Impact of iron overload on hematopoietic stem cell transplantation in pediatric patients with nonmalignant hematological disorders.

Children with nonmalignant hematological disorders (NMHD) often require numerous red blood cell transfusions before hematopoietic stem cell transplantation (HSCT), leading to iron overload. Ferritin and liver iron concentration (LIC) are used to estimate the degree of iron overload to determine eligibility for HSCT, but neither marker has been definitively associated with poorer HSCT outcomes in pediatric cohorts. We conducted a multicenter retrospective cohort study using PEDSnet to examine the association between elevated pre-HSCT ferritin and LIC and HSCT outcomes and to evaluate iron reduction therapy after transplantation. A total of 580 patients with a pre-HSCT ferritin and 260 patients with a pre-HSCT LIC were studied. Patients with high pre-HSCT ferritin of >2500 ng/mL had decreased 3-year overall survival (adjusted hazard ratio [HR], 2.31; 95% confidence interval [CI], 1.06-5.04). A sensitivity analysis demonstrated this trend only in patients with severe aplastic anemia (SAA). Elevated ferritin was associated with a markedly increased risk of bacteremia after HSCT in patients with SAA (HR, 3.33; 95% CI, 1.72-6.44). Elevated pre-HSCT LIC of >5 mg Fe/g dry weight was not associated with decreased survival, bacteremia, graft failure, or veno-occlusive disease (VOD). VOD was assessed only in patients undergoing busulfan-based transplantation. After transplantation, 63% of patients in the multicenter analysis had an elevated ferritin, whereas 68% had an elevated LIC. Chelation and phlebotomy were equally effective in reducing post-HSCT iron. These results challenge the use of LIC as the gold standard for iron-related risk stratification in HSCT. Further research into peri-HSCT iron management is necessary in an era of expanding availability of HSCT for NMHD.