When to Initiate Second-Line Therapy

Transcript:

Zachariah DeFilipp, MD: There are multiple clinical scenarios in which patients are considered to have steroid-refractory or steroid-dependent disease that would warrant second-line therapy. We often in our practice follow the criteria from clinical trials. The criteria from the REACH1 study illustrate some of the scenarios that we see clinically.

Situations in which we may start second-line therapy would include patients who progress after 3 days of at least 2 mg/kg per day, or have no improvement after seven 7 days of at least 2 mg/kilogram per day.

Additionally, we would consider adding second-line therapy in patients who develop GvHD [graft-versus-host disease] in another organ after at least 1 mg/kg per day, being treated for skin or upper GI [gastrointestinal] GvHD. And we also think about adding a second agent if the patient is unable to tolerate the steroid taper. In truth, we don’t know if it’s better to react sooner than to wait; conceptually, we tend to think so.

It would make sense that if a patient’s GvHD is not responding to systemic steroids and an additional agent is needed, adding it earlier seems like a good idea. However, at the onset, it’s sometimes hard to tell who’s going to respond to steroids or not. Also, it’s an easier proposition to begin second-line therapy more quickly when we have a well-tolerated agent with good data behind its use.

Yi-Bin Chen, MD: Given the toll that steroid-refractory graft-versus-host disease takes on our patients, I think oftentimes people have asked, well should we act sooner? Should we add second-line therapy sooner, before they actually meet the definition of true steroid-refractory disease? And the answer to that is complicated. There are pros and cons, if you think about it. You’re adding further therapy, so there is the cumulative risk of toxicity and infections, and maybe the patient is going to respond to your therapy and don’t actually need it. But patients may not respond, and so perhaps treating them earlier will help them before they develop more end-organ damage or medical complications.

It’s a difficult question to answer right now. We don’t have a way of saying yes or no. I think the key to what we’re doing is being able to better evaluate patients. The key to this is not looking at someone’s rash or not measuring the volume of diarrhea, as unfortunately we still do now to evaluate patients. The key here is to have more accurate assessments for patients, and ultimately that will likely to be some sort of noninvasive blood biomarker, and this will help tell us if patients are responding or not. And it could be done much sooner than actually seeing the patient’s diarrhea decrease or skin rash vanish. And so if we’re able to validate these biomarkers after we discover them, then ultimately they’ll help us make much more informed decisions and we can act sooner.

Traditionally, the agents that have been used for steroid-refractory graft-versus-host disease have been more systemic immunosuppression, and that’s intuitive. This was based in the model that this was immunological disease and donor cells were attacking the host body, so we needed to suppress the donor cells even more. The problem with that is the more we suppressed the donor immune system, 1) it didn’t work that well and 2) the more infections recipients were left with. And so, the paradigm of using more systemic immunosuppression has not really succeeded.

I think the novel agents moving forward involve going after specific pathways, defining certain inflammatory cascades that we can target that may be GvHD specific. They may also involve using different modalities such as cellular therapy in the form of mesenchymal stem cells, or ECP [extracorporeal photopheresis] to come up with a good outcome. Ruxolitinib, which we’ll talk about, is the first approved therapy for steroid-refractory graft-versus-host disease, and we look forward to finding more drugs in this setting.

Transcript Edited for Clarity