乌鸦传媒

A recently published review in Pediatric Blood & Cancer by an international team of experts explores the optimal timing for initiating iron chelation in children with transfusion-dependent 尾-thalassemia (TDT), focusing on very young patients. This is a particularly serious concern since patients are typically diagnosed before 2 years of age, after presenting with clinically significant anemia and related symptoms.¹

As with certain other conditions, in TDT sometimes the cure is worse than the disease itself. Chronic red blood cell transfusions, a mainstay of TDT treatment, lead to iron accumulation in the body. This excess iron deposits in vital organs, including the liver and heart, causing life-threatening damage over time. Studies have shown a clear link between iron overload and morbidity and mortality in patients with TDT. However, 鈥渄ata on how rapidly iron overload develops and causes morbidity in young children are limited,鈥� the authors of the new study remarked.¹

Iron chelation therapy is a cornerstone of managing and preventing the severe complications of iron overload in patients with TDT. Established guidelines recommend starting therapy when the patient鈥檚 packed red blood cells or serum ferritin levels exceed certain thresholds. This sometimes translates to waiting until age 6 years or older to initiate treatment, even though the child had likely been diagnosed at a much earlier age. However, the authors highlight a crucial point: By this time, significant iron overload in the liver has already occurred, further complicating disease management.

Iron chelators: evidence for early intervention in young children

Ideally, iron chelation therapy would be started after a certain level of iron burden is reached, which typically begins within the first few transfusions. The authors reviewed safety and efficacy data from various studies supporting potential benefits of earlier management with 3 currently available iron chelators. 

Deferoxamine

Deferoxamine is the preferred first-line treatment for TDT in the U.S. and European Union (EU), but evidence of its effectiveness in very young children is limited. There are concerns about using high doses in children younger than 3 years old with low iron levels because it might hinder growth and bone development. Compliance with daily continuous infusion poses a challenge in both adults and children. Therefore, careful monitoring and reduced dosages for children under 3 are recommended.

Deferasirox

Deferasirox is currently approved as a first-line treatment for children 2 years and older in the U.S. and those 6 years and up in Europe, or as a second-line approach in children 2 to 5 years of age. Deferasirox dispersible tablets and film-coated tablets are safe and effective in children as young as 2 years old without impacting growth and development. In a phase 3 trial of deferasirox versus deferoxamine, a subgroup analysis of patients in the 2 to 6 year age group revealed comparable efficacy and safety.² However, some real-world data suggest a higher risk of kidney problems in children compared to adults. 

Deferiprone

Deferiprone is currently approved for children 3 years and older in the U.S. and 6 years and up in the EU (second-line). Historically, deferiprone studies mainly included patients 6 years and older. The DEEP-3 consortium study demonstrated deferiprone鈥檚 safety and efficacy in children as young as 1 month. However, agranulocytosis and arthropathy have been reported with deferiprone, and close monitoring of blood counts and kidney function is important, especially in younger children. In the randomized DEEP-2 trial, deferiprone was as effective as deferasirox, with similar side effects in children between 1 month and 18 years (~30% <6 years). Early treatment with deferiprone in the START trial showed promising results in reducing iron overload without compromising growth or causing iron deficiency. The authors of the current review also mentioned the potential ability of deferiprone to shuttle excess iron to unbound transferrin, 鈥渨hich reduces the risk of depletion of iron-bound transferrin necessary for normal iron metabolism鈥攅specially in young children with mild iron overload.鈥�¹ Despite these results, more research is needed on the use of deferiprone in children under 2 years old.

How young is too young to initiate therapy?

The current study emphasizes the importance of early intervention with iron chelation therapy in children with TDT and acknowledges the lack of definitive data on the safety and efficacy of iron chelation therapy in children under 2 years old. 鈥淲e believe that patients younger than 2 years of age, especially those with serum ferritin levels less than 1000 ng/mL, may be considered too young for any broad, evidence-based recommendation of iron chelation therapy initiation,鈥� the authors concurred.¹

Ultimately, the choice of chelator for young children would depend on individual factors and the severity of iron overload. The authors propose a risk-benefit analysis approach for each patient. Factors like projected transfusion needs, family support for medication adherence, and close monitoring of iron status and cardiac function should be considered when deciding on the ideal timing for chelation therapy. They also suggest the rate of transfusion, initial ferritin levels, and potential medication side effects should be weighed against the risks of iron overload. 

By initiating iron chelation therapy early and closely monitoring patients, healthcare professionals can potentially improve long-term outcomes and quality of life for these young children. However, ethical considerations and difficulty monitoring compliance in very young children make the research complex; thus, studies exploring this area are ongoing.

鈥淟astly,鈥� the authors wrote, 鈥渙ther biomarkers of iron overload that are convenient to assess in children and that correlate well with signs of early tissue damage should be identified to support assessment of the value of early intervention.鈥�¹

Published: June 28, 2024