Real-World Evidence Finds Low-Dose IL-2 Safe, Well Tolerated in Steroid-Refractory GVHD

New real-world evidence shows low-dose interleukin-2 (LD IL-2) is safe and well tolerated at different dosing regimens in pediatric patients with steroid-refractory chronic graft-versus-host disease (GVHD).

Findings were published in Blood Advances, and they also reveal LD IL-2 is effective in combination with other immunosuppressive medications.

“With broadly immunosuppressive effects, corticosteroids remain the first-line therapy for chronic GVHD; however, prolonged steroid exposure is associated with significant morbidity, and 40% to 50% of patients are steroid refractory,” the authors wrote, underscoring the need for safe and effective therapies in this patient population.

The FDA has approved 3 second-line agents for refractory chronic GVHD: ibrutinib, ruxolitinib, and belumosudil. However, “an alternative approach to refractory chronic GVHD, developed at our center over the last 15 years, is to augment the Treg [regulatory T cells] compartment using LD IL-2. Interleukin-2 is an essential cytokine for the proliferation and function of both regulatory and effector T cells,” the researchers explained.

Five clinical trials carried out at Dana-Farber found subcutaneous LD IL-2 elicited partial responses in around 50% of adults and 82% of children by week 8.

The real-world evidence presented in the current paper includes data from 15 children and young adults. This paper also marks the first real-world evidence of LD IL-2 in pediatric patients for any disease indication. The retrospective chart review included individuals who received LD IL-2 from August 2016 to July 2022 and who were not enrolled in a research trial.

“While clinical trials are well-controlled settings that allow for standardized assessment and correlative studies, they are less permissive to practical aspects of therapy such as dose adjustments, changing concomitant therapies, and intermittent disruptions of therapy,” the researchers wrote.

The median patient age at the start of LD IL-2 was 10.4 (range, 1.2-23.2) years. Patients had a median time of 234 (range, 11-542) days from chronic GVHD diagnosis. In addition, patients had a median of 2.5 (range, 1-3) active organs at LD IL-2 start and received a median of 3 (range, 1-5) prior therapies.

Analyses revealed:

• The median duration of LD IL-2 therapy was 462 (range, 8-1489) days
• Most patients received 1 × 10⁶ IU/m²/day
• There were no serious adverse effects
• The overall response rate in 13 patients who received more than 4 weeks of therapy was 85% (5 complete responses, 6 partial responses) with responses in diverse organs
• Most patients significantly weaned corticosteroids
• Treg preferentially expanded with a median peak fold increase in Treg:CD4+ conventional T-cell ratio of 2.8 (range, 2.0-19.8) by 8 weeks on therapy

Responses for liver and skin chronic GVHD were particularly notable, data showed, as most patients achieved complete response in these organs.

“Low-dose interleukin-2 is a safe and well-tolerated therapy with promising efficacy for chronic GVHD and autoimmune disease,” the researchers said. “Our study reports the first off study clinical experience using LD IL-2. We also build on our center’s unique experience using LD IL-2 in pediatric patients with refractory chronic GVHD, including patients as young as 1.2 years of age.”

Despite the positive results, the authors note it is increasingly difficult to get insurance approval for LD IL-2 because new small molecules have been approved by the FDA for second-line therapy. More research is also needed with larger patient numbers to help determine baseline predictive factors for response to IL-2 and mechanisms of clinical improvement in different organs.

“Our study thus supports the use of LD IL-2 in steroid-refractory GVHD, which has a high clinical unmet need. In addition, these data make a compelling case for further exploring the use of LD IL-2 to promote immune tolerance in pediatric patients with autoimmune disease or following solid organ transplantation,” the researchers concluded.

Reference

Wobma H, Kapadia M, Kim HT, at al. Real-world experience with low dose- IL-2 for children and young adults with refractory chronic graft-versus-host disease. Blood Adv. Published online May 26, 2023. doi:10.1182/bloodadvances.2023009729