The combination of targeted therapies may benefit some patients with refractory chronic graft-versus-host disease (cGVHD), but the evidence is currently limited. Emerging real-world data from treatment centers indicate that targeted therapy combinations are feasible and may be safe and beneficial for select patients with refractory cGVHD.

In the past, we did not have many effective therapies for cGVHD, and we are really fortunate to now have 4 US Food and Drug Administration (FDA)–approved drugs (ie, axatilimab, belumosudil, ibrutinib, and ruxolitinib) for cGVHD that were approved within the last 7 years or so. The registrational studies required patients to stop any targeted systemic therapies that they were previously receiving and go through a washout period, but they could continue traditional immunosuppressive medications such as prednisone, tacrolimus, and mycophenolate mofetil.

Clinically, we worry that cGVHD symptoms can flare during washout periods between medications. Thus, in clinical practice, we do not have to follow the rules of the trials. For example, if I have a patient taking ruxolitinib and I want to put them on belumosudil, which has an average time to first response of approximately 4 to 8 weeks, I will keep them on ruxolitinib and overlap it with belumosudil for a couple of months until I see that they are getting a little better; at that point, I can discontinue the ruxolitinib.

While combination therapy is compelling, one must consider the alternative: if a patient can get by with 1 medication, why would you give them 2? Adding another medication can expose them to additional potential risks and costs. However, if you have already given the patient a targeted therapy and you feel that they need more, people often feel very comfortable adding medications. Now, if the patient is on a medication and clearly has no response and just gets worse, then I do not think that there is any benefit to keeping them on that medication.

I think that the most compelling combinations are with ruxolitinib, belumosudil, axatilimab, and perhaps ibrutinib. The combination of targeted therapies for cGVHD is an area of developing research, with initial reports heavily leaning on the real-world experiences of individual treatment centers. Most of the data thus far are preliminary and are mainly focused on toxicity and feasibility. Given the differences in patients and their cGVHD manifestations, it is hard to make major conclusions about the efficacy of these approaches. An upcoming phase 2 study will evaluate the combination of ruxolitinib and axatilimab in patients with newly diagnosed cGVHD. Thus, data will emerge from a clinical trial specifically looking at combination targeted therapy.

The last point is that much of this is based on proposed mechanisms of action, toxicity profiles, and logistic reasons. Now that we have 4 targeted agents that are FDA approved and available, it would be interesting to go back to the bench and use animal models to determine if some of these agents work better synergistically than others based on biological and/or immunological characteristics.