Madan Jagasia, MBBS, MS, MMHC, discusses the current treatment landscape and next steps in graft-versus-host-disease.
Madan Jagasia, MD, MBBS, chief medical officer, Translational Research and Interventional Oncology Research Program, George and Beverly Rawlings Directorship, professor of medicine, Vanderbilt-Ingram Cancer Center
Madan Jagasia, MD, MBBS
Though treatment options for patients with graft-versus-host-disease (GVHD) are available, there is a need to explore more effective therapies in clinical trials, especially for those who have steroid-refractory disease and progress on ruxolitinib (Jakafi), explained Madan Jagasia, MBBS, MS, MMHC.
"The take-home message is to keep up to date with the literature, use a drug based on its indications, and keep a portfolio of open trials at your institute. Additionally, if a patient cannot go on an FDA-approved product, try to enroll them in a clinical trial—that is the only way we are going to move the field forward," said Jagasia.
The BTK inhibitor ibrutinib (Imbruvica) is one available option for patients with chronic GVHD following failure of ≥1 line of systemic therapy. The August 2017 approval of ibrutinib for this indication was based on data from the single-arm phase Ib/II PCYC-1129 trial, in which ibrutinib elicited an overall response rate of 67% (95% CI, 51-80) in this patient population.1
In acute GVHD, the FDA approved ruxolitinib in May 2019 for adult and pediatric patients ≥12 years old who have steroid-refractory acute GVHD, based on findings from the phase II REACH1 trial, in which ruxolitinib plus corticosteroids demonstrated a 57% ORR at day 28, with a 31% complete response rate.2
Ongoing studies are poised to determine additional treatment strategies in the future. For example, the REACH3 trial (NCT03112603) is designed to determine the efficacy of ruxolitinib against best available therapy in patients with steroid-refractory chronic GVHD.
Additionally, the ROCK2 inhibitor KD025 was granted a breakthrough therapy designation by the FDA in October 2018 for the treatment of adults with chronic GVHD after failure of ≥2 lines of systemic therapy.3 Findings from the phase II ROCKstar trial supported the designation; updated data showed that the agent elicited responses in two-thirds of patients with chronic GVHD, including complete responses in 3 patients.
In an interview with OncLive during the 2020 Transplantation & Cellular Therapy Meetings, Jagasia, chief medical officer, Translational Research and Interventional Oncology Research Program, George and Beverly Rawlings Directorship, professor of medicine, Vanderbilt-Ingram Cancer Center, discussed the current treatment landscape and next steps in GVHD.
OncLive: Could you discuss the prognosis of GVHD?
Jagasia: GVHD is an immune complication from donor T-cells and donor B-cells after allogeneic stem cell transplant. We currently divide GVHD into 2 groups: acute GVHD and chronic GVHD. We tend to see acute GVHD early-on after transplant, and chronic GVHD typically starts 2 to 3 months posttransplant and has heterogeneous manifestations.
If you look at it from a patient's lens, there are 2 major limitations of successful transplantation. One is GVHD and the other is a relapse of the underlying disease. We [are working to] improve the outcomes of GVHD and transplantation, whether it is through prevention or [more effective treatments].
What are the available treatment options for patients with GVHD?
In acute GVHD, frontline therapy is still based on corticosteroids. However, the field is changing. Now, we [are looking to collect] more accurate data based on biomarkers as to which patients will be at risk. [We are hoping to identify] a subset of patients and then augment therapy to add other agents in addition to corticosteroids.
On the other hand, we need to think about patients with low-risk acute GVHD. [This leads us to] ask the question, "Can we de-escalate therapy so that we do not expose them to the adverse events of corticosteroids?" If a patient fails corticosteroids, also known as steroid-refractory acute GVHD, we now have ruxolitinib in that space, which has been FDA approved.
The unmet need today is 2-fold. First, can we de-escalate therapy in low-risk patients? Second, what do we do when a patient has steroid-refractory acute GVHD and has failed ruxolitinib? That is still a large group of patients for whom we do not have any viable options.
Moving onto chronic GVHD, frontline therapy is calcineurin inhibitors and corticosteroids. We know corticosteroids work, but when you look at patients 1 year down the road, many of them are still on corticosteroids and have moved onto a subsequent line of therapy. Frontline therapy of more severe chronic GVHD is also an unmet need.
In terms of advanced chronic GVHD, ibrutinib is approved by the FDA, and KD025 appears very promising. There are also other advances that are emerging in this field.
What are the key toxicity challenges with the available treatments?
Ruxolitinib is a JAK1/2 inhibitor that is effective in steroid-refractory acute GVHD, but it comes with a price. The immune system is suppressed, and the concern is that we will be exposing the patient to more infections. Data will be coming out in the form of a manuscript, in which we have tried to address this in a more granular manner.
It appears that ruxolitinib works and patients respond [to therapy] and the risk of infection decreases. Patients who are non-responder to ruxolitinib are [at high risks of] infection. That is the group that we need to focus on to see how we can improve the outcomes of these patients.
Again, patients who respond to ruxolitinib with current anti-infection strategies are not going to be at high-risk. Another thing to keep in mind is that ruxolitinib is approved for steroid-refractory disease, so I would advise physicians to start the next line of therapy in the form of ruxolitinib as soon as a patient becomes steroid-refractory. Do not wait too long, and do not expose the patient to unnecessary steroids because they generate the milieu of ongoing infections.
What clinical trials are looking at ruxolitinib as a treatment for chronic GVHD?
The most important study that is pending a data analysis is the REACH3 study. Retrospective data appear to show that ruxolitinib is going to be effective [in patients with steroid-refractory chronic GVHD], but we need to see what the phase III data look like and if it is truly superior to the best available therapy. If it is a positive study, it will be a huge step forward for our patients.