<p>The 3 newer treatments for chronic graft-versus-host disease (cGVHD) are known to target pathways that are involved in B-cell and T-cell signaling. Ibrutinib, ruxolitinib, and belumosudil have each shown efficacy with symptom reduction in patients with active steroid-dependent or steroid-refractory cGVHD.</p>

It is very important that we now have different drugs that impact different pathways in cGVHD. When I first started in this field, we had none of this, so this is a big advancement. Still, whether we consider ibrutinib, belumosudil, or ruxolitinib, we also recognize that our understanding of the pathobiology of cGVHD is incomplete.

 

Unlike acute GVHD, which is thought of as mainly a T-cell disease, cGVHD is much more complicated and involves B cells, T cells, and their interactions. There is a lot of subtlety, a bit of art, and quite a bit of clinical experience that goes into trying to optimize these therapies for patients. That is one of the reasons why multispecialty care in cGVHD is so important.

 

As with a lot of immunology, trying to understand cGVHD is like an onion—you keep peeling back layers, only to expose a new layer. Because of this complexity, it is difficult to say whether one immune signaling pathway may be more important than the next. We like to think that these inhibitors are incredibly specific or selective in their targeting, but often we realize that this is not the case. An area of active research is determining how these different pathways interact in the activation and function of B cells and T cells, and we are always interested, for example, in knowing how different drugs impact the regulatory T-cell compartment.

 

Other challenges that we face are the quality of the evidence and the limited numbers of patients in cGVHD in clinical trials. It is very difficult to organize trials around this disease. cGVHD is a chronic problem, and patients have a lot of concurrent medical issues and are receiving many other medications. Ibrutinib and ruxolitinib were initially developed for other indications, and cGVHD has clearly been an orphan disease. For example, ibrutinib has been much better studied in chronic lymphocytic leukemia than in cGVHD. Cardiac toxicity with ibrutinib is definitely a concern in cGVHD, but another concern relates to tolerability. Many patients feel tired, or they just do not like the way that it makes them feel, including the gastrointestinal symptoms. Side effects and tolerability are a big part of the equation with all of our therapies—our patients have been through a lot, and many of them are sick and tired of feeling sick and tired.

 

Finally, as we look to layering therapies that act on different pathways, we are eager to avoid overlapping toxicities, but all of these drugs are, to some extent, immunosuppressive, so we need to be vigilant about the risk of infection.