Efficacy and immunologic effects of extracorporeal photopheresis plus interleukin-2 in chronic graft-versus-host disease

Abstract

Chronic graft-versus-host disease (cGVHD) affects >50% of hematopoietic stem cell transplant patients. Extracorporeal photopheresis (ECP), an immunomodulatory therapy, provides clinical benefit in steroid-refractory (SR) cGVHD, possibly via regulatory T (Treg) and natural killer (NK) cell expansion. We demonstrated that low-dose interleukin-2 (IL2) led to clinical improvement in SR-cGVHD and stimulated preferential Treg and NK-cell expansion with minimal effect on conventional T (Tcon) cells. We evaluated the effect of ECP (weeks 1-16) plus IL2 (1 × 106 IU/m2, weeks 9-16) in 25 adult patients with SR-cGVHD in a prospective phase 2 trial. Objective responses occurred in 29% and 62% of evaluable patients at weeks 8 (ECP alone) and 16 (ECP plus IL2), respectively. Eight weeks of ECP alone was associated with a marked decline in CD4+ Tcon (P = .03) and CD8+ T cells (P = .0002), with minimal change in Treg cells, Treg:Tcon cell ratio, or NK cells. Adding IL2 induced an increase in Treg cells (P < .05 at weeks 9-16 vs week 8), Treg:Tcon cell ratio (P < .0001 at weeks 9-16 vs week 8), and NK cells (P < .05 at weeks 9-16 vs week 8). Patients responding to ECP alone had significantly fewer CD4+ Tcon and CD8+ T cells at baseline compared with patients who responded after IL2 addition and patients who did not respond; neither Treg nor NK cells were associated with response to ECP alone. Altogether, ECP plus IL2 is safe and effective in patients with SR-cGVHD. ECP and IL2 have distinct immunologic effects, suggesting different therapeutic mechanisms of action. This trial was registered at www.clinicaltrials.gov as #NCT02340676.

Conflict of interest statement

Conflict-of-interest disclosure: J.K. reports research funding from Prometheus Laboratories Inc, Miltenyi Biotec, and Millennium Pharmaceuticals; consulting fees from Amgen, Equillium, and Fortress Biotech; and advisory board fees from Takeda and Kadmon. The remaining authors declare no competing financial interests.

© 2019 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Clinical response, survival, and relapse. (A) Study design. (B) Skin, gastrointestinal (GI), joint/fascia (JF), lung, and liver cGVHD scores at baseline, week 8, and week 16. cGVHD severity at baseline (week 0) and overall responses at week 8 and week 16. (C) OS, PFS, and cGVHD PFS (CPFS) for all patients. (D) OS for responders (R) and nonresponders (NR).

Figure 2.

Complete blood counts. Median absolute numbers of peripheral blood leukocytes (A), lymphocytes (B), RBCs (C), platelets (D), neutrophils (E), monocytes (F), and eosinophils (G).

Figure 3.

Immunologic effects on lymphocytes. (A-B) Median absolute numbers of peripheral blood lymphocyte subsets, including CD4+ Tcon cells, CD8+ T cells, B cells, NK cells, NKT cells, and Treg cells. (C) CD4+ Treg:Tcon ratio. Lymphocyte subsets were identified by flow cytometry using specific antibodies described in “Methods.”

Figure 4.

Changes in T-lymphocyte populations among responders and nonresponders. Median absolute numbers of peripheral blood CD3+ T cells (A), CD4+ Tcon cells (B), CD8+ T cells (C), and CD4+ Treg cells (D), and the CD4+ Treg:Tcon ratio (E) in patients who responded to ECP alone at week 8 (blue), patients who responded after ECP plus IL2 at week 16 (green), and patients who did not respond (red).