The Ongoing Fight Against Acute GvHD - Episode 3
John F. DiPersio, MD, PhD: Ruxolitinib is a balanced JAK1/JAK2, Janus kinase 1 and 2, inhibitor. At high concentrations, it can also affect the activity of JAK3, which is particularly important for IL-2 signaling. These balanced JAK1/JAK2 inhibitors block both of these enzymes, which are very critical for signaling in the inflammatory setting through 2 major pathways. One is the gamma-interferon signaling pathway, and the other is the IL-6 signaling pathway.
Gamma interferon signals through JAK1 and JAK2 when it binds its ligand. Then that phosphorylates a protein called STAT1. STAT1 then dimerizes and goes to the nucleus and turns on STAT1-specific genes, which are really a number of genes involved in the acute inflammatory response. If you can block that, you probably will cause much less tissue damage and also much less inflammation. That’s the major mechanism by which JAK inhibitors work.
We showed that the second critical pathway is the IL-6 signaling pathway. There was some evidence of that being an important pathway in other clinical trials, 1 done by Geoff Hill. But at least in preclinical models, blocking both the gamma-interferon pathway and the IL-6 signaling pathway are very important in these preclinical mouse models to completely block GVHD [graft-vs-host disease]. You can do it genetically or pharmacologically. The interesting thing is that JAK1 and JAK2 are critically involved in signaling through the IL-6 pathway as well. And so ruxolitinib blocks the IL-6 signaling pathway, which doesn’t go through STAT1 but goes through a different STAT, called STAT3. That phosphorylates, dimerizes, goes to the nucleus and turns on a number of STAT3-specific genes, which are also involved in another group of overlapping inflammatory transcriptional programs in the cell, which can contribute to the inflammatory response. Blocking those 2 pathways is tantamount to reducing inflammation.
One of the other things that is very important is that for GVHD to continue, you need continued T-cell activation after they see alloantigens, and you need T cells to traffic to sites of inflammation, such as the gut or the skin or the liver. That ongoing process requires movement of T cells out of the lymph nodes into these tissues. That’s where the damage is done. That’s what the symptoms are from. That movement is dependent on certain molecules on the surface of T cells called chemokine receptors. Those chemokine receptors allow activated T cells to chemotax or traffic to sites of inflammation. It turns out that JAK1/JAK2 inhibitors like ruxolitinib block the upregulation of 1 of the chemokine receptors, which is very important in inducing the trafficking of T cells to sites of inflammation. JAK inhibitors not only tone down the inflammation that is ongoing at the sites but also block the trafficking of new T cells that are activated into these sites of inflammation.
The third thing they do is they block the production of ligands for these chemokine receptors in the tissues so that it also blocks the signal that brings T cells into the tissues by blocking the production of these ligands at the tissue level. So there’s a triple whammy of JAK inhibitors. The raging debate is even though they are effective after the fact, what’s their impact when given in a prophylactic setting?
In the case of the REACH2 study, this was a randomized study done in Europe where ruxolitinib was used for steroid-refractory and -resistant patients. I’ve given you that definition, progressive disease after 3 days of methylprednisolone, no improvement in disease after 7 days of 2 mg/kg methylprednisolone, or failure to be able to taper methylprednisolone below 1 mg/kg per day within 28 days of starting. The patients get transplanted, present with GVHD, and then are put on steroids. If there’s no improvement using those 3 criteria, then patients can be randomly assigned to receive ruxolitinib, which was given as 10 mg per day or 10 mg twice a day, or best available care. The centers had to choose their best choice for second treatment—the kinds of treatments, as you might imagine, are going to be very different at various different centers. There were lots of different standard-of-care treatments that were given.
The study showed that the complete response rates—that is, complete response rates of GVHD—were about 30% in the treatment group and 20% in the standard of care. That 10% difference was the difference for complete response. The overall response at 28 days was around 63% in the treatment group and 39% in the control group. That was the primary end point of the study.
There were multiple secondary end points of the study. By the way, that was highly statistically significant. The second is that there was an overall response at 56 days that was looked at. That’s very important too, because you don’t want to just improve things for a month and then have things fall apart after that. The overall response rate at 56 days was around 40% in the pretreatment group and 20% in the control group. That also was highly statistically significant. The 2 main end points, the primary end point and the main secondary end point, were reached in this study.
The overall survival of the 2 groups was also improved in the ruxolitinib group. That’s ultimately the most important thing. It’s 1 thing if your GVHD improves but you die at a higher rate. That’s not serving anybody’s interest. What you really want to do is reduce GVHD and also improve survival. The survivals of the patients treated with ruxolitinib were higher than the patients getting standard of care. Most important, the progression rate on treatment was only about 10% over, I think, a year in the treated group vs 3 times that high in the standard-of-care group.
That’s the other important thing. You want treatment to work. You want it to work for the first 28 days. You want it to work for the first 56 days. And you want it to work for the first year, because you don’t want people to fall off the wagon in 3, 4, 6 months and have to deal with life-threatening graft-vs-host disease.
The failure rate for those who responded was pretty good, meaning it was very low. And the failure rate in responding population that got standard of care was 3 times higher. It means that even if you respond early on, you’re going to keep that response if you got ruxolitinib. If you responded to standard of care, those responses are not going to be durable. That’s very important.
Those are the main findings of the study.
Transcript edited for clarity.