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

John Koreth, Haesook T. Kim, Kyle T. Jones, Paulina B. Lange, Carol G. Reynolds, Marie J. Chammas, Katherine Dusenbury, Jennifer Whangbo, Sarah Nikiforow, Edwin P. Alyea, Philippe Armand, Corey S. Cutler, Vincent T. Ho, Yi Bin Chen, David Avigan, Bruce R. Blazar, Joseph H. Antin, Jerome Ritz, Robert J. Soiffer

Research output: Contribution to journalArticlepeer-review

85 Scopus citations

Abstract

Chronic graft-versus-host disease (cGVHD) is associated with inadequate reconstitution of tolerogenic CD41CD251FOXP31 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 adultswith steroid-refractory cGVHDreceived daily IL-2(13106 IU/m2) for12weeks.MediantimefromtransplantationandcGVHDonsetwas616 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 5 =.005; 249 vs 461 days after cGVHD onset; P 5 .03). Treg:Tcon ratios ‡0.07 at baseline and ‡0.2 at week 1 also predicted clinical response (P 5 =.003; P 5 =.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. Lowdose IL-2 provides durable clinical improvement in active cGVHD and extended therapy is well-tolerated. (Blood. 2016;128(1):130-137)

Original languageEnglish (US)
Pages (from-to)130-137
Number of pages8
JournalBlood
Volume128
Issue number1
DOIs
StatePublished - Jul 7 2016

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