Despite the US Food and Drug Administration (FDA) approvals of new drugs for both acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD), first-line therapy with corticosteroids remains the standard of care. Tapering corticosteroid therapy presents a unique set of challenges, especially in cGVHD, and requires a careful balance between preventing flares and minimizing adverse effects.

Over the last few years, new drugs have been approved by the FDA for both aGVHD and cGVHD; nevertheless, the standard upfront treatment is still corticosteroids. Although corticosteroids are effective, we recognize their limitations and complications, and there has been a major push to try to change the standard of care to move away from steroids or utilize other drugs that may result in a more rapid taper of steroids. Instead of giving steroids to every patient with aGVHD, the field is trying to go in the direction of giving very high-risk patients steroids in addition to other therapies and treating low-risk patients with steroid alternatives.

A study using the Minnesota aGVHD risk score found that patients with standard-risk aGVHD had a 28-day overall response rate to upfront steroids of 69% compared with 43% in the high-risk group. Unfortunately, overall 6-month transplant-related mortality rates were 22% and 44% in patients with standard- and high-risk aGVHD, respectively. So, there is a lot of work to be done in terms of trying to change the mortality rate, with a focus on better prevention, upfront treatment, and drugs. An ongoing phase 3 trial conducted by the Bone and Marrow Transplant Clinical Trials Network (BMT CTN 1705) is evaluating steroids with or without alpha-1 antitrypsin in patients with high-risk aGVHD, and we are looking forward to seeing if that will change the standard of care.

In patients with aGVHD, the first thing you want to do is control symptoms, and, once they are controlled, that is when we start discussing steroid tapering. In general, the goal is to taper the steroids as quickly as possible without the GVHD coming back, as the long-term consequences of chronic steroid use, such as infections, are problematic. Patients are generally okay with that plan because they also realize the potential for side effects.

Steroid tapering in cGVHD is a bit more problematic because this is a chronic process, and most of the underlying tissue damage is not going to reverse quickly. Unfortunately, this means that patients with cGVHD end up being on steroids chronically, and it is not unusual for them to take steroids for 1 to 2 years, or even longer.

Things have changed quite a bit in the last few years with the FDA approvals of ibrutinib, belumosudil, ruxolitinib, and, just recently, axatilimab. Because these drugs are approved, I think that physicians are intervening much sooner and adding other agents rather than waiting 6 to 8 weeks before recognizing that the steroids are not working well enough. Adding drugs relatively early in the course seems to benefit some patients, but we need randomized trials to prove it. We would like to see more studies in the upfront setting combining steroids with other drugs, although we have been burned before with this approach.