New options to treat steroid-refractory chronic GvHD

Chronic graft-versus-host disease (GvHD) is the most common long-term adversity after allogeneic haematopoietic cell transplantation (HCT). Although clinicians are still struggling with steroid-refractory chronic GvHD, novel agents have delivered promising efficacy results in recent years. Prof. Mohamad Mohty (Sorbonne University, France) discussed the emerging options to treat patients with chronic GvHD in whom systemic therapy had failed.

“The number of patients experiencing chronic GvHD has not dropped in recent years,” said Prof. Mohty [1]. “The increased use of peripheral blood stem cells, the treatment of older patients, and the fact that we are treating more advanced disease are all risk factors for increasing the incidence of chronic GvHD [2]. The outcomes in patients with steroid-refractory GvDH are abysmal.” Prof. Mohty added that steroid-refractoriness as well as steroid dependence and steroid intolerance are serious problems for patients [1,3].

Fortunately, there is a wide variety of upcoming drug candidates to treat chronic GvHD. “The use of corticosteroids has been declining, and novel agents are being administered more frequently,” clarified Prof. Mohty [1,4]. “I would like to highlight some of the relevant trials,” he continued. A study by Flowers et al. demonstrated that extracorporeal photopheresis (ECP) plus conventional therapy was associated with an increased cumulative incidence of complete response/partial response in skin compared with conventional therapy alone in patients with steroid-refractory or steroid-dependent chronic GvHD [5]. The most obvious responses were observed in cutaneous and mucosal manifestations.

“However, the largest improvements in the field of chronic GvHD have been made in the last 5 years, with the [FDA] approval of ibrutinib, belumosudil, and ruxolitinib,” emphasised Prof. Mohty. In a phase 2 trial (n=42), ibrutinib displayed an overall response rate of 67% and a complete response rate of 21% in adult patients with chronic GvDH who failed 1 or more lines of systemic therapy [6]. In addition, 24% of the patients had a clinically meaningful improvement on the Lee chronic GvHD Symptom Scale, and 71% of the responders demonstrated a sustained response of ≥20 weeks.

Also in a phase 2 trial, belumosudil showed an overall response rate of 76% in patients ≥12 years of age with chronic GvHD who had failed at least 2 prior lines of systemic therapy [7]. The complete response rate was relatively low, at 5%. “On the other hand, the responses were relatively quick, with a median time to first response of 1.8 months,” said Prof. Mohty. Moreover, this agent displayed efficacy across all organ systems. “Finally, this drug appears to be relatively safe,” mentioned Prof. Mohty.

In a phase 3 trial, ruxolitinib demonstrated an overall response rate of 76% in patients ≥12 years of age with chronic GvHD who had failed one or 2 lines of systemic therapy [8]. This was significantly better than the ‘best-available-therapy’ control arm. Furthermore, the failure-free survival was increased in patients on ruxolitinib compared with those receiving the best available therapy (not reached vs 5.7 months; HR 0.37; P<0.0001), and a significant improvement was seen on the Lee chronic GVHD Symptom Scale in patients who were treated with ruxolitinib. “Safety issues that are commonly seen with JAK inhibitors, such as cytopaenias and infections were quite manageable in this trial,” added Prof. Mohty.

“Beyond ibrutinib, ruxolitinib, and belumosudil, there are many other agents, such as low-dose IL-2, mTOR inhibitors, low-dose methotrexate, mycophenolate mofetil, and rituximab may be of use in these patients as well,” Prof. Mohty said. “Although there is still much work to be done, based on the new drugs that have become available for our patients with steroid-refractory chronic GvHD, I am optimistic,” concluded Prof. Mohty.

1. Mohty M. Treatment and unmet needs in steroid-refractory chronic GVHD. E08-03, European Society for Blood and Marrow Transplantation (EBMT) 49^th Annual Meeting, 23–26 April 2023, Paris, France.
2. Im A, et al. Biol Blood Marrow Transplant. 2020;26:1459–1468.
3. Schoemans HM, et al. Bone Marrow Transplant. 2018;53:1401–1415.
4. Wolff D, et al. Biol Blood Marrow Transplant. 2019;25(7):1450–1455.
5. Flowers MED, et al. Blood. 2008;112(7):2667–2674.
6. Miklos D, et al. Blood. 2017;130:2243–2250.
7. Cutler CS, et al. Blood. 2021;138(22):2278–2289.
8. Zeiser R, et al. N Engl J Med 2021;385:228–238.

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Posted on 15 June, 202327 March, 2024