Refractory chronic graft-versus-host disease (cGVHD) presents a complex therapeutic challenge, necessitating innovative management approaches to improve patient outcomes. Recent advancements in targeted therapies offer new hope, and the next frontiers in the management of refractory cGVHD may be establishing a personalized treatment approach and using combination therapies with targeted agents.

Just a decade ago, we had no US Food and Drug Administration (FDA)–approved drugs for refractory cGVHD. Improvements on the regulatory side, often in drug designation, have allowed companies to focus on this area of rare diseases and develop appropriate drugs. Having since progressed in our understanding of the biology of cGVHD, we now have ibrutinib, ruxolitinib, belumosudil, and, more recently, axatilimab, which are FDA approved for refractory cGVHD. The drugs are approved for slightly different lines of therapy, but sometimes we consider rearranging the order based on how the patient is presenting and what other comorbidities they may have.

I think that it is a very different field today than it was a few years ago in terms of treatment options for our patients. We are seeing these drugs have meaningful clinical responses and impact on patient quality of life, which are very important. Many of the treatments that we used in the past have fallen by the wayside, and we now rely on these new drugs that have been tested (often in randomized trials) to guide our treatment of these patients.

One of the challenges that we face today is identifying the most appropriate drugs for patients based on their efficacy and safety profiles. We know that none of these drugs provides 100% response rates, and complete remission rates are much lower. So, I think that the next frontier in treatment is combination therapy, since some of these drugs have nonoverlapping toxicities and may synergize or at least have additive benefits in patients. I believe that this is where we will hopefully see some improvements.

I think that Dr Perales nailed it. We have an embarrassment of riches with all these drugs now, and the next frontier is figuring out the right drug for the right patient at the right time. I believe that this is the paradigm we must solve. We are moving these active agents into earlier settings, be it first or second line; in combination; or instead of steroids. I think that this is where the field will go next, hopefully, minimizing the effects of steroids and steroid toxicity and learning how to use these drugs most appropriately.

It is probably the underlying biology that will point us toward the correct drug for the correct patient. Thus far, we have not seen patient organ involvement or clinical characteristics that would predict response to 1 agent or another. Certainly, if we had that data, we would use it. However, I suspect that, moving forward, treatment will be based on biology rather than clinical manifestations.

I like to reflect on how much we have advanced, yet still how much we do not know about cGVHD. Ten years ago, traditional immunosuppressive agents were available to treat patients with cGVHD, but many of those agents were not that effective and were associated with a higher risk for infections. Patients with cGVHD already have a dysregulated immune system, and adding more intensive immunosuppression led to many infectious complications. We do not see that as much with the new targeted agents, which also typically have better response rates.

As previously mentioned, we are still learning how to optimize the use of these drugs. When each of these agents was developed and studied in pivotal trials to support FDA approval, they were administered without the concurrent use of many of our current standard therapies. That makes it hard to answer questions about how we can best incorporate these drugs into our clinical practice.

I think that combination or additive therapies are becoming very common in our clinical practice, but we are still learning in real time. Clinical trials to date have typically not allowed for that, but upcoming trials may investigate combination therapies, which I think reflects our desire to enhance efficacy and limit toxicities for our patients.