Key Clinical Summary

• Emerging evidence highlights that toxic, reactive ferrous iron, not total iron stores, is the primary driver of organ damage across hematologic disorders.
• Continuous chelation, rather than dose intensity, is strongly associated with improved survival, cardiac recovery, and prevention of multiorgan injury.
• In transplant and myelodysplastic syndromes (MDS) populations, iron toxicity contributes to inferior outcomes, and early, consistent iron management may improve survival, reduce complications, and preserve organ function.

In a panel presentation at the 67th ASH Annual Meeting and Exposition, experts discussed updated biological insights and clinical strategies for managing iron toxicity and overload across hematologic conditions. A central message from the session was that reactive, labile ferrous iron drives cellular injury, often independent of total iron burden. Presentations by Thomas D. Coates, MD, Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine; Emanuele Angelucci, MD, IRCCS San Martino Hospital, Genova, Italy; and Heather Leitch, MD, PhD, St. Paul's Hospital University of British Columbia, Vancouver, British Columbia, Canada, emphasized how evolving understanding of iron biology should reshape clinical practice.

Session Highlights

Dr Coates opened the session by reframing iron overload as a process driven by toxic, redox-active ferrous iron, especially non-transferrin bound iron (NTBI) and labile plasma iron (LPI). He showed that organ dysfunction correlates poorly with total stored iron but closely with exposure to toxic iron species.

He highlighted data demonstrating that continuous chelation normalizes cardiac function within months, even while cardiac iron stores remain elevated. In landmark studies, patients receiving 24/7 deferoxamine experienced rapid recovery of ejection fraction despite persistently high cardiac T2* values, illustrating that chelators neutralize circulating toxic iron rather than immediately clearing stored iron.

Coates emphasized that dose frequency—not dose size—is prognostic, noting survival advantages in patients receiving chelation on most days of the year. Ferritin was shown to be an unreliable marker because inflammation markedly elevates ferritin independent of iron levels. Disease-specific patterns of iron toxicity were described, including distinct pancreatic and cardiac iron loading in thalassemia compared with sickle cell disease.

Dr Angelucci addressed iron toxicity in the transplant setting, describing 3 phases: pre-transplant, peri-transplant, and long-term survivorship. Historical data show that conventional iron biomarkers do not predict transplant outcomes, whereas toxic iron exposure and oxidative stress correlate with complications such as organ dysfunction, infections, and reduced survival.

He underscored that irregular or insufficient chelation amplifies oxidative stress, contributing to poorer transplant outcomes. He advocated for early, sustained chelation prior to transplant when feasible, noting that reversal of organ injury is possible in non-malignant conditions.

Dr Leitch focused on iron toxicity in MDS, where up to one-half of patients become transfusion dependent. She described how NTBI and LPI drive oxidative injury, impair hematopoiesis, and contribute to inferior survival, acute myeloid leukemia (AML) progression, infections, and cardiac events.

She reviewed data showing improved overall survival, progression-free survival, cardiac outcomes, and hematologic responses in patients with MDS receiving iron chelation. Early intervention is suggested when transferrin saturation approaches 80%, LPI becomes detectable, or organ iron is observed.

According to Dr Coates, understanding iron’s redox behavior clarifies why continuous chelator exposure is essential. Toxic iron rebounds quickly when chelation stops, making adherence more important than dose escalation. He noted that split-dose deferasirox maintains steadier suppression of NTBI compared with once-daily dosing.

Dr Angelucci emphasized that transplant outcomes are strongly influenced by oxidative stress, not merely absolute iron, advocating for pre-transplant optimization whenever the patient’s disease biology permits. He noted the need for improved biomarkers to guide decision-making.

Dr Leitch highlighted practical challenges in older patients with MDS, stressing that chelation decisions must weigh life expectancy, comorbidities, and toxicity risk. She noted rapid improvements in hematologic parameters within weeks of chelation, driven by immediate suppression of LPI. She also discussed emerging strategies, including novel chelation formulations, calcium-channel blockers to inhibit NTBI uptake, and adjunctive agents such as eltrombopag.

Implications for Practice

The session reinforces that iron toxicity, not just iron overload, should guide management strategies across hematology. Continuous chelation, early intervention, and monitoring of transferrin saturation and LPI may better prevent organ injury. These insights may influence pathway decisions, transplant conditioning strategies, and treatment algorithms for thalassemia, sickle cell disease, and MDS.

Conclusion

Advances in iron biology are reshaping clinical management, emphasizing proactive, consistent chelation to neutralize toxic iron species. Ongoing research into biomarkers, novel chelators, and NTBI-targeted therapies may further refine best practices in the coming years.

Reference

Coates TD, Angelucci E, Leitch H. Biology-Based Management of Iron Toxicity and Overload in Hematology Practice. Presented at: ASH 2025; December 6-9; Orlando, FL.