Abstract
Successful engraftment and reconstitution of the innate and adaptive immune system are associated with improved outcomes in recipients of allogeneic hematopoietic stem cell transplantation (HSCT). A clinically meaningful and simple biomarker of immunosuppression could potentially assist clinicians in their decision-making. We aimed to determine the relationship between T-cell production of interferon gamma (IFN-γ) in response to phytohemagglutinin (PHA) to clinical outcomes in HSCT recipients. A prospective observational multicenter study of 73 adult allogeneic HSCT recipients was conducted in Melbourne, Australia. Eligible participants were >18 years and at risk of cytomegalovirus disease. T-cell responses to PHA were assessed at 3, 6, 9, and 12 months post-HSCT using the commercial quantiferon-cytomegalovirus assay, which quantifies IFN-γ production by ELISA following stimulation with PHA. A low response was defined as IFN-γ <0.5 IU/ml following stimulation with PHA. At 3 months post-HSCT, high responses to PHA (median IFN-γ 7.68 IU/ml) were seen in 63% of participants and low responses to PHA (median IFN-γ 0.06 IU/ml) in 37%. IFN-γ responses to PHA were significantly associated with the severity of acute graft versus host disease (AGVHD) (spearman r = -0.53, p < 0.001) and correlated with blood lymphocyte count (spearman r = 0.52, p < 0.001). Twelve month overall survival was greater in individuals with high compared to low IFN-γ response to PHA at 3 months [92 vs. 62%, respectively, Cox proportional hazard ratio (HR): 4.12 95% CI: 1.2-13.7, p = 0.02]. Non-relapse mortality (NRM) was higher in individuals with low IFN-γ response to PHA (competing risk regression HR 11.6 p = 0.02). In individuals with no AGVHD compared to AGVHD and high IFN-γ response to PHA compared to AGVHD and low IFN-γ response to PHA, 12-month survival was 100 vs. 80 vs. 52%, respectively (log rank test p < 0.0001). Low IFN-γ response to PHA at the 3-month time-point following allogeneic HSCT was predictive of reduced 12-month overall survival, increased NRM, and reduced survival in recipients with AGVHD. Assessing IFN-γ response to PHA post-HSCT may be a clinically useful immune biomarker.
Highlights
Despite recent advances in the field of transplantation, recipients of allogeneic hematopoietic stem cell transplantation (HSCT) remain profoundly immunocompromised and at high risk of early death from both infectious and non-infectious complications [1]
Following HSCT, clinicians often need to balance the risk of acute graft versus host disease (AGVHD) against infection, with both complications contributing significantly to transplant-related mortality
Because IFN-γ can be measured as a continuous variable, here, we evaluated T-cell responses to PHA in the Quantiferon-CMV assay as a continuous variable and assessed its relationship to clinical outcome in a prospective multicenter cohort study of adult allogeneic HSCT recipients
Summary
Despite recent advances in the field of transplantation, recipients of allogeneic hematopoietic stem cell transplantation (HSCT) remain profoundly immunocompromised and at high risk of early death from both infectious and non-infectious complications [1]. We aimed to deter mine the clinical utility of measuring IFN-γ response to the positive mitogen control PHA, not CMV peptides Previous studies in both solid and stem cell transplant recipients report that the Quantiferon assay is frequently “indeterminate” due to poor mitogen response as a result of immunosuppression [12, 16]. Because IFN-γ can be measured as a continuous variable, here, we evaluated T-cell responses to PHA in the Quantiferon-CMV assay as a continuous variable and assessed its relationship to clinical outcome in a prospective multicenter cohort study of adult allogeneic HSCT recipients. Successful engraftment and reconstitution of the innate and adaptive immune system are associated with improved outcomes in recipients of allogeneic hematopoietic stem cell transplantation (HSCT). We aimed to determine the relationship between T-cell production of interferon gamma (IFN-γ) in response to phytohemagglutinin (PHA) to clinical outcomes in HSCT recipients
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