Low T-Cell Responses to Mitogen Stimulation Predicts Poor Survival in Recipients of Allogeneic Hematopoietic Stem Cell Transplantation

Background: 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-gamma) in response to phytohemagglutinin (PHA) to clinical outcomes in HSCT recipients. Methods: 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-gamma production by ELISA following stimulation with PHA. A low response was defined as IFN-gamma <0.5 IU/ml following stimulation with PHA. Results: At 3 months post-HSCT, high responses to PHA (median IFN-gamma 7.68 IU/ml) were seen in 63% of participants and low responses to PHA (median IFN-gamma 0.06 IU/ml) in 37%. IFN-gamma 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-gamma 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-gamma response to PHA (competing risk regression HR 11.6 p = 0.02). In individuals with no AGVHD compared to AGVHD and high IFN-gamma response to PHA compared to AGVHD and low IFN-gamma response to PHA, 12-month survival was 100 vs. 80 vs. 52%, respectively (log rank test p < 0.0001). Conclusion: Low IFN-gamma 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-gamma response to PHA post-HSCT may be a clinically useful immune biomarker.