Efficacy, durability, and response predictors of low-dose interleukin-2 therapy for chronic graft-versus-host disease

Abstract

Chronic graft-versus-host disease (cGVHD) is associated with inadequate reconstitution of tolerogenic CD4(+)CD25(+)FOXP3(+) regulatory T cells (Tregs). Previous phase 1 studies identified a low daily dose of interleukin-2 (IL-2) that was well tolerated, did not exacerbate alloimmunity, augmented Treg in vivo, and was associated with improvement of active cGVHD. In the current phase 2 study, 35 adults with steroid-refractory cGVHD received daily IL-2 (1 × 10(6) IU/m(2)) for 12 weeks. Median time from transplantation and cGVHD onset was 616 days (range, 270-2145 days) and 317 days (range, 28-1880 days), respectively. Two patients withdrew and 5 required IL-2 dose reductions due to side effects. Twenty of 33 evaluable patients (61%) had clinical responses at multiple cGVHD sites (liver, skin, gastrointestinal tract, lung, joint/muscle/fascia). Three patients (9%) had progressive cGVHD. Compared with pretreatment levels, Treg and natural killer cell counts rose >fivefold (P < .001) and >fourfold (P < .001), respectively, without significant change in conventional CD4 T cells (Tcons) or CD8 T cells. The Treg:Tcon ratio rose >fivefold (P < .001). Clinical responders initiated IL-2 earlier (508 vs 917 days after transplantation, P = .005; 249 vs 461 days after cGVHD onset; P = .03). Treg:Tcon ratios ≥0.07 at baseline and ≥0.2 at week 1 also predicted clinical response (P = .003; P = .0003, respectively). After a 4-week treatment hiatus, clinical responders were eligible to continue IL-2 therapy indefinitely. During 2 years of extended IL-2 therapy, clinical and Treg immune responses persisted, while Tcon count and Treg:Tcon ratio gradually normalized. Low-dose IL-2 provides durable clinical improvement in active cGVHD and extended therapy is well-tolerated.

Figure 1

Survival outcomes. (A) OS and PFS for the phase 2 cohort for responders (PR) and nonresponders (PD, SD, MR). Landmark analysis by week 12 response is indicated, and results did not differ when assessed from study entry. (B) Cumulative incidence of relapse and NRM for the phase 2 cohort.

Figure 2

Immunologic outcomes. (A) Immunologic impact of 12 weeks of low-dose IL-2: median Treg, Tcon count, and Treg:Tcon ratio in the study cohort during 12-week IL-2 and 4 weeks off IL-2. Line with arrows indicates IL-2 therapy. Box-and-whisker plots indicate median and IQR for healthy donors. Number of patients evaluated at each time point is indicated at the bottom. (B) Treg:Tcon ratios and IL-2 clinical response: week 0 and week 1 Treg:Tcon ratios in clinical responders (R: PR) and nonresponders (NR: PD/SD/MR) are displayed separately. Each line indicates an individual patient’s data at baseline and week 1. Threshold ratios of 0.07 (baseline) and 0.20 (week 1) are indicated by the dashed lines. (C) Naive and EM Treg percentage by IL-2 clinical response: week 0 and week 1, 2, and 4 naive and EM Treg percentage for clinical responders (R: PR) and nonresponders (NR: PD/SD/MR) are displayed separately. P values at relevant time points are indicated. Number of patients evaluated at each time point is indicated at the bottom. (D) Plasma IL-2, sIL-2R, and Treg cell counts during IL-2 therapy. Median plasma IL-2, plasma sIL-2R, and Treg cell counts during 12-week IL-2 and 4 weeks off IL-2. Box-and-whisker plots indicate median and IQR for healthy donors. Number of patients evaluated at each time point is indicated at the bottom of the image.

Figure 3

Immunologic impact of extended-duration IL-2 therapy. (A) Median Treg, Tcon count, and Treg:Tcon ratio during extended IL-2 is indicated. Box-and-whisker plots indicate median and IQR for healthy donors. Number of patients evaluated at each time point is indicated at the bottom of the image. (B) Median NK, CD8 T, and CD19 B-cell counts during extended-duration IL-2 are indicated. Box-and-whisker plots indicate median and IQR for healthy donors. Number of patients evaluated at each time point is indicated at the bottom.