Safah Explores Risk Factors and Poststeroid Treatment for GVHD

Case-Based Roundtable Meetings Spotlight, Case-Based Roundtable Meetings Spotlight: July 2, 2022,
Pages: 79

During a Targeted Oncology case-based roundtable event, Hana F. Safah, MD, discussed risk factors for acute graft-versus-host disease and data supporting treatment for steroid-refractory disease.

Targeted OncologyTM: What is this patient’s risk of developing acute GVHD (aGVHD)? What are other risk factors for aGVHD?

SAFAH: [For this patient, risk factors include] sex mismatch [and] the source and dosing of stem cells that are being infused. Risk factors that we look at to evaluate risk for GVHD in general can be divided into donor-recipient factors, stem cell factors, and transplant factors.

[The donor-recipient factors that increase risk of GVHD are] HLA [human leukocyte antigen] mismatch vs a matched donor, unrelated vs related donor, sex mismatching, multiparity of the donor vs nulliparity, older age of donor vs younger age. ABO blood type mismatch, CMV positivity of the donor—and I would say of the recipient too—and cytokine gene polymorphism, which outside of HLA typing also adds to the risk of GVHD, play a role in identifying patients who are at a higher risk for GVHD.

For stem cell factors, peripheral blood source has a higher risk than bone marrow source, which has more risk than cord blood source, especially when it comes to chronic GVHD. For the composition of the graft, a higher CD34 count has a higher risk than a lower one.… For transplantation factors, myeloablation can lead to more aGVHD followed by chronic GVHD compared with reduced-intensity regimens.

Are there preferences for grading or staging systems of aGVHD?

After diagnosing acute GVHD, we must do the staging and grading. From what has been reported in the clinical trials, we are still looking at ways to standardize staging and grading. It is different among different clinical trials. The one that is currently used and still considered as the standard way of staging and grading GVHD is the Glucksberg staging system. However, there [needs to be] some form of unifying that staging and grading system so that we can understand the data being presented in clinical trials and report the GVHD that we are witnessing with different treatment for data research.

Right now, MAGIC [Mount Sinai Acute GVHD International Consortium] guidelines [are] being used to improve usability of the data being collected as well as presented. [The guidelines stage] GVHD according to organ involvement. For instance, with respect to skin [BSA involvement] of less than 25%, 25% to 50%, or greater than 50%, and if there is generalized erythema, it would be stage 4.

For liver, staging is according to bilirubin; upper GI [gastrointestinal] is based on nausea, vomiting, and anorexia; and lower GI depends on the number of bowel movements and the volume of the diarrhea per day. It is stage 4 if there is severe abdominal pain with or without ileus, or bloody stools. Depending on those stages we grade the disease, and we go from grade 1 to grade 4. Usually grade 1 and grade 2A are considered low-risk, [whereas] 2B to 4 are considered high risk.1

We combine the MAGIC risk certification with the Minnesota scoring system, and we come up with what we call the acute GVHD risk stratification. So it is not only staging and grading, but also risk stratification. By allocating patients according to their risk, we can determine not only their progression but also their response to treatment, which is mainly steroids, and the expectation with respect to treatment-related mortality [TRM] as well as overall survival [OS]. It is just a combination of the scoring according to whether they have 1 organ involved and the stages, or 2-organ involvement. Whenever we have 3 organs involved, patients usually [have] high-risk disease.2

Risk stratification is usually associated with the depth of response to steroids as well as TRM. High-risk GVHD is usually associated with lower CR [complete response] to steroid therapy and high TRM when compared with standard-risk GVHD.2

What is the standard treatment approach for patients with aGVHD?

The standard first-line therapy for aGVHD now is corticosteroids, although there are studies that are looking at ways of treating with steroid-sparing therapy early on. There have been reports of success using sirolimus [Rapamune], for instance, in patients with standard-risk disease without GI involvement— maybe with skin involvement only. There are data now available showing that it could be treatment in the first-line setting.3

It doesn’t have to always involve steroids, and we can customize treatment according to the risk and the presentation. Now when we look at patients who [don’t improve with] steroids and we are looking at what else we can do for them, ruxolitinib [Jakafi] is approved for second-line therapy. The goal of treatment is to improve or stabilize, but it is very important to not just stabilize the organ involved, but also improve the limitation of long-term treatment-related toxicity, especially when we are using steroids because we know that steroids are toxic. A lot of steroid adverse effects [AEs] involved are Cushing syndrome, diabetes, cataracts, avascular necrosis, osteoporosis, and myopathy, especially with long-term treatment.

My main concern with aGVHD, especially when it starts early, is prolonged hospitalization. Improvement in the functional capacity or quality of life is very important. We need those patients to respond to treatment because their response, especially when we assess them at 6 months, will indicate which of those patients [will] be alive and doing well at not only 12 months but also at 2 years.

How do you determine whether a patient is steroid refractory or steroid dependent?

Steroid refractoriness is when there is a progression of aGVHD within 3 to 5 days of therapy when we use 2 mg/kg/day of prednisone or more, failure to improve within 5 to 7 days of treatment initiation, or incomplete response after more than 28 days of immunosuppressive treatment, including steroids.4

Steroid dependence usually occurs in 31% of the cases. It is the inability to taper prednisone below 2 mg/kg/day, or recurrence of GVHD during steroid taper. Steroid intolerance is an emergence of unacceptable toxicity due to the use of steroids, [such as] if you have a patient on steroids and the glucose is uncontrolled and you cannot use steroids anymore.4 Definitions can vary from one person to the other, but, in general, these are what we use.

What are suggested second-line therapies for steroid refractory GVHD?

The NCCN [National Comprehensive Cancer Network] guidelines don’t tell us what their preferred treatment agent is because the data are not showing that one is better than the other. First, there is no comparison, and then the effect on certain end points across studies did not vary, especially when we look at OS or response rate. However, out of those available, ruxolitinib has a category 1 recommendation. It is very important to enroll patients in clinical trials if available. But, otherwise, there are about 8 other drugs that we can use as second-line therapy according to clinical presentation or the underlying comorbidities that the patient [has].5

What data support the importance of ruxolitinib as second-line GVHD treatment?

Ruxolitinib, by inhibiting JAK1 and JAK2, inhibits STAT1 and STAT3 signaling by the dendritic cells. This inhibits the dendritic cells that function as antigen-presenting cells from the activation, differentiation, and proliferation of T cells to become Th1, Tc1, Th17, and Tc17 cells. As a result, you have decrease in inflammatory cytokines such as interferon-γ, interleukin-2, TNF-α, interleukin-17, and interleukin-22.6 So that’s the theory behind the use of JAK [Janus kinase] inhibitors in treatment of aGVHD.

In vitro studies have shown that JAK inhibitors can also affect T-cell migration, proliferation, and activation. T-cell migration can play a role in inhibiting the chemokine receptors on them, and those are very important in the early phase of GVHD, with tissue damage and T cells migrating to the organ, where most of the time they create further damage. So, thinking of that, ruxolitinib becomes an attractive treatment for steroid refractoriness. The phase 2 REACH1 trial [NCT02953678] enrolled patients with steroid-refractory aGVHD.

They treated them with 5 mg of ruxolitinib twice daily, steroids, plus or minus a calcineurin inhibitor, and evaluated patients at day 28 for the primary end point, which was overall response rate [ORR]. They then followed patients to the end of treatment and looked at OS. There were several other secondary end points, including the duration of response [DOR] and nonrelapse mortality [NRM], but also the incidence of chronic GVHD afterward, which is not to be associated with the incidence of aGVHD or the outcome of aGVHD treatment.7

The ORR at day 28 was 54.9%, and the best ORR at any time during treatment was 73.2%. ...Again, when we look at different trials it is very important to evaluate what they mean by ORR. Is it any response during the 28 days? In this study, they looked at both, so 54.9% at day 28 and 73.2% at any time. The median time to response was 7 days. Median DOR after more than 6 months' follow-up was 345 days; 49.3% deaths had causes other than malignancy relapse, most being infections. NRM at 6 months was 44.4%, and median OS for day 28 responders was not reached, which is very important, especially in patients with GVHD post transplant.8

REACH1 led to the phase 3 randomized REACH2 study [NCT02913261], where investigators randomly assigned patients again with steroid-refractory aGVHD. Patients received ruxolitinib at 10 mg twice daily with the continuation of steroids, plus or minus a calcineurin inhibitor vs the best available therapy [BAT] based on the treating physician or institution decision.

They followed all patients and at day 28 checked ORR, which again was the primary end point. They allowed patients to cross over from BAT if they had no response or worsening of their GVHD. Patients then continued the ruxolitinib, which was given at 10 mg twice daily with steroids, plus or minus a calcineurin inhibitor, and they assessed at week 24, which was approximately the end of treatment. The secondary end points looked at DOR, OS, failure-free survival, and mortality rate, as well as others. The BAT included ATG [antithymocyte globulin], ECP [extracorporeal photopheresis], methotrexate [Trexall], and basically whatever we used for patients in the past before ruxolitinib was available as second-line therapy.7

The ORR at day 28 was 62% in the ruxolitinib arm compared with 39% in the control arm with an odds ratio [OR] of 2.64 [95% CI, 1.65-4.22; P < .001 (Table9)]. The DOR at day 56 is again very important because you want to make sure that those who responded are not going to lose response. So the DOR was 40% with ruxolitinib compared with 22% with the control arm [OR, 2.38; 95% CI, 1.43-3.94; P < .001].

The ruxolitinib was still better on day 28 and day 56 compared with the control arm.9 The best response was seen in grade 2 GVHD followed by grade 3 and 4 for ruxolitinib compared with BAT. The loss of response was less with ruxolitinib compared with the control arm. At 6 months it was [approximately] 10% for ruxolitinib and [39% for the control arm], and at 12 months it was, again, close to 10% but much better than the control arm.9

The shift in organ staging from baseline to day 28 looked at the skin and lower GI. There was more improvement, or downstaging with the skin and lower GI on the ruxolitinib arm, compared with BAT. I would say for liver, lung, or upper GI, there were more similarities between the 2 arms. The median failure-free survival was 5.5 months with the ruxolitinib arm compared with 1 month with the control arm [HR, 0.46; 95% CI, 0.35-0.60].8 Remember that the patients were allowed to cross over from BAT to receive ruxolitinib.

For the safety data, which are important especially post stem-cell transplant, ruxolitinib had more thrombocytopenia, as we expected, compared with the control arm. Anemia was similar in both arms, maybe just a touch of increase in anemia for ruxolitinib. There was some increase in the risk of reactivation of CMV, at 26% for ruxolitinib compared with 21% for the control arm. However, when we look at other AEs, other than decrease in platelet count and maybe some neutropenia, the rest of them were like what was seen in the control arm.9


1. Harris AC, Young R, Devine S, et al. International, multicenter standardization of acute graft-versus-host disease clinical data collection: a report from the Mount Sinai Acute GVHD International Consortium. Biol Blood Marrow Transplant. 2016;22(1):4-10. doi:10.1016/j.bbmt.2015.09.001

2. MacMillan ML, Robin M, Harris AC, et al. A refined risk score for acute graft-versus-host disease that predicts response to initial therapy, survival, and transplant-related mortality. Biol Blood Marrow Transplant. 2015;21(4):761-767. doi:10.1016/j.bbmt.2015.01.001

3. Pidala J, Hamadani M, Dawson P, et al. Randomized multicenter trial of sirolimus vs prednisone as initial therapy for standard-risk acute GVHD: the BMT CTN 1501 trial. Blood. 2020;135(2):97-107. doi:10.1182/blood.2019003125

4. Schoemans HM, Lee SJ, Ferrara JL, et al. EBMT-NIH-CIBMTR Task Force position statement on standardized terminology & guidance for graft-versus-host disease assessment. Bone Marrow Transplant. 2018;53(11):1401-1415. doi:10.1038/s41409-018-0204-7

5. NCCN. Clinical Practice Guidelines in Oncology. Hematopoietic cell transplantation, version 1.2022. Accessed June 22, 2022.

6. Chao N. Finally, a successful randomized trial for GVHD. N Engl J Med. 2020;382(19):1853-1854. doi:10.1056/NEJMe2003331

7. Jagasia M, Zeiser R, Arbushites M, Delaite P, Gadbaw B, Bubnoff NV. Ruxolitinib for the treatment of patients with steroid-refractory GVHD: an introduction to the REACH trials. Immunotherapy. 2018;10(5):391-402. doi:10.2217/imt-2017-0156

8. Jagasia M, Perales MA, Schroeder MA, et al. Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label phase 2 trial. Blood. 2020;135(20):1739-1749. doi:10.1182/blood.2020004823

9. Zeiser R, von Bubnoff N, Butler J, et al; REACH2 Trial Group. Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease. N Engl J Med. 2020;382(19):1800-1810. doi:10.1056/NEJMoa1917635