Dose-escalated interleukin-2 therapy for refractory chronic graft-versus-host disease in adults and children.

Abstract

Low-dose interleukin-2 (IL-2) therapy for chronic graft-versus-host disease (cGVHD) generates a rapid rise in plasma IL-2 levels and CD4+CD25+CD127-Foxp3+ regulatory T-cell (CD4Treg) proliferation, but both decrease over time despite continued daily administration. To test whether IL-2 dose escalation at the time of anticipated falls in plasma levels could circumvent tachyphylaxis and enhance CD4Treg expansion, we conducted a phase 1 trial in 10 adult and 11 pediatric patients with steroid-refractory cGVHD (www.clinicaltrials.gov: NCT02318082). Daily IL-2 was initiated in children and adults (0.33 × 106 and 0.67 × 106 IU/m2 per day, respectively). Dose escalations were scheduled at weeks 2 and 4 to a maximum dose of 1 × 106 IU/m2 per day in children and 2 × 106 IU/m2 per day in adults. Patients continued at their maximum tolerated dose (MTD) until week 8. Children tolerated IL-2 dose escalation with partial responses (PRs) in 9 of 11 patients (82%) at multiple cGVHD sites, including lung. Patient-reported outcome scores for skin and lung improved significantly in pediatric patients. In contrast, 5 of 10 adults required dose reduction, and only 2 of 7 evaluable patients (29%) had PRs at week 8. CD4Tregs and natural killer cells expanded in both cohorts without significant changes in conventional CD4+ T cells (Tcons) or CD8+ T cells. Children achieved a higher median CD4Treg/Tcon ratio at week 8 (0.4 vs 0.18, P = .02) despite lower IL-2 doses. We show for the first time that low-dose IL-2 is safe and effective in children with advanced cGVHD. In adults, escalation above the previously defined MTD did not improve CD4Treg expansion or clinical response.

• Authors: Jennifer S Whangbo, Haesook T Kim, Nikola Mirkovic, Lauren Leonard, Samuel Poryanda, Sophie Silverstein, Soomin Kim, Carol G Reynolds, Sharmila C Rai, Kelly Verrill, Michelle A Lee, Steven Margossian, Christine Duncan, Leslie Lehmann, Jennifer Huang, Sarah Nikiforow, Edwin P Alyea 3rd, Philippe Armand, Corey S Cutler, Vincent T Ho, Bruce R Blazar, Joseph H Antin, Robert J Soiffer, Jerome Ritz, John Koreth
• Journal: Blood advances (Blood Adv) Vol. 3 Issue 17 Pg. 2550-2561 (09 10 2019) ISSN: 2473-9537 [Electronic] United States
• PMID: 31471324 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 by The American Society of Hematology.

Chemical References

• Interleukin-2

Topics

• Adult
• Cell Proliferation (drug effects)
• Child
• Chronic Disease
• Female
• Graft vs Host Disease (drug therapy, pathology)
• Humans
• Immunotherapy (methods)
• Interleukin-2 (administration & dosage, pharmacology)
• Killer Cells, Natural (cytology)
• Lung Diseases (drug therapy)
• Male
• Maximum Tolerated Dose
• Skin Diseases (drug therapy)
• T-Lymphocytes, Regulatory (cytology)