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

J Koreth, HT Kim, KT Jones, PB Lange… - Blood, The Journal …, 2016 - ashpublications.org
J Koreth, HT Kim, KT Jones, PB Lange, CG Reynolds, MJ Chammas, K Dusenbury…
Blood, The Journal of the American Society of Hematology, 2016ashpublications.org
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× 106 IU/m2) for 12 weeks. Median time from transplantation and cGVHD onset was …
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 × 106 IU/m2) 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.
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