Low-dose interleukin-2 (IL-2) therapy for chronic graft-versus-host disease (cGVHD) generates a rapid rise in plasma IL-2 levels and CD4⁺CD25⁺CD127^-Foxp3⁺ regulatory T-cell (CD4Treg) proliferation, but both decrease over time despite continued daily administration. To test whether IL-2 dose escalation at the time of anticipated falls in plasma levels could circumvent tachyphylaxis and enhance CD4Treg expansion, we conducted a phase 1 trial in 10 adult and 11 pediatric patients with steroid-refractory cGVHD (www.clinicaltrials.gov: NCT02318082). Daily IL-2 was initiated in children and adults (0.33 × 10⁶ and 0.67 × 10⁶ IU/m² per day, respectively). Dose escalations were scheduled at weeks 2 and 4 to a maximum dose of 1 × 10⁶ IU/m² per day in children and 2 × 10⁶ IU/m² per day in adults. Patients continued at their maximum tolerated dose (MTD) until week 8. Children tolerated IL-2 dose escalation with partial responses (PRs) in 9 of 11 patients (82%) at multiple cGVHD sites, including lung. Patient-reported outcome scores for skin and lung improved significantly in pediatric patients. In contrast, 5 of 10 adults required dose reduction, and only 2 of 7 evaluable patients (29%) had PRs at week 8. CD4Tregs and natural killer cells expanded in both cohorts without significant changes in conventional CD4⁺ T cells (Tcons) or CD8⁺ T cells. Children achieved a higher median CD4Treg/Tcon ratio at week 8 (0.4 vs 0.18, P = .02) despite lower IL-2 doses. We show for the first time that low-dose IL-2 is safe and effective in children with advanced cGVHD. In adults, escalation above the previously defined MTD did not improve CD4Treg expansion or clinical response.

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