Defining the Impacts of Iron Overload in Children Receiving Hematopoietic Stem Cell Transplantation for Non-Malignant Hematologic Conditions

Background: Hematopoietic stem cell transplant (HSCT) is curative for patients with non-malignant blood disorders. Children with these conditions often require numerous red blood cell transfusions prior to HSCT, leading to iron overload. It has been hypothesized that pre-HSCT iron overload leads to poorer post-HSCT outcomes, and studies have demonstrated a prognostic link between portal fibrosis, hepatomegaly, and post-transplant survival in thalassemia. Ferritin and liver iron concentration (LIC) are used as surrogate markers of iron overload to determine eligibility for HSCT, but neither has been definitively associated with poorer HSCT outcomes in this population. Further, patients receiving HSCTs for non-malignant conditions may require post-transplant iron reduction therapy (IRT), but whether chelation or phlebotomy is more effective in reducing iron overload is unknown.

Objectives: In children with non-malignant blood disorders, determine if higher pre-transplant ferritin and LIC are associated with poorer post-HSCT outcomes including GVHD-free, relapse-free survival (GRFS), overall survival (OS), higher rates of veno-occlusive disease (VOD), and longer neutrophil and platelet engraftment times. Determine whether post-HSCT chelation or phlebotomy is associated with a faster rate of ferritin reduction.

Methods: We conducted a single-center retrospective cohort study of children with sickle cell disease, beta thalassemia major, aplastic anemia, and other disorders requiring RBC transfusion from a large pediatric academic center from 2010-2023 as a pilot study for our in-progress multi-center analysis. GRFS and OS were compared using a Kaplan-Meier survival analysis. GRFS analysis excluded autologous SCTs. Engraftment times were compared using a competing risks analysis. VOD rates were compared using logistic regression. Rate of ferritin reduction was analyzed using a Wilcoxon Rank-Sum test. Statistical analyses were conducted using StataBE v17.0.

Results: Among 152 patients with non-malignant blood disorders who underwent HSCT, 136 patients received allogeneic SCTs and 16 received gene-modified autologous SCTs. 90 patients had a pre-transplant LIC <5mg/g dry tissue or if no LIC was available, ferritin <1000ng/mL (low iron). 41 patients had a pre-transplant LIC of 5-10mg/g dry tissue or ferritin 1000-3000ng/mL (moderate iron). 21 patients had a pre-transplant LIC ≥10mg/g dry tissue or ferritin ≥3000ng/mL (high iron).

GRFS rates were 20% for the low iron group, 13% for moderate iron, and 22% for high iron, and were not statistically distinct (p = 0.55). OS was 92.2% for low iron, 97.6% for moderate iron, and 95.2% for high iron. Survival analysis showed no significant difference in OS (p = 0.51). Minimum detectable hazard ratios were 2.00 and 1.92 comparing high and low iron groups for GRFS and OS, respectively. Logistic regression showed an odds ratio of 3.25 for VOD in high iron versus low iron in patients who received busulfan, though this was not statistically significant, p = 0.38. Median time to neutrophil engraftment did not differ among groups (15 days for low iron, 15 days for moderate and 14 days for high). Median time to platelet engraftment was 18 days for low iron, 19 days for moderate iron and 26 days for high iron, though due to wide variance in engraftment times, this was not statistically significant (p = 0.81).

11 patients underwent post-HSCT IRT with chelation and 12 with phlebotomy. Median rate of ferritin reduction for patients receiving post-HSCT chelation was 53 ng/mL/month on therapy, compared to 64 ng/mL/month for those who received phlebotomy (p = 0.24).

Conclusions: In this pilot study, higher pre-transplant LIC and ferritin were not significantly associated with poorer post-transplant outcomes. Patients in the high iron group showed a trend toward increased VOD risk and longer time to platelet engraftment, but GRFS and OS were not impacted. Post-HSCT phlebotomy and chelation showed similar rates of ferritin reduction as a marker for elimination of residual iron overload. These data suggest a need to reevaluate the utility of LIC and ferritin as prognostic markers for HSCT risk. Additional data are needed to determine if IRT targeting specific iron thresholds is truly needed prior to HSCT. This pilot study informs our in-progress multi-center analysis of the impact of iron overload on post-HSCT outcomes in children with non-malignant blood disorders.