John DiPersio, MD, PhD, shares his thoughts on approaching initial therapy for chronic GVHD and early intervention with JAK inhibitors.
John DiPersio, MD, PhD:The other issue is the role of post-transplant [PT] Cytoxan [cyclophosphamide], which has been increasingly intertwined in the treatment of all patients undergoing transplant, not just haploidentical transplants but now unrelated and even matched sibs. A number of matched sibs are getting PT cyclophosphamide as well. The main benefit of PT cyclophosphamide is to reduce the risk of chronic graft-vs-host disease. This is another example of an early intervention that seems to make a difference in chronic GVHD [graft-vs-host disease], and that’s post-transplant Cytoxan. The only other thing I can think of that alters chronic GVHD that has been shown in randomized studies is antithymocyte globulin.
Michael Bishop, MD: That was my next question.
John DiPersio, MD, PhD: This is an early intervention. Obviously, T-cell depletion is the third, and that’s an early intervention too. But that results in all sorts of negative aspects with increasing relapse, graft failure, and infections. Those are the 2 things that seem to alter the long-term fate, incidence of chronic GVHD, and they’re both early interventions. I want to comment on how we do the same thing with JAK inhibitors. We did a lot of these initial mouse studies. We had, ironically, a lot of discussions with Incyte [Corporation] when we were publishing our papers initially, with a mouse clearly showing that early intervention with JAK inhibitors was much more powerful as a preventive measure than waiting for the mice to develop GVHD and then treating them, although there was a beneficial effect.
But the worry always was that this early intervention with JAK inhibitors would prevent or delay in graft because the inhibition of signaling in the JAK kinase pathway. A lot of these cytokine signal through the JAK kinase pathway, and there was lots of worry that giving a JAK kinase inhibitor right after transplant would be detrimental, probably what the Johns Hopkins [Sidney Kimmel Cancer Center] folks thought about before they gave their first dose of high-dose Cytoxan on day 3. When you think about it, it’s a crazy idea. But it was crazy like a fox because it did just enough to kill all those highly alloreactive T cells. That prevented both severe acute GVHD in the haploidentical setting but also has a profound effect long-term on the rates of chronic GVHD. Atgam is the same thing—early intervention with Atgam through a number of mostly European studies and randomized trials have shown that that.
Michael Bishop, MD: What do you think about Atgam? Atgam is essentially in vivo T-cell depletion. Why is that? We could talk about Hopkins, and there’s something about how stem cells are stem cells. They’re the cockroaches of the body. They survive everything. But the Atgam story is interesting because that’s in vivo T-cell depletion, at least from my perspective. But maybe it’s doing more, and from an immunologist such as yourself, I’d love to hear your thoughts.
John DiPersio, MD, PhD: It’s an in vivo T-cell depletion, but it’s a very incomplete T-cell depletion. It functions more like killing the most proliferative T-cell population. The T cells that are proliferating the most rapidly early on in response to hosting antigens are the ones that seem to be eliminated the best. That’s exactly how Cytoxan works. Cytoxan seems to inhibit these alloreactive T-effector cells. And Cytoxan, by the way, is not the only drug that does this. The hypomethylating agents do it too, but they have a direct effect on the stem cell population, whereas Cytoxan doesn’t. It’s more dicey to give hypomethylating agents right after transplant because that will suppress stem cell proliferation.
But with Cytoxan, the stem cells have enzyme activities that degrade Cytoxan, and they’re resistant to the effects of Cytoxan. But Cytoxan and hypomethylating agents, for instance, and Atgam, all seem to kill these highly proliferative T-effector cells right after transplant, while the ones that are less proliferative survive, and also the T-regs [regulatory T cells] survive.
The T-regs are less proliferative after transplant than these T-effector cells. You get right after with Cytoxan or hypomethylating agents in a mouse, or with Atgam you get this. Without these things you get a massive expansion of T-effector cells, which cause acute GVHD. And you get a slow expansion of the T-regs. With these drugs you get a marked inhibition of T-effector cell expansion and a continued expansion of T-regs, which are relatively resistant to those 3 drugs, all 3 approaches. You get a more balanced T-effective to T-reg ratio, which also probably impacts both acute and chronic GVHD. The biology is interesting, but it’s been hard for any intervention after chronic GVHD develops to get it to go away.
Michael Bishop, MD: Yes, that’s exactly the point even in those half-loads. That comes down to where you and I think our clinical challenge is in the steroid-refractory graft-vs-host disease cases. Unfortunately, that makes up about half our patient population, for which you’d need a continually high dose of steroids. For the other half, you’re trying to bring down that steroid dose. Every time you do you see Mrs Jones, all of a sudden there are still frequencies up to 5 times per day or they’re coming back to the ER [emergency department] because of a blatant diarrhea. Then you’re trying to balance all the adverse effects that are going along with steroid administration concurrent with a calcineurin inhibitor. This is why all these new second-line options being introduced to us are being welcomed with open arms. And it comes back to the biology you described before.
John DiPersio, MD, PhD: I want to also say 1 other thing about how we do the same thing you do. The question always is: “How many days do you wait before you start a JAK inhibitor if someone has GVHD?” Obviously, if someone gets steroids and they calm down immediately, we couldn’t add a JAK inhibitor at our center for probably 5 to 7 days if they’re not getting better.
Then there are those exceptional patients who Mike mentioned briefly. Although those patients have explosive symptoms over the first 3 days, in spite of adequate steroid dosage, those are the patients we might start right away on a JAK inhibitor as early as possible. Because we know the implications of grade 3 and grade 4 GVHD.
We don’t always know if by intervening early that we’re going to prevent the long-term outcomes, but we know the outcomes of patients who get severe GVHD is terrible. Some survive, but a lot of them survive marginally. Some survive with poor blood count recovery and they’re very debilitated, and they have ongoing symptoms and multiple infections. A lot of them don’t survive because of these 3 infections of progressive GVHD.
We’re like you. We start a JAK inhibitor as a second-line treatment within 3 to 7 days if things aren’t dramatically better. We’re all afraid of prolonged steroid exposure, also like you, and we try to cut back on the steroid dosing as soon as the disease quiets down a little because of the issues with steroid excesses and some of the toxicities associated with steroids.
Transcript Edited for Clarity