Introduction to a How I Treat series on iron overload in hematologic disorders

Most medical providers understand that iron overload is toxic and can be fatal based on textbook descriptions of heart failure, bronze diabetes, endocrine dysfunction, growth failure, and premature death in children on transfusion for thalassemia major. The thalassemia experience has driven the expectation of severe toxicity and poor outcomes for all disorders associated with iron loading even though the trajectory of toxicity and outcomes are often disease specific. Many disease-specific publications about iron overload management give the impression that biology of iron toxicity is disease specific as well. In fact, the toxicity in all iron overload disorders is due to the magnitude and duration of exposure to reactive ferrous iron (Fe²⁺) by way of non–transferrin-bound-iron (NTBI). In hematologic disorders, generation of NTBI occurs because of inability to use iron, and thus to regenerate unsaturated transferrin because of ineffective erythropoiesis. Patients with ineffective erythropoiesis have increased iron absorption, but regularly transfused patients with ineffective erythropoiesis have the highest NTBI of all and the most organ toxicity per unit time of exposure. The mechanism of toxicity is the same, but the magnitude of NTBI generation and duration of exposure depend on the underlying diagnosis.

The survival for transfusion-dependent β-thalassemia major has increased from a median of about 17 years in the 1970s to today, when 87% of patients born after 1975 are alive at 50 years of age,¹ with the median survival having not yet been reached. There has been a 72% decrease in cardiomyopathy and 86% decrease in hypogonadism when the 1985 birth cohort is compared with the 1975 cohort.¹ This dramatic improvement in survival and reduction in iron-related complications can be attributed to the availability of effective iron chelation and introduction of the ability to monitor tissue iron content noninvasively by magnetic resonance imaging (MRI). We know from following patients with thalassemia that it takes 8 to 10 years of exposure to toxic iron to reach clinically apparent organ failure² and that effective treatment can prevent or reverse iron toxicity.¹ We can exploit the substantial advances in understanding of iron biology derived mainly from animal models and the ability to follow the redistribution of iron in various tissues clinically in patients with hemoglobinopathy over decades to arrive at a framework for understanding and treating iron toxicity in all disorders.

Although the potential duration of Fe²⁺ exposure is lifelong in the hemoglobinopathies, this is not the case in other iron-loading conditions like hemopoietic cell transplant and adult myelodysplastic syndrome. These differences in duration of exposure and considerations due to non-iron-related treatment have important bearing on iron management recommendations. The biology and management of iron overload in hematologic disorders are discussed in this three-part series:

• Thomas D. Coates, “Management of iron overload: lessons from transfusion dependent hemoglobinopathies”

• Emanuele Angelucci, “How I manage iron overload in the hemopoietic cell transplantation setting”

• Heather A. Leitch and Rena Buckstein, “How I treat iron overload in adult myelodysplastic syndrome”

In the first article,³ I review the clinically relevant iron biology and its relation to monitoring of tissue iron distribution by MRI. I discuss how NTBI is generated subsequent to increased saturation of transferrin and describe the relation of transferrin saturation and NTBI to ineffective erythropoiesis and how this affects distribution of iron into extrahepatic sites like the heart and endocrine organs. The application of these principles to management of iron overload in general is presented through clinical examples from patients with hemoglobinopathy.

In the second article,⁴ Angelucci discusses exposure to toxic iron and the effects of iron overload before, during, and after bone marrow transplant for malignant and nonmalignant disorders. He discusses the role of NTBI, transferrin saturation, and iron loading on outcome in transplant and the “iron irony” of determination of the effects of iron toxicity in the complex transplant setting. He presents iron treatment considerations for different phases of the transplant process.

In the third article,⁵ Leitch and Buckstein discuss the relation of myelodysplastic syndrome (MDS) outcomes to toxic iron as assessed by transferrin saturation and ferritin and make recommendations regarding chelation in patients with various MDS disease trajectories dependent largely on the likely longer duration of exposure to NTBI in lower-risk forms of MDS. Data regarding the effect of chelation on MDS outcomes is presented, importantly pointing out that chelation can improve marrow function, increase blood counts, reduce transfusion, and perhaps reduce risk of malignant transformation. The important question of in whom and when iron chelation therapy should be considered in MDS is addressed.

You will see a common theme in all 3 articles pointing to ferrous iron/NTBI as the cause of toxicity rather than iron seen by biopsy or MRI. You will also see that chelation therapy for iron toxicity can be very effective at least in well-resourced parts of the world. Iron overload remains a major and life-threatening issue in regions where access to care is limited.

Conflict-of-interest disclosure: T.D.C. is a consultant for Chiesi Farma, Bristol Myers Squibb, and Agios Pharma.