High IL-15 Serum Levels on Day 7 After Hematopoietic Cell Transplantation Are Associated with a Low Likelihood of Graft-Vs-Host Disease and a High Likelihood of Infections

High levels of soluble IL-2 receptor alpha, IL-5, IL-6, IL-7, IL-15, soluble TNF alpha receptor and vascular endothelial growth factor have been associated with a high likelihood of GVHD. The levels were typically measured during or shortly before the development of GVHD. As preemptive therapy of GVHD would likely be efficacious if started early posttransplant, we set out to determine whether the levels of the above cytokines/cytokine receptors (hereafter referred to as “cytokines”) on day 7 are associated with subsequent development of GVHD and, if yes, whether the levels are also associated with relapse or infections.

In a cohort of 153 consecutive allogeneic transplant recipients in Calgary who gave consent we determined serum levels of the above cytokines. All patients were adults, received myeloablative conditioning including rabbit antithymocyte globulin and typically filgrastim-mobilized blood mononuclear cells from HLA-matched unrelated donors or siblings, typically for hematologic malignancy. Cytokine levels were measured using sandwich ELISA (R&D). For each cytokine, levels in patients with versus without aGVHD (grade 2–4), cGVHD (needing systemic therapy) or relapse were compared using Mann-Whitney-Wilcoxon test, and correlation between the cytokine level and infection rates (number of infections per number of days at risk) was evaluated using Spearman rank correlation test. For each cytokine for which the levels appeared to be significantly associated with aGVHD, cGVHD, relapse or an infection rate, multivariate analyses were performed (using log-binomial regression for aGVHD, cGVHD or relapse, and Poisson regression for infection rates) adjusting for recipient age (continuous), donor type (HLA-matched sibling versus other), donor/recipient sex (M/M versus other), stem cell source (marrow versus blood stem cells) and, for relapse, also disease/disease stage (good vs poor risk) and, for infections, also engraftment day (continuous) and aGVHD or cGVHD (yes/no) using days at risk as the offset.

In univariate analyses, the only cytokine levels significantly associated with subsequent development of aGVHD or cGVHD were IL-15 levels (median 29 vs 40 pg/mL in patients with vs without aGVHD, p=.02, and median 25 vs 40 pg/mL in patients with vs without cGVHD, p=.02). IL-15 levels were similar in patients who did vs did not develop relapse (30 vs 39 pg/mL, p=0.60). There was a significant or near-significant positive correlation between IL-15 levels and the rates of definite (microbiologically documented) infections (p=.008), total (definite or presumed) infections (p=.008), viral infections (p=.06), bacterial infections (p=.06) and fungal infections (p=0.03) occurring between day 7 and 83. In multivariate analyses, IL-15 levels above31.0 pg/mL were associated with a 0.38-fold risk of aGVHD (p=0.005), and levels above 31.3 pg/mL with a 0.35-fold risk of cGVHD (p<.008). For a unit increase of IL-15 level (change of 1 pg/mL), the rate of infections increased 1.02-fold (p<.001) for definite infections, 1.03-fold for total infections (p<.001), 1.03-fold for viral infections (p<.001), 1.02-fold for bacterial infections (p<.001) and 1.03-fold for fungal infections (p=.06).

Unexpectedly, high IL-15 levels were associated with a low likelihood of GVHD. For this we do not have an explanation. High IL-15 levels were also associated with a high likelihood of infections. This may reflect the fact that the most lymphopenic patients (at the highest risk of infections) may have had the highest levels of IL-15, a homeostatic growth factor for CD8 T cells and NK cells. Consistent with that, post-hoc analyses showed negative correlations between day 7 IL-15 levels and day 28 counts of CD8 T cells (p=.0002), NK cells (p=.06) and total lymphocytes (p=.03).

No relevant conflicts of interest to declare.