Interleukin-18 and outcome after allogeneic stem cell transplantation: A retrospective cohort study

Abstract

Background: Interleukin-18 (IL-18) is involved in endothelial activation and dysfunction, and in the pathogenesis and severity of acute graft-versus -host disease (aGVHD). Its relevance for patient outcome after allogeneic stem cell transplantation (alloSCT) has not yet been comprehensively addressed. Methods: Pre-transplant serum levels of free IL-18 were retrospectively assessed in a cohort of 589 patients (training cohort). Results were validated in 688 patients allografted in a different centre. The primary endpoint was overall survival (OS). Secondary endpoints included incidences of non-relapse mortality (NRM), relapse, and aGVHD. Findings: In the training cohort, higher pre-transplant levels of free IL-18 were significantly associated with worse OS (hazard ratio [HR] per 1-log2 increase, 1.25, P = 0.008) in multivariable models. This was due to a higher hazard of NRM (HR per 1-log2 increase, 1.39, P = 0.001), rather than relapse. The associations of pre-transplant free IL-18 with higher NRM (HR per 1-log2 increase, 1.24, P = 0.02) and shorter OS (HR per 1-log2 increase, 1.22, P = 0.006) were confirmed in the validation cohort. In both cohorts, the correlations of higher pre-transplant free IL-18 serum levels with increased NRM and worse OS were mainly driven by fatal infectious complications. No associations with incidence of aGVHD were observed. Interpretation: Higher pre-transplant levels of free IL-18 were associated with non-relapse and overall mortality after alloSCT. Our results may provide a rationale for prospective studies evaluating IL-18 status and inhibition of IL-18 activity in patients undergoing allografting.

Interleukin-18 and Hematopoietic Recovery after Allogeneic Stem Cell Transplantation

“…We have previously reported that elevated pre-conditioning IL-18 is a predictor of worse survival due to increased NRM (HR per doubling in IL-18, ~1.2–1.4 in both centers) [ 16 ].…”

“…Interestingly, no associations of IFNγ and the IFNγ-inducible CXC family chemokines CXCL9 and CXCL10 on platelet and neutrophil recovery were observed. Since IL-18 is an IFNγ-inducing cytokine and IL-18 and CXC family chemokines show a high level of intercorrelation [ 16 ], these findings suggest that myeloid recovery might be affected by IL-18 independently of IFNγ.…”

“…Consequently, a correlation of IL-18 with GVHD severity was found in some alloSCT studies [ 27 , 28 ] but not in others [ 29 , 30 ]. We have previously reported that elevated pre-conditioning IL-18 levels predicted worse survival due to increased NRM [ 16 ]. In this previous study, median levels of total and free IL-18 in healthy controls were 175 and 141 pg/mL, respectively, which is approximately 4- and 3-fold lower as compared to the median pre-conditioning levels observed in allografted patients [ 16 ].…”

“…We have previously reported that elevated pre-conditioning IL-18 levels predicted worse survival due to increased NRM [ 16 ]. In this previous study, median levels of total and free IL-18 in healthy controls were 175 and 141 pg/mL, respectively, which is approximately 4- and 3-fold lower as compared to the median pre-conditioning levels observed in allografted patients [ 16 ]. We can only speculate about the underlying causes.…”

“…In addition, being part of the human host defense against infection, elevated IL-18 was reported to correlate with infection severity and outcome [ 14 , 15 ]. Accordingly, higher pre-conditioning levels of free IL-18 were found to be associated with non-relapse and overall mortality after alloSCT [ 16 ]. While no correlations with acute GVHD were observed, IL-18-related excess mortality was mainly driven by fatal infectious complications.…”