The Ongoing Fight Against Acute GvHD - Episode 5

REACH2 Trial Regimen Adverse-Event Profile

John DiPersio, MD, PhD

John F. DiPersio, MD, PhD: As far as toxicity is concerned, the ruxolitinib was relatively well tolerated. The major toxicity was thrombocytopenia, secondarily anemia. This occurred about twice as high in the treated group, but it also occurred frequently in the standard-of-care group. As you might imagine, acute GVHD [graft-vs-host disease] is associated with thrombocytopenia and anemia often. There were higher rates of both of those, especially thrombocytopenia, in the treated group. And the question is whether that’s clinically significant and whether that alters survival. It probably does not.

We don’t know because we think that—we’re not sure what the cause of thrombocytopenia is. There are many theories. It’s odd in mouse models that the degree of thrombocytopenia is not as great as we see in humans. Many of us have used different drugs to enhance platelet recovery. These oral thrombopoietin agonists, such as eltrombopag and the IV [intravenous] MPL agonist Nplate, have been used in some patients who have thrombocytopenia with some success. But I can tell you that the reason people get thrombocytopenia when they have acute GVHD is because of this inflammatory process that’s either interferon related or TGF-data related or related to something else thanks to this immune inflammatory environment. If you can block that immune-inflammatory environment, then you have a better chance of improving the platelet count. Sometimes even steroids in addition to ruxolitinib can help a little. Right now, the only things that have been really effective have been these thrombopoietin agonists Promacta, or eltrombopag, and Nplate.

This came on the heels of a study that we did and was done 4 years earlier but took a long time to finish. That was a phase 1 study of another JAK inhibitor called itacitinib. This JAK1 inhibitor showed very similar results in the treatment of steroid-refractory graft-vs-host disease. So it is conceivable that the balanced JAK1/JAK2 inhibitor of ruxolitinib might not be absolutely necessary and that we know also that if you block, in a mouse model, JAK1, you don’t signal through the gamma interferon receptor. If you knock out JAK2, you don’t signal through the gamma interferon receptor. So you need both. And if you’re missing 1 of them, then you can’t signal through the gamma interferon receptor. It’s conceivable that even though ruxolitinib is a balanced JAK1/JAK2 inhibitor, you may need only to inhibit 1 of those two JAK kinases to get the same results. There’s no evidence right now that ruxolitinib is clearly better than itacitinib. But I can say that both are active in this setting, and a randomized study between the 2 would need to be done to determine which is better. But I suspect that will never be done.

Transcript edited for clarity.