Corticosteroids remain the mainstay of therapy for the treatment of cGVHD, but many patients who receive steroids will become refractory within the first year of therapy. Most individuals with cGVHD are not adequately managed with first-line corticosteroids, and subsequent lines of therapy are needed.

Steroid-refractory cGVHD has been defined as progression after 2 weeks of 1 mg/kg/day or higher equivalent of steroids, no response after 4 to 8 weeks, or an inability to taper steroids. And when the need for subsequent therapy arises, there are several factors to consider. Ibrutinib is US Food and Drug Administration (FDA) approved for cGVHD after failure of prior therapy. Most recently, belumosudil was approved based on the results of the ROCKstar trial, where patients had received 2 to 5 prior lines of systemic therapy. Other agents are in development and are likely to be approved soon, such as ruxolitinib, which is under review for the treatment of steroid-refractory cGVHD in adults and children age 12 years and older. Thus, as we begin to have more options, we would then be able to weigh several factors, including, most importantly, existing comorbidities in choosing a second-line agent. For example, if the patient has thrombocytopenia due to cGVHD, then perhaps ruxolitinib would not be the best choice. If the patient is older with preexisting heart disease, then perhaps ibrutinib is not the best choice. As even more agents become available, patient preference will also need to be considered (eg, does the patient want an oral or intravenous agent?). 

What we would like to be able to do—and we are not quite there yet—is to look at the disease phenotype and choose a second-line agent based on the patient’s clinical features. At this point, we can only say that some therapies may work better than others in patients with fibrotic disease. Some of the newer agents in clinical trials look promising, but we have yet to see a trial that has shown a certain agent to be better than others for a certain patient subtype. Unfortunately, the combination strategies involving the incorporation of additional agents to frontline corticosteroids have been unsuccessful to date. 

In our practice, we will almost always suggest to the patient that they consider enrolling in a clinical trial if one is available because that is how we move the field forward. However, some individuals are not interested in clinical trials and others live too far away from the transplant center and cannot participate without great duress. Participation in clinical trials is not for everyone. And we do have FDA-approved therapies now, so enrollment in a clinical trial is not always necessary.