Michael Bishop, MD

There are still massive unmet needs for patients with steroid-refractory acute graft-versus-host disease [GVHD]. Acute GVHD is still a major cause of morbidity and mortality, even though we’ve got ruxolitinib. Again, 50% of patients are either going to be steroid refractory or steroid dependent. Among those patients, the outcomes are abysmal, with a 50% mortality rate. We also see morbidity in patients who respond to corticosteroid administration. I have seen a lot of problems related to that. Thinking about ruxolitinib, what about the 25% to 30% of patients with grade 2 disease who don’t respond? What about the other 50% to 60% with grade 3 or grade 4 disease? And then what about the toxicities? Those are our challenges, and we have to get to the point where we can care for patients better.

Where do we go moving forward? There are a number of newer therapies that people are looking at to be complementary. I think when we look at ruxolitinib, we look at pathways. One is the JAK pathway. Well, there are other pathways that are involved in either tissue inflammation or T-cell activity and function. And so, I’m most excited about small molecules, which have relatively low toxicity profiles and target the pathways that we know are involved in graft-versus-host disease. There are still people going back to the same treatments I saw being used when I first starting doing allogeneic stem cell transplantation. A lot of the things have not changed in 30 years. Now people are saying, “Well, maybe we can add these newer things to the old things.” That may be correct.

Ruxolitinib is the only drug approved for steroid-refractory acute graft-versus-host disease, yet we’ve been dealing with this for nearly 50 years, and this is the first drug approved. We have a long way to go. But now that we’re homing in on the biology, I think targeting those pathways will be important. Those are the things I’m most excited about. I think that’s the future for the treatment of acute graft-versus-host disease.

I think Bruton tyrosine kinase is another pathway that is very exciting, and it is different from the JAK pathway. Some of the monoclonal antibodies are targeting specific proteins expressed on the surface of T cells that may inhibit their trafficking. People are also looking at targeting hedgehog [signaling pathway], which also plays an important role in T-cell activation. Again, this is all because we now have a deeper understanding of the biology of the disease. Those are the trials that I’m most interested in hearing about and seeing, because they’re taking on acute graft-versus-host disease from perspectives that we haven’t tested before.

I think if I had one piece of advice for community oncologists, we’re markedly better at treating patients with allogeneic stem cell transplantation. I mentioned we’ve been doing this for close to 50 years. But if you look at the last 3 decades, treatment-related mortality rates have dropped in every single decade. That’s because we have better supportive care measures. The other thing that is important to know is that there’s not an age limit. As a matter of fact, almost any patient at any age can successfully go through allogeneic stem cell transplantation. It’s more physiologic age than chronologic age.

If you look at the SEER [Surveillance, Epidemiology, and End Results program] data, older patients who go through an allogeneic transplant do better in terms of survival than patients who don’t go through a transplant. The greatest fear is, “Oh, I don’t want my patient to get graft-versus-host disease.” This is because the only time oncologists ever see transplant patients is when they are in the hospital. Guess who gets admitted to the hospital? The sick patients do. They never see those patients who are long-term survivors, who are doing great outside the hospital. But now with a better understanding of the biology, we’re able to treat better, and we’re having a significant impact on how patients are doing, particularly in regard to their quality of life. Those are the things I would want community oncologists to know about allogeneic stem cell transplantation, in general, and acute graft-versus-host disease, specifically.

Case: A 53-Year-Old Man With Steroid-Refractory Acute Graft-Versus-Host Disease

A 53-year-old man presents on day +40 for a routine follow-up visit after matched donor peripheral blood stem cell transplant. He complains of a new rash, abdominal pain and ‘countless’ loose stools every day for the last 4 days

PE: Rash noted on arms and upper trunk (~45% BSA); diarrhea was quantified to about 1100 cc/day



Labs: total bilirubin 2.6 mg/dl, AST 60 U/L, ALT 75 U/L, Hb 9.8 g/dl

Stool testing negative for bacterial/viral infection

Skin biopsy of the rash showed exocytosed lymphocytes, and dyskeratotic epidermal keratinocytes with follicular involvement

Colonoscopy with biopsy showed numerous apoptotic bodies in the crypt epithelium

Modified Glucksberg Criteria: grade II; MAGIC Criteria: grade II

Initiated methylprednisolone 1.0 mg/kg and topical steroids

There was minimal response to treatment after 2 days, dose was increased to 2.0 mg/kg/day

Continued on systemic steroids for 5 more days; rash subsided minimally

He was started on ruxolitinib 5 mg PO BID, tolerated well; increased to 10 mg PO BID at day 3

Videos

Newer therapies being explored to address treatment gaps in acute graft-versus-host disease (GVHD), and advice to community oncologists/hematologists who manage cases of GVHD and/or care for patients who receive allotransplants.

Managing Acute GVHD in Community Settings

Ruxolitinib is an interesting molecule. We know that the JAK pathway plays an important role in numbers of cells, but it also plays an important role in T cells. T cells mediate graft-versus-host disease. And so, it can lead to T-cell activation, important cytokine production, trafficking of T cells. Based on this knowledge, people had the clever idea of, “If it does all those things and T cells are mediating graft-versus-host disease, maybe we can use ruxolitinib as treatment for graft-versus-host disease.

This was first tested this in murine models, and the drug was very good at treating mice with established graft-versus-host disease. Now, that doesn’t always translate well into humans. However, there were some early studies where people did use ruxolitinib, because it’s approved for other indications, and we saw some initial preliminary responses. And then there was the REACH1 study, which demonstrated that patients with steroid-refractory disease had responses to this therapy. That’s what led to the development of the phase 3 REACH2 study.

The major adverse event that we think about with ruxolitinib is myelosuppression. It’s very important to monitor platelets and neutrophil counts during therapy. That correlates with infection, and there can be neutropenic fever. In the trial, there was an increased risk of respiratory infections. Again, if you think you’re inhibiting T cells, you have to worry about an increased risk of viral infections. There was a higher incidence of viral infections. There was an overall higher risk of infections in general, but particularly pulmonary and upper respiratory infections. There can be some mild elevations in liver enzymes and creatinine, but those are easily manageable on a relative scale. It’s really those blood counts and infections that we worry about the most.

The rationale for treating steroid-refractory acute graft-versus-host disease with ruxolitinib, a JAK inhibitor, and recommendations for monitoring and managing treatment-related adverse events.

Using Ruxolitinib to Treat Steroid-Refractory Acute GVHD

The REACH2 study, which was published in 

 by Robert Zeiser, MD, et al, was an international, multi-institutional trial of patients with steroid-refractory acute graft-versus-host disease using the criteria that I described before. Patients were randomized to receive either ruxolitinib or investigator’s choice. The FDA approval for ruxolitinib in the United States allows ruxolitinib to be started right off the bat at 10 mg twice a day. This is based upon REACH1, where they started at 5 mg twice a day, and then, if a patient was tolerating it well you could go up to 10 mg twice a day, if your blood cell counts were fine after 3 days on treatment. Again, in this study, patients got randomized to ruxolitinib, 10 mg twice a day, or the investigator’s choice. The investigator’s choice included sirolimus, extracorporeal photopheresis, mycophenolate mofetil, as well as a number of anti-inflammatory cytokines. And so, they could use any one of these as part of treatment. That was how the study was designed. The end point was response after 56 days on treatment.

What the study demonstrated very significantly is that there was significant organ improvement in grade 2, 3, and 4 disease. Then they randomized patients according to grade of their graft-versus-host disease. What is demonstrated also was it didn’t depend which organ was involved. If you looked at patients who had hepatic involvement, which we all think of as being the worst and the hardest to treat, the ruxolitinib arm was superior in terms of response in liver involvement versus the investigator’s choice arm. That was also seen for GI [gastrointestinal involvement]; it was also seen for skin. When we’re treating graft-versus-host disease, the best response is typically seen with the skin. The second best response is seen in the gut, and the worst is seen in the liver. Yet we saw a significant improvement on the ruxolitinib arm compared to the control arm in every single organ, in every single grade.

The overall response rate in grade 2 graft-versus-host disease on the ruxolitinib arm was between 70% and 75%. In grade 3 graft-versus-host disease, if I’m correct, the overall response rate on the ruxolitinib arm was about 40% to 45%. The impressive thing is that even in grade 4 graft-versus-host disease, ruxolitinib had about a 40% response rate. I think that’s impressive because, as I mentioned before, as you go to a higher grade, the response rate with conventional therapies tends to go down. Yet, response to ruxolitinib therapy was pretty similar in grade 3 and grade 4 disease. As I mentioned, in all 3 situations ruxolitinib was superior to the investigator’s choice of treatment in terms of response.

Dr Michael Bishop, of the David and Etta Jonas Center for Cellular Therapy, University of Chicago, describes the rationale for the design of the phase 3 REACH2 trial in steroid-refractory acute graft-versus-host disease and provides perspective on important takeaways from data presented.

The REACH2 Study in Steroid-Refractory Acute GVHD

In terms of considerations for treating the patient in our case presentation with steroids, I said he doesn’t have any other specific medical problems. The one thing I worry about is, what about that patient who has underlying diabetes mellitus, especially type 1 diabetes? While patients are on calcineurin inhibitors, we often uncover that they have underlying borderline type 2 diabetes. Calcineurin inhibitors inhibit insulin production and downregulate insulin receptors. Therefore, a lot of these patients have hyperglycemia.

So if you have a patient who’s already in that trouble and all of a sudden you add steroids, you know you’re in trouble. If the patient has bad hypertension, steroids will cause problems. Again, this patient had an ECOG 1 performance status, which would be a Karnofsky score of 70 to 80. The modified Glucksberg criteria are taking into consideration what the performance status is, although it has to be a pretty bad performance status to affect overall outcomes. But I’m worried about using steroids here, because it’s going to be debilitating to that individual.

And then finally and probably most importantly, does the patient have any active infections? When you start using big time steroids, you’re at increased risk for fungal infections and you’re going to suppress the patient. They’re going to be at increased risk for viral infections. All of those things play an important role when determining how much therapy and for how long, and whether I’m going to think about using alternative therapies. But my goal in almost every single patient is to get them off steroids as soon as possible.

In regard to determination of clinical response—there’s been a ton of research done on this—you want to see complete resolution in all organ involvement as an overall goal. We use the same staging system that we do for organs. Every time I see a patient in clinic who has graft-versus-host disease, we mark out what their maximum stage for each organ is and each grade. Every time we see them, we also look at what is happening with each of those organs. For example, if the patient’s BSA [body surface area] involvement was about 45%, and when I saw him it was down to 30%, that 30% still puts his condition at stage 2 disease.

I’m going to look at what their stool volume is. When the guy says, “I can’t count the number of times,” I make him maintain a strong diary. Then I know he was having stool volumes 8 to 9 times a day, and now that’s down to 5 to 6 times per day, and he is starting to get his appetite back. So for a clinical response, we want to see a downgrading in the organ system. But the other thing is we just want to see our patients doing better. If they’re able to function despite having active graft-versus-host disease, that’s an improvement, overall. However, I realize that likely can’t be sustainable for a long time.

Considerations for assessing response to steroid therapy as initial therapy for acute graft-versus-host disease and factors that impact next-line therapy, when necessary.

Michael Bishop, MD | Authors

Articles

Managing Acute GVHD in Community Settings

Using Ruxolitinib to Treat Steroid-Refractory Acute GVHD

The REACH2 Study in Steroid-Refractory Acute GVHD

Acute GVHD: Assessing Response to Steroid Therapy