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

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, Philippe Armand, Corey S. Cutler, Vincent T. HoBruce R. Blazar, Joseph H. Antin, Robert J. Soiffer, Jerome Ritz, John Koreth

Research output: Contribution to journalArticle

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 CD41CD251CD1272Foxp31 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 3 106 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 5 .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.

Original languageEnglish (US)
Pages (from-to)2550-2561
Number of pages12
JournalBlood Advances
Volume3
Issue number17
DOIs
StatePublished - Sep 10 2019
Externally publishedYes

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Graft vs Host Disease
Interleukin-2
Maximum Tolerated Dose
Therapeutics
Pediatrics
Tachyphylaxis
T-Lymphocytes
Lung
Regulatory T-Lymphocytes
Natural Killer Cells
Steroids
Cell Proliferation
Skin

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Whangbo, J. S., Kim, H. T., Mirkovic, N., Leonard, L., Poryanda, S., Silverstein, S., ... Koreth, J. (2019). Dose-escalated interleukin-2 therapy for refractory chronic graft-versus-host disease in adults and children. Blood Advances, 3(17), 2550-2561. https://doi.org/10.1182/bloodadvances.2019000631

Dose-escalated interleukin-2 therapy for refractory chronic graft-versus-host disease in adults and children. / Whangbo, Jennifer S.; Kim, Haesook T.; Mirkovic, Nikola; Leonard, Lauren; Poryanda, Samuel; Silverstein, Sophie; Kim, Soomin; Reynolds, Carol G.; Rai, Sharmila C.; Verrill, Kelly; Lee, Michelle A.; Margossian, Steven; Duncan, Christine; Lehmann, Leslie; Huang, Jennifer; Nikiforow, Sarah; Alyea, Edwin P.; Armand, Philippe; Cutler, Corey S.; Ho, Vincent T.; Blazar, Bruce R.; Antin, Joseph H.; Soiffer, Robert J.; Ritz, Jerome; Koreth, John.

In: Blood Advances, Vol. 3, No. 17, 10.09.2019, p. 2550-2561.

Research output: Contribution to journalArticle

Whangbo, JS, Kim, HT, Mirkovic, N, Leonard, L, Poryanda, S, Silverstein, S, Kim, S, Reynolds, CG, Rai, SC, Verrill, K, Lee, MA, Margossian, S, Duncan, C, Lehmann, L, Huang, J, Nikiforow, S, Alyea, EP, Armand, P, Cutler, CS, Ho, VT, Blazar, BR, Antin, JH, Soiffer, RJ, Ritz, J & Koreth, J 2019, 'Dose-escalated interleukin-2 therapy for refractory chronic graft-versus-host disease in adults and children', Blood Advances, vol. 3, no. 17, pp. 2550-2561. https://doi.org/10.1182/bloodadvances.2019000631
Whangbo, Jennifer S. ; Kim, Haesook T. ; Mirkovic, Nikola ; Leonard, Lauren ; Poryanda, Samuel ; Silverstein, Sophie ; Kim, Soomin ; Reynolds, Carol G. ; Rai, Sharmila C. ; Verrill, Kelly ; Lee, Michelle A. ; Margossian, Steven ; Duncan, Christine ; Lehmann, Leslie ; Huang, Jennifer ; Nikiforow, Sarah ; Alyea, Edwin P. ; Armand, Philippe ; Cutler, Corey S. ; Ho, Vincent T. ; Blazar, Bruce R. ; Antin, Joseph H. ; Soiffer, Robert J. ; Ritz, Jerome ; Koreth, John. / Dose-escalated interleukin-2 therapy for refractory chronic graft-versus-host disease in adults and children. In: Blood Advances. 2019 ; Vol. 3, No. 17. pp. 2550-2561.
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AU - Silverstein, Sophie

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AU - Margossian, Steven

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AU - Huang, Jennifer

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AU - Alyea, Edwin P.

AU - Armand, Philippe

AU - Cutler, Corey S.

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AU - Blazar, Bruce R.

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