Individual Patient Dose-Escalated Low-Dose Interleukin-2 for Steroid-Refractory Chronic Graft-Vs.-Host Disease in Children and Adults: Safety, Efficacy and Immune Correlates

Daily low-dose interleukin-2 (IL-2) at a fixed dose of 1 × 106 IU/m2/day leads to preferential expansion of CD4+CD25+CD127-Foxp3+ regulatory T cells (Treg) and clinical responses in 50-60% of adult patients with steroid-refractory chronic GVHD. During fixed-dose IL-2 therapy, plasma IL-2 levels rise rapidly, but decrease over time despite continued daily administration. Lower IL-2 levels correlate with decreased Treg proliferation, possibly due to IL-2 sequestration via binding to high-affinity IL-2 receptors on Treg. We reasoned that IL-2 dose escalation at the time of anticipated fall in plasma IL-2 levels would avoid tachyphylaxis and enhance Treg expansion. We conducted a phase 1 trial of individual patient IL-2 dose escalation over 8 weeks in adult and pediatric patients with steroid-refractory cGVHD. Daily SC IL-2 was initiated at 0.67 × 106 and 0.33 × 106 IU/m2/day in the adult and pediatric cohorts, respectively. Each participant had dose escalations at weeks 2 and 4 to a maximum dose of 2 × 106 IU/m2/day in adults and 1 × 106 IU/m2/day in children. We studied 21 participants (10 adult, 11 children) with median ages of 57 (range, 33-71) and 12 years (range, 3-22) in the adult and pediatric cohorts, respectively. The cohorts did not differ in terms of time since cGVHD onset, number of organ sites involved or failed therapies prior to enrollment. Individually dose-escalated IL-2 was well tolerated in children with 1 patient requiring dose reduction for electrolyte imbalances. In the adult cohort, 1 patient withdrew for cGVHD progression, 4 required dose reduction for injection site reactions and 2 were unevaluable. At week 8, objective cGVHD responses (PR) were seen in 8 of 11 pediatric patients (73%), but in only 1 of 8 evaluable adult patients (13%). Response sites included skin (n=4), joint/fascia/muscle (n=1), lung (n=5), and GI tract (n=2). 11 pediatric and 4 adult participants with clinical benefit (PR or SD with minor response) continued extended duration IL-2 therapy. 9 pediatric patients on IL-2 therapy were able to wean steroid therapy with a median dose reduction of 67% at 6 months (Fig. 1). Children had a superior immunologic response despite lower IL-2 doses. The median Treg:Tcon ratio at week 8 was significantly higher in the pediatric cohort (0.42 vs 0.21, p = 0.02). Both cohorts had increased NK cell numbers, with no significant changes in CD4Tcon, CD8 T cell or B cells (Fig. 2). Pediatric patients had greater thymic output of naive Treg as well as a larger fraction of PD-1-expressing effector memory Treg at baseline and during IL-2 therapy (Fig. 3), which has been correlated with improved Treg expansion and survival. We show for the first time that low-dose IL-2 is safe in children with advanced steroid-refractory cGVHD and results in a high clinical response rate. In adults, dose escalation above fixed-dose MTD did not improve Treg expansion or clinical response relative to fixed daily dosing.