure of one or more prior lines of therapy and may be considered when ruxolitinib is contraindicated or not tolerated.^2,5 Be aware of bleeding and arrhythmia risks and adverse CYP3A interactions; monitor for cytopenias with monthly complete blood counts.⁵  

Extracorporeal photopheresis (ECP) is a second-line procedure in which the patient’s blood is removed from the body and treated with ultraviolet light and drugs that are activated when exposed to this light; the blood is then returned to the body. A literature review of 735 patients with steroid-refractory/intolerant/dependent cGVHD who had this procedure showed overall response rates of between 50% to 65%. A portion of patients were also able to significantly taper steroid doses, particularly useful when cytopenias limit drug therapy.¹   

Key takeaway: Early, criterion-based escalation to ruxolitinib as second-line therapy is consistent with expert guidance and supported by durable, 3-year outcomes, enabling steroid-sparing while preserving options for BTK inhibition, ECP, and later transition to ROCK2 or CSF1R targeting when needed.^1–4 

References 

1. Zeiser R. UpToDate. Treatment of chronic graft-versus-host disease. Updated September 25, 2024. https://www.uptodate.cn/contents/treatment-of-chronic-graft-versus-host-disease?topicRef=3548&source=see_link  
2. NCCN Clinical Practice Guidelines in Oncology National Comprehensive Cancer Network (NCCN Guidelines^®) for Hematopoietic Cell Transplantation Disease. V.1.2025.  
3. JAKAFI® (ruxolitinib). Prescribing information. Incyte; 2023.  
4. Zeiser R, Russo D, Ram R, et al. Ruxolitinib in patients with corticosteroid-refractory or corticosteroid-dependent chronic graft-versus-host disease: 3-year final analysis of phase III REACH3 study. J Clin Oncol. 2025;43(23):25662571. doi.org/10.1200/JCO-24-02477 
5. IMBRUVICA® (ibrutinib). Prescribing information. Pharmacyclics LLC; 2024.