Usama Gergis, MD

Usama Gergis, MD, MBA Professor of Oncology Director, Bone Marrow Transplant and Immune Cellular Therapy Sidney Kimmel Cancer Center Thomas Jefferson University Hospital Philadelphia, PA, reviewed that difference in acute and chronic graft-versus-host disease (GVHD) and the treatment available for each.

: How would you treat a patient with GvHD in the second line?

: If you [have a patient with] second-line acute GVHD, your answer should be ruxolitinib [Jakafi] because it’s the only drug that has been tried in phase 3 trials. If you get a [case of] chronic GVHD, your answer should be ibrutinib [Imbruvica].

What is the efficacy of peripheral blood stem cells (PBSC) versus bone marrow from unrelated donors in patients with acute and chronic GvHD?

[Results from] a phase 3 study of bone marrow versus stem cells for unrelated donors [showed] the acute GVHD population [cumulative incidence] was the same between both.

 For the chronic population, the bone marrow did better [PBSC 53% vs bone marrow 41%; P = .01]. This was published almost 8 years ago, [and it] was reported almost 10 years ago, but we still use stem cells.

This has not changed practices, and the reasons are, number 1, there was more primary graft failure on the bone marrow than the PBSC, and number 2, it’s pretty involved to do bone marrow harvest, although I have done it for 15 years, at least a few every month.

The benefit of bone marrow versus PBSC—and this benefit was only studied in unrelated donors, not in matched related donors—was seen across all organs affected with chronic GVHD except lungs, [gut, and serosa].

 So, there was no real benefit in the lungs.

Can you explain the difference between acute and chronic GvHD?

Chronic GVHD is more complicated and involved than acute GVHD. In acute, you have the skin, gastrointestinal organs, and the liver [that may be affected]. That’s it. In chronic, all the patient’s other organs can be affected. The patient’s weight can be affected. [Chronic GVHD is] more debilitating over a long time and [can] go unrecognized for a while. [If a patient is] experiencing acute GVHD, you see them twice a week, whereas if the patient has chronic GVHD, you probably see them once a month. So you can see a very stark change in your patients within that month if they lose 10% of their body weight and they already lost a lot of weight in the period right after [transplantation], so that can be obvious to you.

[In my institution], we have the GVHD clinic where we [grade the patient based on] studying the degree of fibrosis, how many organs are affected, the patient’s range of motion, and the degrees in range of motion. We do frequent pulmonary function tests and various [other] testing. By looking at all the affected organs, you reach a grade, and that can be mild, moderate, or severe [chronic GVHD].

How do you treat moderate-to-severe chronic GVHD at initial presentation and in the second line?

First-line treatment for chronic GVHD are steroids. For second line, there are many agents [to consider]. I’ve tried most of them. I like photopheresis because it’s not pharmacological, but it’s pretty involved. Your patient will need a permanent catheter, and they will need to come to the transplant center twice a week, and you see a response after a long time. It takes an average of 50 photopheresis sessions for a response. But the beauty of photopheresis [is that] you could try it with other agents, so it’s not mutually exclusive. You could use it with ruxolitinib, ibrutinib, or any other agents.

The answer will be ibrutinib [for chronic GVHD], and that’s based on the [results of a] phase 2 clinical trial that treated 42 patients with steroid-refractory chronic GVHD, and the efficacy was 69% [best overall response rate], and 31% complete response rate.

Everybody agrees on giving ibrutinib. When I gave this talk a couple months ago, lenalidomide [Revlimid] was not included in the poll. I added it because [recently], a nice study in Blood came out from the National Institutes of Health where they tried lenalidomide at a small dose, 2 mg, in steroid-refractory chronic GVHD. It’s a large trial; I think it’s about 100 patients. They’ve seen responses that are comparable with ibrutinib....I treated a patient for multiple myeloma; he received a transplant for multiple myeloma, and now, 6 months later, he has chronic GVHD and some clonal plasma cells. So for him, I was comforted to know the results of the lenalidomide trial.

How does ruxolitinib play a role in this setting?

Ruxolitinib was reported in the REACH3 trial [NCT03112603] with very good responses in chronic GVHD.

 I think it probably will get approved for that indication. Looking at this study about 2 years ago, nothing was studied well in this indication, and ibrutinib was approved.

REACH3 was a large trial, almost 300 patients, and everybody was randomized to ruxolitinib 10 mg twice a day versus best available treatment. They looked at everybody about 6 months later for response.

What should physicians keep in mind when treating?

Chronic GvHD is pretty involved. Your patients will need a multidisciplinary approach. You need to pay attention to their bones. In the first 100 days post transplant, the average bone aging is 17 years.

So although we’re trying to treat acute GVHD, viruses, and prevent relapses, [by putting] your patients on some steroids, you are aging your patients’ bones by 17 years only in the first 100 days. No matter what you do, give your patients vitamin D, calcium, and Fosamax [alendronate sodium].

1. Anasetti C, Logan BR, Lee SJ, et al. Peripheral-blood stem cells versus bone marrow from unrelated donors. N Engl J Med. 2012;367(16):1487-1496. doi:10.1056/NEJMoa1203517 

2. Flowers ME, Martin PJ. How we treat chronic graft-versus-host disease. 

d. 2015;125(4):606-615. doi:10.1182/blood-2014-08-551994

3. Waller EK, Miklos D, Cutler C, et al. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy: 1-year update of a phase 1b/2 study. 

. 2019;25(10):2002-2007. doi:10.1016/j.bbmt.2019.06.023

4. Zeiser R, Polverelli N, Ram R, et al. Ruxolitinib (RUX) vs best available therapy (BAT) in patients with steroid-refractory/steroid-dependent chronic graft-vs-host disease (cGVHD): primary findings from the phase 3, randomized REACH3 study.

. 2020;136(suppl 1):22-24. doi:10.1182/blood-2020-137694



Articles

Usama Gergis, MD, MBA, reviewed that difference in acute and chronic graft-versus-host disease and the treatment available for each

Gergis Explains the Differences Between Acute and Chronic GVHD

A 61-Year-Old Man With Graft-Versus-Host Disease

Steroid-Dependent Versus Steroid-Refractory Graft-Versus-Host Disease

Phase 2 REACH1 Overview

REACH1 Regimen: Steroid Combination and Adverse Events

Phase 3 Trials: REACH2 and GRAVITAS-301

The Future of GVHD Management

A 61-year old man presented with a generalized pruritic rash, abdominal pain and diarrhea (8-12 BMs/day)

PMH: he underwent haploidentical allogeneic hematopoietic-cell transplantation for AML 40 days ago

PE: maculopapular erythematous rash on bilateral palms, cheeks, ears and upper back (rash involvement >50% of skin); abdomen is tender to palpation diffusely



Labs: ANC 0.7 x 109/L, plt 75 x 109/L, total bilirubin 8 mg/dl, AST 54 U/L, ALT 60 U/L

Lower GI biopsy showed moderate mixed inflammation in the lamina propria and scattered apoptotic bodies without crypt loss

Skin punch biopsy of the back shows hyperkeratosis, hypergranulosis associated with lichenoid inflammatory infiltrate

Modified Glucksberg criteria: grade 3; MAGIC criteria: grade III



Systemic corticosteroids (prednisone 2 mg/kg/day) + topical steroids (triamcinolone)

He was started on ruxolitinib 5 mg PO BID, increased to 10 mg PO BID on day 6

Videos

Usama Gergis, MD, presents the case of a 61-year old man with GvHD, and provides an overview of available treatment options for similar patients, with consideration of the REACH1, REACH2, and GRAVITAS-301 trial regimens. 

A 61-Year-Old Man With Acute Graft-Versus-Host Disease

Just to summarize, graft-versus-host disease [GVHD] is 1 of the most common adverse events after allogeneic transplant. The acute disease state takes place earlier, the first 100 days or so, after transplant. Chronic disease takes place later. Acute disease is acute inflammatory T-cell driven. Chronic is more of an autoimmune fibrotic phenomena. Acute disease affects approximately 40% to 80% of patients. Chronic disease affects approximately 40% to 50% to 60% of patients. Many variables affect the incidence of acute graft-versus-host disease, such as the severity and other prognostic indicators.

The treatment for both—the first-line treatment is usually corticosteroids. For patients with acute graft-versus-host disease, most of the time, the initial dose is 2 mg/kg prednisone or the equivalent. It’s easy to know earlier whether patients will respond—50% generally will respond, 58% will not respond or respond but become dependent on the steroids. The second-line treatment and the only FDA-approved second-line treatment for steroid-refractory acute graft-versus-host disease is ruxolitinib. And, again, the response rate is approximately 50%.

You can tell from my summary I’m semi-optimistic. In the past 50 years or so since the inception of allografting, there was nothing better to add to glucocorticosteroids. Now that we have ruxolitinib as an approved agent that was confirmed in a state-of-the-art phase 3 trial, there is a lot of excitement for our community but we want more. We still have 50% of patients who will not respond. We still have people who respond initially and then they fully erupt and they lose that response. Even for the responders, the intense immune suppression leads to increased mortality—50% treatment-related mortality at 6 months, 60% treatment-related mortality at 1 year. So, the picture is not so good. I am shy of saying dismal. We have nothing better than steroids at this point to treat chronic graft-versus-host disease. But there are a lot of other agents in the pipelines. We are running a multitude of trials in various treatment modalities, so I am optimistic that soon enough we will have a couple of other agents for these 2 very difficult-to-treat diseases.

Let me comment on 2 very interesting trials with recently reported results. The REACH2 trial is a multicenter, phase 3 trial in patients with steroid-refractory acute graft-versus-host disease [GVHD] comparing ruxolitinib plus steroids versus best available treatment and steroids. Just like REACH1, the primary end point is overall response rate at day 28. The results of this very important trial were recently announced, and the trial reached the primary end point of overall response rate at day 28.

A paradox to this is the GRAVITAS-301 trial, which compared itacitinib, a JAK1 inhibitor in patients with chronic graft-versus-host disease versus placebo. The patients had chronic GVHD and were receiving itacitinib plus steroids versus placebo plus steroids, and there were no statistically significant responses. Let me take that back. There were no statistically significant differences in resolution of chronic graft-versus-host disease between the 2 arms or survival data. REACH2 is for [patients with] acute steroid-refractory [disease], and GRAVITAS-301 is for chronic GVHD. REACH2 is a blockbuster. GRAVITAS-301 is a bust.

Classically, we use steroids as a first-line treatment for acute graft-versus-host disease [GVHD]. About 50% of the time, you will get a response, and then you work through tapering down your steroids—as I said earlier, as fast as you can, but then you’ll be faced with flare-ups of acute GVHD. And in the 50% of patients who either do not respond to steroids or—as we defined earlier—they become steroid-refractory or -dependent, we use ruxolitinib [RUX]. At first, we use both, and as we see responses, personally, and most surgeons who perform transplantations will share this view with me, we start to taper down the steroids. If there’s no response after using steroids, you add the ruxolitinib. They overlap and then you start to taper down the steroids and stay with the ruxolitinib unless there are adverse effects to ruxolitinib, intolerance or other problems, then we start to taper the ruxolitinib first.

There are a multitude of adverse events, and now we have 3 variables. You have acute graft-versus-host disease, you have high-dose corticosteroids, and you have ruxolitinib. As most patients will have some sort of adverse events, either from the disease, the steroids, or the RUX, the most common adverse events are infections. These patients have intense immunosuppression from the GVHD, from the steroids, and from the ruxolitinib. A small percentage of patients in the REACH1 trial had to discontinue ruxolitinib, and the most prominent cause was infections. We just manage the adverse events as they come, such as diabetes and hypertension, for example. I personally push for physical therapy and occupational therapy.

As far as ruxolitinib, the most common initial reaction is myelosuppression. So, in the first couple of weeks, you might see a decrease in hemoglobin, platelets, and ANC [absolute neutrophil count]. The good news is this does not stay for a long time, so most people will have a little dip and then they go back up and they plateau. So, if that decrease is severe for whatever reason, I personally support these patients with growth factors or transfusion. Invariably, in most of these patients, unless they have other causes, their blood counts will go back up and then they plateau. The problem is that there are many factors. Graft-versus-host disease decreases; it’s a myelosuppressive condition. With intense immune suppression, people might reactivate their CMV [cytomegalovirus], other infections, particularly fungal infections, and in a significant number of patients, relapse of the primary disease. This is as complex as medicine can get.

In this case, we have a patient with corticosteroid-refractory acute graft-versus-host disease [GVHD] who was not responding to the first-line treatment of prednisone 2 mg/kg, or the equivalent. There are many treatment options. This patient’s case is more complicated because he has 3-fold involvement. Historically, photopheresis works well for skin graft-versus-host disease. If the patient only had skin graft-versus-host disease, I would probably start him on photopheresis. Liver and GI [gastrointestinal] disease can be more resistant to this. So, the best option for him at this point would be ruxolitinib [RUX] and he was appropriately started on this drug.

The REACH1 trial was the phase 2 multicenter trial that led to the approval of ruxolitinib in patients with corticosteroid-refractory acute graft-versus-host disease. Whenever I say 

. As I said earlier, the prognosis, the treatment, and survival is the same. The trial was a phase 2 multicenter trial with inclusion criteria of patients with steroid-refractory or steroid-dependent acute graft-versus-host disease. This trial studying graft-versus-host disease enrolled 71 patients who were followed for adverse effects. However, only 49 patients were followed for efficacy, as about 22 did not qualify for the efficacy follow-up. These patients either had other lines of therapy not including steroids before starting the ruxolitinib or they were not optimized on steroid treatment. The primary end point of the trial was an overall response rate at day 28. Other end points included similar trials, duration of response, degree of response, SAEs [serious adverse events], and others.

Ruxolitinib was studied in patients with acute graft-versus-host disease because ruxolitinib is a JAK/STAT pathway inhibitor. The JAK/STAT signaling pathways help to regulate the development of proliferation in immune types important for graft-versus-host disease. So, the signaling of proinflammatory cytokines, the activation of cytotoxic T cells, the separation of regulatory T cells—all these mechanisms are JAK/STAT dependent. If you block this very important acute GVHD pathway, you probably can help with acute GVHD. And that’s basically the background of using RUX in this arena.