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.

• Authors: 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 3rd, Philippe Armand, Corey S Cutler, Vincent T Ho, Yi-Bin Chen, David Avigan, Bruce R Blazar, Joseph H Antin, Jerome Ritz, Robert J Soiffer
• Journal: Blood (Blood) Vol. 128 Issue 1 Pg. 130-7 (07 07 2016) ISSN: 1528-0020 [Electronic] United States
• PMID: 27073224 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 by The American Society of Hematology.

Chemical References

• IL2 protein, human
• Interleukin-2

Topics

• Adult
• Aged
• Chronic Disease
• Female
• Follow-Up Studies
• Graft vs Host Disease (blood, drug therapy)
• Humans
• Interleukin-2 (administration & dosage)
• Killer Cells, Natural
• Lymphocyte Count
• Male
• Middle Aged
• T-Lymphocytes, Regulatory
• Time Factors