Dose-escalated interleukin-2 therapy for refractory chronic graft-versus-host disease in adults and children.
Jennifer S WhangboHaesook T KimNikola MirkovicLauren LeonardSamuel PoryandaSophie SilversteinSoomin KimCarol G ReynoldsSharmila C RaiKelly VerrillMichelle A LeeSteven MargossianChristine DuncanLeslie LehmannJennifer HuangSarah NikiforowEdwin P AlyeaPhilippe ArmandCorey S CutlerVincent T HoBruce R BlazarJoseph H AntinRobert J SoifferJerome RitzJohn KorethPublished in: Blood advances (2020)
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.
Keyphrases
- low dose
- young adults
- patient reported outcomes
- end stage renal disease
- newly diagnosed
- chronic kidney disease
- nk cells
- physical activity
- clinical trial
- open label
- signaling pathway
- peritoneal dialysis
- high dose
- prognostic factors
- transcription factor
- magnetic resonance imaging
- immune response
- regulatory t cells
- contrast enhanced
- preterm birth