In a child or adolescent with thalassemia, when should red blood cell transfusions be started, what pre‑transfusion hemoglobin target should be maintained, and when should iron‑chelation therapy be initiated?

Management of Thalassemia Major in Children: Transfusion and Iron Chelation

In children with thalassemia major, start regular red blood cell transfusions immediately upon diagnosis to maintain pre-transfusion hemoglobin at 9-10 g/dL and post-transfusion hemoglobin at 13-14 g/dL, and initiate iron chelation therapy after 12-20 transfusions or when serum ferritin reaches ≥1000 ng/mL. 1, 2

When to Start Transfusions

Begin regular transfusion therapy immediately upon diagnosis of thalassemia major to suppress ineffective erythropoiesis and ensure appropriate growth and development. 1, 3 The diagnosis of thalassemia major is established when a child demonstrates severe anemia with hemoglobin typically below 7 g/dL, along with molecular confirmation of β-thalassemia mutations. 4

• Do not wait for symptoms to worsen or for the child to become transfusion-dependent through clinical deterioration. 1
• Early initiation prevents complications from chronic anemia including growth failure, skeletal deformities, and hepatosplenomegaly. 4

Hemoglobin Targets During Transfusion Therapy

Maintain pre-transfusion hemoglobin at 9-10 g/dL and post-transfusion hemoglobin at 13-14 g/dL. 1 This "supertransfusion" regimen effectively suppresses ineffective erythropoiesis while minimizing iron loading by reducing total blood volume requirements. 5

• The pre-transfusion target of 9-10 g/dL prevents the bone marrow from attempting compensatory erythropoiesis, which would otherwise drive increased iron absorption and worsen iron overload. 1, 5
• Post-transfusion targets of 13-14 g/dL normalize oxygen delivery and maintain suppression of endogenous erythropoiesis. 1
• Transfuse every 2-4 weeks to maintain these targets consistently. 3

Critical Transfusion Practices

• Use leukoreduced red blood cells for all transfusions to reduce febrile reactions and alloimmunization risk. 3
• Phenotype the patient for extended red cell antigens (C, c, E, e, K) before the first transfusion and provide antigen-matched blood for at least Rh (CcDEe) and Kell antigens. 3, 6
• Starting transfusions before 12 months of age significantly reduces alloimmunization rates (7.69% vs 27.9% when started after 12 months). 6
• Screen for red cell antibodies every 3-6 months, as alloimmunization occurs in 14-23% of regularly transfused patients despite matching protocols. 3, 6

When to Initiate Iron Chelation Therapy

Start iron chelation after 12-20 red blood cell transfusions or when serum ferritin reaches ≥1000 ng/mL, whichever comes first. 1, 2 The American Society of Hematology and European Society for Pediatric Hematology and Immunology both recommend this threshold to prevent transfusion-associated iron overload complications. 1, 2

Rationale for Early Chelation

• Each unit of packed red blood cells contains approximately 200-250 mg of elemental iron, and the body has no physiologic mechanism to excrete excess iron. 4
• After 12-20 transfusions, total body iron burden reaches levels that begin causing organ damage, particularly to the heart, liver, and endocrine glands. 1, 2
• For children being considered for hematopoietic stem cell transplantation (HSCT), consider starting chelation even earlier to minimize iron burden before transplant, as this improves transplant outcomes. 2

Chelation Agent Selection

Deferasirox is the first-line oral chelator for most pediatric patients ≥2 years of age due to once-daily dosing and proven efficacy. 2 However, agent selection should be tailored to specific clinical scenarios:

• Deferoxamine (subcutaneous or IV): Use for severe cardiac iron overload (T2* <10 ms) or acute cardiac decompensation, administered at 50 mg/kg/day via subcutaneous infusion 5-7 nights per week. 2
• Deferiprone: Consider for combined therapy with deferoxamine in patients with significant cardiac involvement, dosed at 75 mg/kg/day divided in three doses, but monitor for neutropenia risk. 2
• Avoid deferasirox in patients with acute heart failure or marginal renal perfusion. 7, 2

Monitoring During Chelation Therapy

Monitor serum ferritin every 3 months (monthly if possible) to assess chelation efficacy and adjust dosing. 2 The goal is to maintain serum ferritin <1000 ng/mL while preventing organ dysfunction. 2

• Perform cardiac MRI T2 annually* to detect early iron-related cardiomyopathy, as cardiac iron removal is very slow and requires several years of intensive chelation even after resolution of acute cardiac failure. 1, 2
• The prospective risk of developing heart failure within 1 year is 47% if cardiac T2* is <6 ms, with relative risk of 270 compared to patients with T2* >10 ms. 2
• Monitor renal function, hepatic function, and complete blood count monthly during chelation therapy. 2
• Annual echocardiography complements cardiac MRI for comprehensive cardiac assessment. 1

Endocrine Surveillance

Screen annually for endocrine complications including hypogonadotropic hypogonadism, diabetes mellitus, growth hormone deficiency, hypothyroidism, and adrenal insufficiency, as iron overload affects multiple endocrine glands. 1

Curative Treatment Considerations

Hematopoietic stem cell transplantation from an HLA-matched sibling donor offers the only definitive cure and should be pursued as soon as possible in eligible patients. 1 HSCT is recommended before progression to advanced iron overload (stage 3) for children aged 2-6 years, with optimal results achieved when transplanting before age 14 years. 7, 1

• Young, low-risk children achieve transplantation-related mortality ≤5%. 1
• For patients ≥12 years old with non-β⁰/β⁰ genotypes who lack a matched sibling donor, consider gene therapy such as betibeglogene autotemcel (LentiGlobin BB305). 1

Critical Pitfalls to Avoid

• Do not delay transfusions waiting for symptoms to develop; start immediately upon diagnosis to prevent irreversible complications. 1, 4
• Do not use aggressive diuretic therapy in heart failure related to iron overload, as this can worsen cardiac function. 1
• Avoid vitamin C supplementation above 500 mg daily, as excess vitamin C mobilizes iron and can precipitate cardiac arrhythmias in iron-overloaded patients. 1
• Do not discontinue chelation prematurely when ferritin normalizes; cardiac iron removal requires years of continued therapy. 2
• Do not transfuse without extended phenotype matching in children starting therapy after 12 months of age, as this dramatically increases alloimmunization risk. 6