How do you approach steroid-refractory GVHD in patients who either cannot receive ruxolitinib or do not respond to ruxolitinib?

Both acute and/or chronic GVHD could be steroid-refractory.

In patients with acute steroid-refractory GVHD, I would target therapy based on organ involvement. If skin is involved and the patient cannot take or get ruxolitinib, I would use ATG first, in particular if severe disease, but there is a number of other agents that can be tried. I have had excellent results with tocilizumab/infliximab combination in a very severe skin GVHD, as well as moderate doses of cyclophosphamide (500-750 mg/sqm) repeated 2-3 times.

In acute gut GVHD, we prefer vedolizumab and alpha-1 antitrypsin combination in steroid refractory gut GVHD and have had excellent results with those agents, ATG would be my second choice.

For chronic GVHD that is steroid refractory/dependent, a number of agents can be tried. They include: extracorporeal photopheresis (ECP), belumosudil, ibrutinib, mycophenolate mofetil, weekly methotrexate, sirolimus, pentostatin, hydroxychloroquine, mesenchymal stem cells, cyclophosphamide, and others.

Note that a limited number of treatments are FDA approved for GVHD (ruxolitinib, ibrutinib, belumosudil).