What is the recommended treatment for a child with Thalassemia major?

Treatment of Thalassemia Major in Children

Children with thalassemia major require lifelong regular red blood cell transfusions combined with iron chelation therapy, with hematopoietic stem cell transplantation (HSCT) from an HLA-matched sibling donor offering the only definitive cure and should be pursued as soon as possible in eligible patients. 1

Primary Treatment: Regular Transfusion Therapy

Transfusion Protocol:

• Initiate regular packed red blood cell (PRBC) transfusions within the first two years of life when severe anemia presents 2
• Maintain pre-transfusion hemoglobin at 9-10 g/dL and post-transfusion hemoglobin at 13-14 g/dL to suppress ineffective erythropoiesis while minimizing iron loading 3
• Transfusions can be safely administered at 10 mL/kg/h, which is well-tolerated and reduces treatment time burden on families 4
• Complete each transfusion within 4 hours per safety requirements 4

Critical Pitfall: Never supplement iron in thalassemia patients based on low hemoglobin alone—these patients develop iron overload from transfusions, not iron deficiency 5

Mandatory Iron Chelation Therapy

Initiation Criteria:

• Start iron chelation after 12-20 red blood cell transfusions 1, 3
• Alternative threshold: when serum ferritin reaches ≥1000 ng/mL 3
• Begin chelation as soon as possible to prevent transfusion-associated complications 1

Chelation Agent Selection:

• Deferasirox (oral): First-line option for children ≥2 years old with transfusional iron overload 3, 6

  • Dose: 20-40 mg/kg/day orally once daily 3
  • Can be taken on empty stomach or with light meal 6
  • May crush tablets and mix with soft foods like yogurt or applesauce if swallowing difficulty 6
  • Avoid in patients with marginal renal perfusion or acute heart failure 3

• Deferoxamine: Reserved for severe cardiac iron overload or cardiac failure, requiring subcutaneous or intravenous administration 3

• Combined therapy (deferoxamine + deferiprone): Highly effective for significant iron overload or cardiac involvement 3

Monitoring Requirements:

• Serum ferritin every 3 months (monthly if possible) 3
• Renal function, hepatic function, and complete blood count monthly 3
• Goal: Maintain serum ferritin <1000 ng/mL 3
• Annual echocardiography and cardiac MRI T2* to detect early iron-related cardiomyopathy 5
• Liver function tests every 3 months with liver iron concentration monitoring via MRI 5

Critical Warning: Cardiac iron removal requires several years of intensive chelation even after resolution of acute cardiac failure 3. The risk of heart failure within 1 year is 47% if cardiac T2* is <6 ms 3.

Curative Treatment: Hematopoietic Stem Cell Transplantation

Optimal Timing and Donor Selection:

For HLA-matched sibling donors (MSD):

• Perform HSCT as soon as possible after diagnosis to avoid transfusion-associated complications 1
• Transplant before age 14 years achieves optimal results: 96% disease-free survival vs. 74% for older patients 1
• Young, low-risk children achieve transplantation-related mortality ≤5% 1, 5
• Overall survival 91% and disease-free survival 83% in large EBMT survey 1

Patient Assessment Before HSCT:

• Evaluate clinical condition according to Pesaro risk score—this is the critical element predicting outcome 1
• Ensure adequate transfusions and chelation regimen before transplantation 1
• Patient status at transplantation determines success more than any other factor 1

Alternative Donor Sources (in order of preference when MSD unavailable):

1. HLA-identical sibling cord blood:

   • Overall survival 96%, disease-free survival 81% 1
   • Lower acute GvHD (10%) and chronic GvHD (5%) compared to bone marrow 1
   • Requires adequate nucleated cell count (>3.5×10⁷/kg) 1

2. Matched unrelated donors:

   • Requires high-resolution molecular typing for HLA-A, B, C, DRB1, and DQB1 loci 1
   • Suitable donor found in approximately one-third of Caucasian patients 1

3. HLA-phenotypically identical related donors:

   • TM-free survival 94% in small series 1
   • Should be performed only in expert centers 1

Experimental approaches (HLA-mismatched family members, haploidentical donors) should only be pursued within well-designed controlled trials 1

Important Caveat: Peripheral blood stem cell transplantation from matched sibling donors carries increased risk of chronic graft-versus-host disease in most studies, despite feasibility 1

Emerging Curative Options

Gene Therapy:

• Betibeglogene autotemcel (LentiGlobin BB305) approved for transfusion-dependent thalassemia patients ≥12 years old with non-β⁰/β⁰ genotypes who lack a matched sibling donor 5
• Consider for patients without suitable HSCT donors 5

Comprehensive Monitoring Strategy

Cardiac Surveillance:

• Annual echocardiography and cardiac MRI T2* required 5
• Transfer to specialized thalassemia centers with integrated cardiology and hematology expertise if cardiac complications develop 5
• Heart disease accounts for approximately 70% of deaths in transfusion-dependent patients 7

Endocrine Monitoring:

• Screen for hypogonadotropic hypogonadism (most common endocrinopathy), diabetes mellitus, growth hormone deficiency, hypothyroidism, and adrenal insufficiency 7
• These complications result from iron overload affecting multiple endocrine glands 7

Hepatic Monitoring:

• Liver function tests every 3 months 5
• Monitor for cirrhosis (10-20% prevalence in adults) and hepatocellular carcinoma risk 7

Critical Pitfalls to Avoid

1. Never use aggressive diuretic therapy in heart failure—thalassemia patients require adequate preload; use minimal diuretics only 5

2. Avoid vitamin C supplementation above 500 mg daily 5

3. Do not delay HSCT in eligible patients—perform before iron-related complications develop and before age 14 years 1

4. Avoid deferasirox in acute heart failure or marginal renal perfusion 3

5. Do not assume thalassemia carriers need iron restriction—they are at same risk of iron deficiency anemia as general population and need iron therapy when iron deficient 8

Treatment Algorithm Summary

Step 1: Diagnose thalassemia major in first two years of life 2

Step 2: Initiate regular PRBC transfusions (maintain Hb 9-10 g/dL pre-transfusion, 13-14 g/dL post-transfusion) 3

Step 3: Start iron chelation after 12-20 transfusions or when ferritin ≥1000 ng/mL 1, 3

Step 4: Immediately perform HLA typing of entire family 1

Step 5: If HLA-matched sibling donor available, proceed to HSCT as soon as possible, ideally before age 14 years and before iron complications develop 1

Step 6: If no matched sibling donor, continue transfusion/chelation and consider gene therapy (if ≥12 years old with non-β⁰/β⁰ genotype) or matched unrelated donor HSCT 1, 5

Step 7: Maintain lifelong monitoring for cardiac, hepatic, endocrine, and renal complications 5, 7