The Ongoing Fight Against Acute GvHD - Episode 2

Second-Line Treatment Decision Factors

John F. DiPersio, MD, PhD: Steroid refractoriness and dependence aren’t always translatable to specific interventions at the bedside. Steroid-refractory and steroid-resistant graft-vs-host disease [GVHD] definitions are slightly different. Generally speaking, patients who have progression of their symptoms after 3 days of 2 mg/kg of methylprednisolone are considered steroid refractory or patients who have had no improvement in their symptoms after 7 days or patients who have not tolerated tapering of the steroid dose below 1 mg/kg in the first 28 days. Those are patients considered to have steroid-refractory or steroid-resistant graft-vs-host disease. Those patients are eligible for additional interventions or therapies. There are many. We’re mostly talking about interventions that occur after the fact, as opposed to early interventions that are more prophylactically oriented.

One of the problems with graft-vs-host disease is that once activated, T cells traffic to target organs. Then much of the damage, by the time the patient is symptomatic, has already been done, as manifested by the serum biomarkers, which are often elevated sometimes in patients way before they develop any symptoms or any signs of engraftment. The raging intellectual and scientific argument, in my view, is that we have these interventions that work for steroid-refractory and -resistant graft-vs-host disease, and they work. Steroids work. Second-line therapies, such as JAK inhibitors and ruxolitinib, work nicely. But if you really want to maximally limit acute GVHD, the biology of the disease suggests that an earlier intervention before the symptoms even develop, such as intervening in the prophylactic setting or in a way that is responsive to biomarkers being elevated, those kinds of interventions may have even more impact on outcome than waiting for the disease symptoms to begin because at that point, the die is cast.

Well somebody went to a bar with their buddies and wrote down a bunch of definitions. But in reality, the translation of these things at the bedside is not so cut-and-dried. For patients having rapidly progressive symptomatology on 2 mg/kg, that’s a no-brainer. They need something else. Otherwise, they’re going to die. For patients who have severe disease and after 7 days have no improvement, that’s a problem too. They’re going to die. And so the intervention for those steroid-refractory and steroid-resistant patients is a no-brainer.

The other group of patients that is more difficult are the patients who have a response to therapy and then fail with a steroid taper. The problem with interpreting those approaches is that the steroid tapers never define specifically in these clinical trials exactly how you do it. Everybody does it a different way, and everybody is convinced that their way is the best way. But I can tell you that if you fail—meaning, if the patient fails to tolerate steroid tapering in the first month—that is also a big problem and results in a very limited prognosis long term. Those 3 things are severe manifestations of GVHD and representative of a very poor prognosis going forward and deserving of second-line therapies.

The refractoriness depends on lots of factors. If you’re doing matched-sibling transplants, steroid refractoriness is probably 10%. If you’re talking about matched unrelated transplants, it’s probably 20%. In mismatched unrelated donor transplants, it’s probably in the range of 30%. This is when certain GVHD prophylaxis measures are not in place, such as post-transplant Cytoxan. Post-transplant Cytoxan has reduced primarily chronic graft-vs-host disease. But it also has a modest effect on reducing acute GVHD. Patients can tolerate mismatching better. And the rates of resistant and refractory disease are a little reduced in the acute setting, with patients getting post-transplant Cytoxan.

The biggest impact of post-transplant Cytoxan has been on the rates of chronic graft-vs-host disease, although obviously we couldn’t even do haploidentical transplants without post-transplant Cytoxan, for the most part. But in Asia and Japan, it’s done, maybe because of the less genetic complexity of donors vs recipients.

Transcript edited for clarity.