Feasibility, Safety, Efficacy And Immunologic Impact Of Daily Ultra-Low-Dose Interleukin-2 For Steroid-Refractory Chronic Graft-Versus-Host Disease: A Phase I Study

Regulatory T cells (Treg) are deficient in chronic graft-versus-host-disease (cGVHD). Interleukin-2 (IL-2) is critical in Treg development, expansion and activity. We hypothesized daily subcutaneous (SC) ultra-low-dose IL-2 (8 weeks on, 4 weeks off) may expand Tregs in steroid-refractory cGVHD. We report phase-I IL-2 outcomes at dose-levels: A) 0.3×10^6 IU/m2 and B) 1×10^6 IU/m2. Dose-level-C accrual is ongoing. Concurrent immunosuppression was allowed. 11 patients accrued; 7 and 4 at dose-levels-A and -B. Median age was 44 years (30-57). Median time from HSCT and cGVHD was 1021 (420-4714) and 784 (117-2233) days. cGVHD sites were skin (11 pts), mouth (6 pts), eyes (4 pts), liver (3 pts), lung (2 pts), esophagus (1 pt). Patients had a median of 3 (range, 1-3) concurrent immunosuppressives: steroids (11 pts), sirolimus (5 pts), MMF (5 pts), tacrolimus (4 pts). Discontinued prior therapies were rituximab (6 pts), ECP (4 pts), MMF (2 pts), sirolimus (2 pts), cyclosporine (1 pt), thalidomide (1 pt), denileukin-diftitox (1 pt), alemtuzumab (1 pt). No dose-limiting toxicity (DLT) GVHD flare occurred. One patient (lvl-A) had CTC grade-4 hemolytic-uremic-syndrome after Hemophilus-B bacteremia at 5 weeks of IL-2 (and prednisone, tacrolimus, sirolimus), reported as a DLT. No other DLT occurred. Another patient (lvl-A) had CTC grade-4 MRSA pneumonia at 8 weeks, unrelated to IL-2 (on prednisone, sirolimus, MMF; also had MRSA pneumonia pre-IL-2). No other significant infection was documented. One patient (lvl-B) discontinued IL-2 at 4 days for CTC grade-1 fatigue. Of 9 evaluable patients, 5 had a partial response, 1 had a mixed response, and 3 had stable disease. Responses were scored in skin and liver (mouth, eye received topical therapy). 4 of 5 responders chose extended IL-2 (range, 1.5-15 months) given clinical benefit. The 5th, with resolving liver cGVHD, had IL-2 withheld for MRSA pneumonia. He died of progressive liver cGVHD off IL-2. IL-2 induced a 3-5-fold increase in CD4+CD25+CD127- Tregs (Table). At 1, 2, 4, 6 and 8 weeks, IL-2 increased Treg significantly over baseline (median difference=17, 36, 60, 62, 59; p=0.03, 0.04, 0.06, 0.05, 0.03, respectively). Similar changes were not seen in NK, NK-T, or conventional T-cells. We identify feasibility, safety, and efficacy of IL-2 in refractory cGVHD. Treg expansion was marked despite steroid and calcineurin-inhibitor use. Ultra-low-dose SC IL-2 is a promising strategy for cGVHD therapy and in-vivo Treg expansion.TableSummary Statistics for CD4+CD25+CD127- T-regulatory Cells: Absolute CountsWeekNMedian (range) cells/μLTregPre917.3 (1.7, 41.8)1826.3 (14.3, 97.5)21050.2 (5.7, 400.9)4787.5 (22.2, 227.0)6967.7 (7.4, 188.5)8752.5 (22.3, 235.6)12732.2 (10.6, 47.3)On IL-2: Week 1-8; Off IL-2: Week 8-12. Open table in a new tab On IL-2: Week 1-8; Off IL-2: Week 8-12.