# Transfusion-Related Iron Overload in Children With Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma: Addressing an Overlooked Treatment Complication

## TL;DR

Children with leukemia and lymphoma often develop dangerous iron overload from blood transfusions, but it's not being properly managed or monitored.

## Contribution

This study highlights the high prevalence and inadequate management of transfusion-related iron overload in pediatric cancer patients.

## Key findings

- 96% of patients had significant hyperferritinemia after intensive chemotherapy.
- Only four patients underwent MRI for tissue iron quantification despite high risk.
- Older age and high-risk disease were identified as major risk factors for iron overload.

## Abstract

Introduction: Transfusion-related iron overload (TRIO) is a common antineoplastic treatment complication in children undergoing aggressive chemotherapy for hematological malignancies. Iron deposition leads to numerous morbidities, with the most devastating outcomes being liver and heart failure.

Materials and methods: An observational retrospective study on TRIO was performed on children with acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL) treated at the Department of Oncology and Hematology, Children's Hospital Zagreb, Croatia, from January 1, 2018, to December 31, 2023. Epidemiological and basic clinical data were retrieved from the patients’ electronic medical records. Serum ferritin (SF) concentration (ng/mL) was used as a marker of TRIO. Mildly elevated ferritin was defined as SF >500 ng/mL and severely elevated as SF >1000 ng/mL. Results of magnetic resonance imaging (MRI) studies for tissue iron quantification, HFE genetic analyses, and management with chelators (preparation, dose, duration, compliance) were described.

Results: Initial SF concentrations ranged from 17.5 to 808 ng/mL, rose to the range from 368 to 6562.3 ng/mL at the end of the intensive chemotherapy, sunk to the range from 11.9 to 3885 ng/mL at the end of the maintenance therapy, and additionally receded to the range from 36.2 to 1924 ng/mL during the follow-up (FU). Upon cessation of intensive chemotherapy, significant hyperferritinemia was detected in 96% of the patients tested and during the FU in 60% of them. Risk factors for TRIO included age six and older, high-risk (HR) disease, and a substantial transfusion load (≥10 red blood cell transfusions (RBCTs)). Hepatic and/or cardiac MRI, as part of the TRIO work-up, was performed in only four patients. HFE genotyping was conducted in five participants, and the results were altered in three of them - H63D heterozygosity. Four children received chelation therapy, i.e., deferasirox, which was discontinued in two of them due to gastrointestinal discomfort.

Conclusion: We have demonstrated a high occurrence but an unsatisfactory approach to TRIO. A fair number of patients lacked SF measurements during the treatment and FU. Despite a considerable proportion of patients at risk of TRIO in our cohort, only four underwent MRI for tissue iron quantification. Unlike the ferritin assay, MRI is neither accessible nor cheap, and the need for sedation/anesthesia in young children probably leads to underutilization of the method. Furthermore, there was no consensus on genotyping for hereditary hemochromatosis. Older age and HR disease posed a greater risk for TRIO. Transfusion burden significantly impacted ferritin levels. We advise clinicians to follow a restrictive transfusion strategy and track the number of red blood cell units administered throughout the treatment to identify patients with especially worrisome iron influx. There is a strong need for the development of TRIO treatment guidelines for patients and survivors of childhood cancer.