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

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Koreth J, Kim HT, Jones KT, Lange PB, Reynolds CG, Chammas MJ, Dusenbury K, Whangbo J, Nikiforow S, Alyea EP, Armand P, Cutler CS, Ho VT, Chen YB, Avigan D, Blazar BR, Antin JH, Ritz J, Soiffer RJ,


Koreth J, Kim HT, Jones KT, Lange PB, Reynolds CG, Chammas MJ, Dusenbury K, Whangbo J, Nikiforow S, Alyea EP, Armand P, Cutler CS, Ho VT, Chen YB, Avigan D, Blazar BR, Antin JH, Ritz J, Soiffer RJ, (click to view)

Koreth J, Kim HT, Jones KT, Lange PB, Reynolds CG, Chammas MJ, Dusenbury K, Whangbo J, Nikiforow S, Alyea EP, Armand P, Cutler CS, Ho VT, Chen YB, Avigan D, Blazar BR, Antin JH, Ritz J, Soiffer RJ,

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Blood 2016 04 12128(1) 130-7 doi 10.1182/blood-2016-02-702852

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.

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