Impact of Iron Overload On Immune Function for Patients Undergoing Allogeneic Transplants for Hematologic Disorders: Results of Pilot Study

Introduction: Chronic iron (Fe)overload represents a serious threat to patients undergoing allogeneic transplants and is associated with increased morbidity and mortality. The effects Fe overlaod on immune function is largely unknown and not studied in this population.

Patients: The study was conducted at the Comprehensive Center of Wake Forest University (CCCWFU) in patients (pts)with transfusional Fe overload. All pts had received allogeneic transplants for treatment of hematological disorder.The eligible study participants underwent assays for 16 serum cytokines, lymphocyte subtypes, and neutrophil function to assess cellular immune function before and after chelation. We then assessed cytokine production in response to lipopolysaccharide (LPS) in mononuclear cell culture from four additional pts and healthy controls.

Methods: Iron overload was defined as 1) serum ferritin > 1,000 ng /mL; 2) >25 transfusions; and 3) marrow Fe stain of 6+. Baseline MRI of heart and liver were performed for confirmation of Fe overload. We enrolled 4 pts prior to receiving chelation. Patients underwent chelation with deferasirox (Exjade) for six months. Co-morbidities and microbial and infection data were collected. We examined respiratory burst of neutrophils before and after ex vivo stimulation, lymphocyte subtypes, and serum levels of 16 cytokines, assessed before and after chelation paired with four healthy controls. A follow-up study enrolled four additional patients with Fe overload before chelation therapy.  Mononuclear cells were collected from pts and healthy control subjects and cultured for 48 hrs in the presence or absence of LPS.  Media was collected and assessed for 16 cytokines in a multiplex assay. 

Results: The patients had marked improvement in overall functional as well as hospitalization due to infection during the study period while on chelation. However, no differences were observed in serum cytokine levels, lymphocyte profiles, or neutrophil respiratory burst before and after chelation.In a follow-up preliminary study, cultured mononuclear cells from patients with Fe overload had statistically significant log increases in the levels of TNFα (p=0.0004) and IL-6 (p=0.0004) secreted in response to LPS.All eight patients had polymicrobial infections prior to chelation.

Conclusion: The increased susceptibility to unusual infections may be related to abnormally high iron in macrophages. The increase in TNF α and IL-6 in mononuclear cells (presumably produced by monocytes/macrophages) before chelation is suggestive of intracellular Fe overload correlating with increased susceptibility to infection. This pilot study has limitations due to small sample size. Future studies involving a large cohort of patients would help us understand the effect of iron overload on monocyte/macrophage function and also impact of chelation to improve co-morbidities related to infection.